Recent Advances in Neurology 2018

2/16/2018

71 yo Man-Difficulty Holding His Head Recent Advances in Neurology 2018 Up for 7 Months: Other Symptoms • Fatigue with neck extension-mild pain Challenging Cases • No weakness or numbness in arms and legs • Unstable going from sitting to standing, but John Engstrom, M.D. legs are strong • No bowel or bladder symptoms February 16, 2018 • No fever, sweats, weight loss, SOB, stiffness of limbs, cramps/muscle spasms

71 yo Man-Difficulty Holding His Head 71 yo Man-Difficulty Holding His Head Up for 7 Months: General Examination Up for 7 Months: Neuro Exam • MS, CN, Sensory normal • Chin on chest deformity present • Motor: Neck extensors 3-; neck flexors 5 • Neck supple-no stiffness – Nl tone and no rest tremor • No lateral collis or anterocollis – No UMN signs; reflexes symmetric; • Nl thoracic kyphosis and lumbar lordosis – Nl limb coordination and gait • No palpation tenderness over the spine • Power: deltoids, biceps, triceps, IP, • No Lhermitte’s sign hamstrings, quadriceps, distal hand/leg muscles normal bilaterally

1 2/16/2018

Q1-Which medical condition is Head Drop (aka “Head Ptosis”) associated with head drop? A. Upper cervical myelopathy 90% • Upper cervical myelopathy B. Anterocollis • Dystonia-anterocollis C. Bent spine syndrome • Assoc with PD, thoracic kyphosis, or both D. Parkinson’s disease • Orthopedic-Larsen syndrome

E. All of the above 5% 3% 0% 2% • With camptocormia (bent spine syndrome)

is e y ll s ve • As a neuromuscular disease th a a co e o p o is ab o r d l te s e ye n n’ th A o f l m s o a in ll ic rk A rv a e P c er Bent spine syndrome pp U

Camptocormia 71 yo man with Head Drop: Cervical Spine Flexion • Camptocormia (Bent Spine Syndrome)- anterior curvature of thoracolumbar spine – Orthopedic-Scheuermann’s kyphosis – Idiopathic – Parkinsonism – Motor neuron disease – Myopathies • Camptocormia and head drop can co-exist

2 2/16/2018

71 yo man with Head Drop: Cervical 71 yo man with Head Drop: Axial T2 Spine-Attempted Extension C4: Attn Paraspinal Muscles

71 yo man with Head Drop: Axial T2 Q2-Which neuromuscular condition C7-T1: Attn Paraspinal Muscles is associated with head drop? A. Motor neuron disease 88% B. Myasthenia gravis C. Polymyositis D. Muscular dystrophy E. All fo the above 5% 3% 2% 2%

e s is e s vi t v a a si o se r o b i g y a d ia m e n n ly th ro e o u h P o e st l f n a l r y A o t M o Muscular dystrophy M

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DDX of Head Drop as a Neuromuscular Disease 71 yo Man with Head Drop-Lab Studies • Motor Neuron disease (e.g.-ALS) • CK 67, AChRAb -, ESR 2, CRP 3.2-all nl • Proximal Polyneuropathy (e.g.-CIDP) • EMG-NCV/needle EMG studies nl except • Neuromuscular Junction Dz (e.g.-MG) right lower cervical paraspinal muscles • Myopathies – No fibs or positive waves – Inflammatory-Polymyositis, IBM – Short duration, low amplitude motor units with – Endocrine-Cushing syndrome, hypothyroidism early recruitment – Dystrophy-LGMD, FSH, a myotonic dystrophy – Myopathy-no muscle membrane instability – Idiopathic

Cervical Paraspinal Muscle Biopsy Results Normal Muscle biopsy-H and E

• Variation muscle fiber size-sugg dystrophy • Increased central nuclei • No perivascular or vascular inflammation • No significant mitochondrial abnormality • No degenerating or regenerating fibers • No inflammation • Not a treatable myopathy

4 2/16/2018

Head Drop: Cervical paraspinal Head Drop: Cervical paraspinal muscle biopsy-H and E muscle biopsy-NADH

