[PPT] - Tale of Two Neuritidies 21 year old woman PowerPoint Presentation

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Dr. Ari Green, MD MCR

Department of Neurology Department of Ophthalmology

Tale of Two Neuritidies

21 year old woman with severe HA developing
ver a few days.
Day 3 noted visual distortion and scattered

scotomas over 2 days

OD- Coalescing into severe widespread

scotoma and by day 5- BLIND

Day 9 developed bilateral involvement now

20/80-20/100 OS

Friday- Day 11 Neurologist

Light Perception OD, 20/80 OS
RAPD OD

UCSF Neuroinflammation & MS Center: Prevent Control Repair

EPIC 2 program – What are the environmental trigger(s) of MS (and other inflammatory diseases of the CNS)? Imaging and Antigen Identification (CSF and Microbiome)

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LP Results

LP Op 10 cm H20
1 wBC, 0 RBC
Normal glucose, mild protein elevation
IgG Index 0.52 and OCBs negative
NMO IgG negative
ANA negative, SSA/SSB negative

Treated with 5 days IV solumderol

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What do you do next?

Stable profound residual deficit one week

after steroids with no response to steroids A) Treat with 5 more days of steroids B) Treat with Erythropoetin 33,000 IU IV C) Admit for PLEX D) Watch and wait

Redux?

54 year old man painless decline in vision over

a few days especially notable when playing sports

No PMHx
Sees PMD and eye care specialist who note

nothing on exam

Send labs

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Labs

CBC normal
NMO negative
ACE normal
ANA/ SSA/SSB negative
RPR negative
Lyme negative

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Utility of EPs acutely LP results

21 WBCs, 0 RBCs with 81 Lymphs 2% PMNs

and 6% plasmacytoid lymphocytes

OP 20.5 cm H20
IgG Index elevated at 0.9
2 OCBs present
Protein 54 (ULN 50)
Glucose 66

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“Syphilidis sive Morbus Gallicus”

Neurosyphilis Diagnosis

CSF-VDRL specific, not sensitive

– False negatives 30-70%

Elevated CSF WBCs

– Can be hard to distinguish from HIV

RPR negativity in very high titer secondary

syphilis

Sensitivity and Specificity of CSF- VDRL

“Gold Standard” for Diagnosis CSF WBC >20/ul Ocular Syphilis Sensitivity (“SNNOUT”) 50% 28% Specificity (“SPPIN”) 90% 88%

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Primary Syphilis

enter the body via minute abrasions of

epithelial cell linings

followed by rapid systemic spread via the

blood and lymphatics

chancre is always painless and indurated
associated with regional lymphadenopathy

Natural History of Syphilis

Infection 2 - 6 weeks Primary

Chancre, regional adenopathy

1 - 3 months Secondary

Rash, generalized adenopathy

1 - 3 months Lifetime latency Latent > 70% months - decades Tertiary

Gumma Cardiovascular

Neuroinvasion

Early neurosyphilis Late neurosyphilis

Secondary Syphilis

Symptoms/Signs: Malaise, HA, arthralgia, sore throat, fever, lymphadenopathy, Skin lesions Lab findings: High titer RPR or VDRL, + syphilis PCR Neuroinvasion Transient Meningitis Spontaneous Resolution Persistent Meningitis +CSF PCR, RT- PCR, RIT Symptomatic Neurosyphilis Clearance 70%

30% 10-20%

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Tertiary Neurosyphilis

Asymptomatic (no sx, + CSF)
Meningovascular meningitis

– 2-5 years after infection (rarely > 10) – Strokes, intellectual deterioration, cranial nerve palsies/brainstem signs

General Paresis

– >20 years after infection – Personality change (paranoid, neurotic, euporic, depressed), Affect (childlike), Reflexes (hyperactive), Eyes (argyl robertson), Sensorium (clouded), Intellectual deterioration, Slurred speech (sometimes perseverative)

Tabes Dorsalis

– Dysesthesias --> Posterior column dysfunction --> ataxia --> paralysis

Secondary Neurosyphilis

“Acute meningitis”
Headache
Nausea/Vertigo
Cervical rigidity
Cranial neuropathies
Ocular syphilis
Within first few years of infection (typically

months)

Syphilis cases by country US Primary and Secondary Syphilis 2000-2006

5000 5500 6000 6500 7000 7500 8000 8500 9000 9500 10000 2000 2001 2002 2003 2004 2005 2006