71 yo Man with Head Drop: Head Drop: Cervical paraspinal Further Inquiry muscle bx-Electron Microscopy • Athena-Muscular Dystrophy Adv Eval – 33 dystrophy genes negative – 3 mutations (2 likely benign, 1 unknown signif) – 1 heterozygous mutation in Titin • Titin-”giant” muscle protein that regulates the length of the striated muscle thick filament with 363 coding exons – Assoc with 9 myopathies inclu LGMD type 2J – Adult recessive proximal muscular dystrophy

5 2/16/2018

Titin Shortens During Contraction- Q3-What Rx option is least attractive Stretches Myosin Thick Filament for management of head drop? A. Hard collar 73% B. Soft collar C. Physical therapy

D. Cervical spinal fusion 18% 6% 3%

r r a y lla ll p o o ra c c e d ft h r o l t a S a H c si hy P Cervical spinal fusion

71 yo Man with Head Drop: 71 yo Man with Head Drop: Initial Symptom Management Return to Clinic with Questions • Hard Collar • What is my prognosis? • Soft Collar • Will other muscles deteriorate? • Physical Therapy • Specific subtype of muscular dystrophy? • Adapted brace found online • How does this information influence the • Initially declined to seriously consider decision to have surgery at this point? surgery

6 2/16/2018

71 yo Man with Head Drop: 71 yo Man with Head Drop: Surgery Post-Surgery • Decision 2/17 for surgery to improve QOL – Limits lateral neck motion post-op understood – Cannot live well looking at the ground – Deferred until his wife’s affairs settled • Surgery 8/30/17-two stage procedure – C3-T2 posterior screw and rod fixation – C5-T1 ACDF

Outcome in the Patient’s Words: What Take Home Points: Head Drop Has Surgery Done to Your Self-Image? • Axial weakness is best considered as a form of proximal weakness in neurologic Ddx • What are the limitations of the surgery? • Can be neurologic or non-neurologic origin • How do you interpret and mange the long • Can be disabling both in terms of physical term risks? and psychosocial function • What has surgery change your self-image • In the context of long term management, and improved your quality of life? patients (and physicians) are allowed to change their minds regarding management

7 2/16/2018

Disclosures

 I have nothing to disclose. Difficult Diagnosis

E. ALEXANDRA BROWN, MD ASSISTANT PROFESSOR OF NEUROLOGY, UCSF DIRECTOR, ZUCKERBERG SAN FRANCISCO GENERAL NEUROLOGY CLINIC

54F with 6 month history of headache 54F with 6 month history of headache ICHD-3 Criteria: Migraine without Aura

-Out of medical care x 7 years -Out of medical care x 7 years -Headaches are 2-3 days per month -Headaches are 2-3 days per month -Pulsating, severe, bitemporal location -Pulsating, severe, bitemporal location -Nausea, photophobia, phonophobia -Nausea, photophobia, phonophobia -Previously relieved by rest and OTCs -Previously relieved by rest and OTCs -OTCs no longer help -OTCs no longer help -Neuro exam reportedly normal per PCP -Neuro exam reportedly normal per PCP

Cephalalgia 2013;33:629-808.

1 2/16/2018

54F with 6 month history of headache 54F with 6 month history of headache ICHD-3 Criteria: Migraine without Aura

Cephalalgia 2013;33:629-808.

Red flags Neurology consultation further details

 What features should worry you about secondary headache? ∙ Awakens from sleep with occipital headache x 1 year -Systemic symptoms (fevers, chills, weight loss, HIV, cancer) ∙ No previous headache history -New headache in an older patient >50 y.o. ∙ Born in Mexico -Abrupt onset reaching maximum intensity in < 1 minute ∙ Has not been taking any medications for HA ∙ Neurological exam reveals right dysmetria -Exacerbated by positioning or Valsalva -Abnormal neurological/fundoscopic exam MRI brain with and without Gad was performed

Nye BL, Ward TN. Headache 2015 Oct: 1301-1308.