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Presenting symptoms

Among 100 cases in Los Angeles County

from 2001-2004

– 42% presented with visual changes – 42% presented with HA – 23% presented with cognitive issues or AMS

60% occurred in patients who were HIV+

Treatment

Penicillin G 2.4 Million units/day (divided
ver 4 doses) x 2 weeks
Alternative therapy with ceftriaxone in Pen

allergic patients

Adjunctive therapy with probenecid and

amoxicillin not shown to be of benefit (“enhanced therapy”)

Normalization of CSF WBCs

~86%

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Normalization of Serum RPR

RPR < 1:32 RPR > 1:32 P<0.005

Monitoring for treatment failure

CDC recommends at 6, 12, 18 and 24

months

Repeat LP – pending

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57 yo right-handed man referred
Chief complaint: “very forgetful” x 1 m
Forgot names of restaurants. Colleagues at work said he

repeated conversations and forgets work tasks. He is unable to recount deficits himself

Discrete episodes of “lip quivering,”, groaning, looking at his

arm, trouble getting words, poor memory after, spells ~1

minute. No LOC.

“Very Forgetful”

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Very Forgetful - 2

PPD+, neg CXR, untreated, works in a prison
No fevers/chills. Pet dog. Lives in Central

Valley and no other travel.

Former 30+ pack year smoker

FLAIR T2

CSF exam 1 month into the clinical syndrome was entirely normal. HSV PCR

negative (HSV antibodies not sent).

EEG normal
Chest/Abdomen/Pelvis CT normal , Labs: Na normal, ANA low titer +

Very Forgetful - 3

Discharged from outside hospital with

valacyclovir and decadron taper

Improved to 80-90% of normal cognitively, but

had frequent spells as before

Within 3 weeks of finishing the taper, 10-15

spells per day. Says memory “good”

Very Forgetful - 4

Evaluated in UCSF MS and Neuroinflammation clinic
Afebrile. Well-appearing. Unremarkable general exam.
MOCA 24/30 (-5/5 for delayed recall, recalled 2 with category cues

and 3 with multiple choice cues with no false positives; -1 for day

f week (says Friday when visit was on Monday).
Normal language. Generated 22 F words in 1 minute.
Normal motor, coordination, sensory and gait exams

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2/12/2015 13 Working diagnosis

Limbic encephalopathy, which is most likely

limbic encephalitis given the imaging appearance, clinical syndrome and improvement with steroids

Amnestic syndrome secondary to limbic

encephalopathy

Seizures, localization related.

Emerging Paradigm: CNS Antibody Disorders

Neuronal Intracellular Neuronal Synaptic Astrocytic Myelin Other CNS proteins CRMP-5, Hu, Yo (Purkinje cells), Ri, Ma, amphiphysin.... NMDA, VGKC LGI-1, CASPR, AMPA, GABA-B, VGCC… AQP4 ?MOG A-beta

Frequently associated with cancer Usually not cancer related (i.e. autoimmune) Usually not cancer related Not Not cancer related Cytotoxic T-cell Response Antibodies “epiphenomenon”? Antibody/complement mediated Antibody/compleme nt mediated Less clear Treatment often unsatisfactory More robust response to standard immunosuppression Robust response to immunosuppression Unsatisfactory treatment responses

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

Common autoimmune encephalitides

NMDAR LGI1 CASPR2 AMPAR GABAb Glycine

Approx number of cases (mid-2014)

>700 in 6 years ~250 in 3 years ~30 in 3 years ~25 in 4 years ~30 in 3 years ~60 in 5 years

Classic phenotype Diffuse encephalitis, neuropsychiatric features, movement disorder, seizures, autonomic LE: Amnesia, seizures, hyponatremia Morvan’s syndrome: dysautonomia, neuropsychiatric, neuromyotonia; Sometimes LE LE LE Progressive encephalomyel itis with rigidity and myoclonus (PERM) Expanding phenotype Pure neuropsychiatric

r “milder” cases

FBDS, Bradycardic prodrome, cryptogenic epilepsy Cryptogenic epilepsy, GBS- like Psychosis (atypical) LE, brainstem syndromes, epilepsy Tumor Ovarian teratoma (~30%) <10% (various) Thymoma (~30%) Lung, breast, thymoma Lung (~50%) Thymoma (<10%) Infectious Post-HSV encephalitis

Adapted from Irani, Gelfand, Al-Diwani, Vincent, Annals of Neurology, 2014

VGKC 0.37 (normal <0.02) Mayo LGI1 positive Quest CASPR2 negative Final Diagnosis: LGI1 (VGKC-complex) Limbic Encephalitis

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Voltage-gated potassium channel radioimmunoassay-induced enigma

Cramps Stiffness Hyperhidrosis Tumours Neuromyotonia

Newsom-Davis and Mills 1993 Hart et al 2002

Neuromyotonia

PLUS

Encephalopathy

OFTEN

Autonomic 50% tumours Morvan’s Syndrome

Liguori et al 2001 Cotrell et al 2001 Irani et al 2012

Limbic Encephalitis Amnesia Seizures Hyponatraemia Rare tumours

Buckley et al 2001, Schott et al 2003 Vincent et al 2004, Thieben et al 2004 Tan et al 2008, Irani et al 2010, Lai et al 2010

Faciobrachial Dystonic Seizures Frequent Arm and face Seizures No/rare tumours

Irani et al 2008, Barajas et al 2009, Irani et al 2011 Slide modified from Irani

VGKC-antibody associated limbic encephalitis (LE)

Older age of onset
Subacute onset with Amnesia and

Seizures +/-

–Psychiatric features –Dysautonomia –Sleep

~10% neoplasms
Hyponatraemia ~60%

Normal CSF

Only one intracellular antigen
ver the same time period

Vincent et al. Brain 2004; Thieben et al Neurology 2004

The concept of the VGKC-complex – more specific to LGI1 or CASPR2

125I-

DTX

C A S P R 2 LGI1

C O N T A C T I N 2 Poliak et al. 1999. JBC ; Schulte et al. 2006. Neuron

RADIOIMMUNOPRECIPITATION ASSAY

The new antigenic targets explain much

f the clinical heterogeneity

% Lgi1 antibody positive % CASPR2 antibody positive % Contactin2 antibody positive % no antigenic target

Limbic Encephalitis (N=78) 75 9 2 14 Faciobrachial Seizures (N=30) 90 10 Morvan’s (N=29) 50 80 5 10 Neuromyotonia (N=17) 6 35 10 47 Tumour? (N=12) 92 8

Slide modified from Irani

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JAMA Neuro 2014

Treatment

Oral steroids +/- IVIG or PLEX acutely
Consider add maintain immunosuppression

for prevention of relapses (very little data). Outcomes potentially poor with hippocampal atrophy and severe amnesia

Earlier and sustained immunosuppression may

be favorable

But what about his +PPD?

Started levitiracetam 750 mg BID for seizure
PET-CT showed no cancer – and no active TB
ID started Rifampin 600 mg/day x 4 months for latent TB
IV Methylprednisolone 1000 mg/day x 5 days, then

maintained initially on prednisone 20 mg/day

No spells since day 2 of the steroids pulse. But still with

prominent amnesia (MOCA 27/30, -3 for delayed recall). Living at home but on disability.

Less Forgetful

3 months later, still with prominent amnesia. MOCA 26/30 (-4 for

delayed recall). Hoping to get off steroids.

Considered mycophenolate and Rituximab, but given concurrent

treatment with Rifampin ultimately decided on azathioprine 2 mg/kg/day, while tapering steroids slowly over several months. PCP prophylaxis while on steroids + AZA.

3 months later (9 months after onset), MOCA 28/30 (-2 delayed recall).

VGKC antibody normal now, but LGI1 (we see this pattern frequently when treating)

11 months after onset, normal delayed recall. Back to work full time.
Will repeat cancer screening. Taper AZA and ensure no return of

disease monitoring clinically and serologically.

Less Forgetful

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Clues of an autoimmune encephalitis…

Rapidly progressive encephalopathy
Characteristic phenotypes
MRI and/or CSF evidence of CNS inflammation (but

remember LGI1 can have normal MRI and CSF)

Culprit or associated antibodies

Cautions

Seropositive antibodies without clinical correlation
“Steroid” responsiveness based on history alone

Dahm, et. al. Annals of Neurology 2014 Black = Disease Gray = Healthy Lesson: We are going to be dealing more with interpreting antibody results in clinical context – phenotyping and clinical experience with these disorders is critical – we don’t just treat the antibody

Case History

Headaches 2009 – MRI normal
December 2010: Difficulty focusing, mild short term

memory problems

Intermittent nausea (about 1x/month). By summer

2011 increased nausea, admitted for IV fluids.

Feb 2012 – Unremitting nausea x 1 week. MRI brain

revealed hydrocephalus. VP shunt placed. Kept vomiting in SNF. Readmitted.

T1 Post Gadolinium March 2012

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T1 Post Gadolinium April 2012

CSF exam 4/13/2012: Opening Pressure 7 (VP shunt in place) WBC 94 (99% Lymphs, 1% PMN) RBC 252 Protein >300 Glucose 30 (no serum recorded) IgG index 1.1 4 oligoclonal bands CSF exam 4/20/12: 82 WBC (80% Lymphs, 20% monos) 2 RBC Protein 300 Glucose 35 (serum 111) Cytology/Flow negative CSF Ace 15; cultures, AFB, fungal neg, CRAG neg, Cocci/histo neg

CT Chest with Contrast 4/2012: “Nonspecific” hilar and right mediastinal lymphadenopathy, single nonspecific nodule, no evidence

f interstitial lung disease

Endobronchial biopsy of lung 5/7/12 (UCSF): Benign, no granulomas Endobronchial ultrasound guided fine needle aspiration of subcarinal lymph node Small non-necrotizing granulomas… These findings are… consistent with sarcoidosis. Cytologic mimics of sarcoidosis include infection, metal-related sarcoid reaction and rare drug reactions…”

Gelfand and Stern, Neurosarcoidosis, ACP Medicine, in press

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Sarcoidosis is a Complex Genetic Disorder

Support for an Autoimmune/Primary Inflammatory Etiology:

All genes identified in multiple GWAS to date are associated with other inflammatory diseases

10 20 30 40 50 60 70 80 Monozygotic Dizygotic Sibling (non-twin) Population

Series 1

80x 7x 2-5x

Koth, L, et. al. AJRCCM, 2011

Sarcoidosis and active pulmonary TB Involve Similar Patterns of Gene Expression

Maertzdorf, et. al. PNAS, 2012

An “Autoimmune” Harnessing of Shared Inflammatory Pathways?

General approach to immunosuppression for CNS Sarcoidosis

1) Glucocorticoids (start high and cautious tapers) 1) Weekly oral methotrexate (up to 20 mg/week) with folic acid, second choice azathioprine, 3rd choice mycophenolate mofetil (some groups use leflunomide) 2) Infliximab 5 mg/kg IV 0, 2, 6, Q8 wks

(Should we start this much earlier in high-risk patients?)

Gensler, Neurohospitalist, 2012

Major complications Infection Weight gain Osteoporosis Osteonecrosis Diabetes/Hyperglyce mia Cataracts Cardiovascular Dx Adrenal insufficiency Myopathy

Complications of chronic steroids

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The long road of immunosuppression…

Pulse steroids, then slow oral prednisone taper Started Methotrexate + Remicade 10/2012 11/27/12: Interval decrease on MRI Dropped prednisone to 10 mg/day, MTX 15, Remicade 2/15/13: MRI stable, minimal enhancement

Repeat CSF Exam March 2013: 18 WBC (69 L, 30 M, 1 E), 0 RBC Protein 231 Glucose 50 (serum 154) IgG index 0.7, 2 OCBs

The long road of immunosuppression… May 2013 – Doing well overall On steroids, MTX + Remicade Since May 2012 gained 60 lbs(!) Decided to try to taper prednisone slowly to off

Brain MRI 7/11/2013: Stable very minimal basilar enhancement

August 2013 (while in Alaska)… More lethargic Na 134129 Prednisone to 5 mg/day; methotrexate 15 mg/week. Last Remicade July 2013 (dosed Q8 weeks)

H&E CD 68

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Leptomeninges, Chronic Meningitis, Neurosarcoidosis

H&E H&E CD 68

Leptomeninges, Chronic Meningitis, Neurosarcoidosis Multinucleated Giant Cell CD68 (Macrophage Predominant)

H&E H&E CD 68 Gelfand and Stern, Neurosarcoidosis, ACP Medicine, in press

Resolution

Increased frequency of Remicade, initially Q

month, then Q6 weeks. Continued methotrexate

Symptoms resolved except for those secondary to

chronic steroids

Last visit this week – asymptomatic, down to

physiological hydrocortisone, MRI with minimal (but not entirely resolved) leptomeningeal enhancement

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