2 2/16/2018

Neurocysticercosis

 CNS infection by larval form of pork tapeworm Taenia solium  Most common helminthic CNS infection  A leading cause of acquired epilepsy worldwide  Clinical presentation depends on:  Location of cysts  Stage of parasite  Host immune response T1 T2 FLAIR Post Gad T1

Garcia HH, et al. Lancet Neurol. 2014;13: 1202-15.

Endemic regions Q1: How do humans become infected with neurocysticercosis?

A. Eating undercooked pork containing viable cysticerci 46% B. Ingesting food or water contaminated with 33% human feces containing T. solium eggs C. Ingesting food or water contaminated with 19% porcine feces containing T. solium eggs D. Transmission through blood from an infected 0% 2% person . . . . e ...... v vi . . i o ed ed n b g t t a a in a a e n in in m h i o t ta m m r f E. None of the above n a a f o o t t d e c n n o n k co co lo o r r r b N o e e p t t h d a a g e w w u k ro o r r h o o o t c d d n er o o o d fo fo si n g g is u n n g ti ti sm in es es n t g g ra Garcia HH, et al. Lancet Neurol. 2014;13: 1202-15. Ea In In T

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Life cycle of Taenia solium Life cycle of Taenia solium Taeniasis: 1 parasite, 2 infections ∙ Adult tapeworm infection

Taeniasis ∙ Human eats and undercooked pork containing viable Cysticercosis cysticerci

Kraft R. Am Fam Physician. 2008 Mar 15;77(6):748. Kraft R. Am Fam Physician. 2008 Mar 15;77(6):748.

Life cycle of Taenia solium T. Solium Cyst Stages of Development Cysticercosis: Vesicular Colloidal Granular nodular Calcified ∙ Viable ∙ Begins Degeneration ∙ Degenerates further ∙ Dead ∙ Infection caused by larval ∙ Non-enhancing ∙ Ring enhances ∙ Ring enhances ∙ Punctate Ca2+ stage of tapeworm T. ∙ Scolex=“hole-with-dot” ∙ +/- Scolex ∙ No Scolex ∙ No Scolex solium ∙ No edema ∙ Edema ∙ Less edema ∙ Minimal/No Edema

Garcia. Lancet Neurol. 2014;13: 1202-15. Del Brutto OH. Scientific World Journal 2012;2012:159821. Sinha S, et al. Journal of Clinical Neuroscience 2009;16: 867-76. Kraft R. Am Fam Physician. 2008 Mar 15;77(6):748. Zhao JL, et al. Radiology of Infectious Disease 2015;1:94-102.

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NCC brain locations Subarachnoid NCC

 Excessive T. solium larval growth enlarged multiloculated cysts (racemose=“bunch of grapes”)

 MRI spine should be performed in basal subarachnoid NCC

 High risk asymptomatic spinal cord Parenchymal Extraparenchymal involvement. If present  treat surgically Usually gray-white junction Intraventricular (usually 4th ventricle) (consensus) Subarachnoid (basal cisterns, sylvian fissure) Can manifest as seizures Can manifest as hydrocephalus, focal neurological deficits, complications of ↑ ICP Callacondo et al. Neurology 2012;78(18):1394-1400. Sinha S, Sharma BS. Journal of Clinical Neuroscience 2009;16: 867-76. Garcia HH, et al. Clin Microbiol Rev 2002;15:747-56.

Immunological Diagnosis Diagnostic Criteria for NCC

Imaging EITB assay (Western Blot): TEST OF CHOICE (MAINSTAY)

ELISA based assay Clinical Exposure Presentation Dx Hx

Serologic Testing

Gripper. Acta Tropica 2017;166:218-224.

5 2/16/2018

Q2: What is the next step in this Subretinal cysts

patient’s care?  Dilated eye exam is essential prior to initiating Albendazole or Praziquantel

A. Start antihelminthic therapy with Albendazole 15  Antihelminthic therapy provokes inflammatory response around dying cysticerci 72% mg/kg/day for a minimum of 10 days can lead to blindness B. Start steroid therapy with Dexamethasone 0.1 mg/kg/day then administer Albendazole 15 mg/kg/day  Surgical removal of cyst is treatment of choice for ocular cysts (consensus) for a minimum of 10 days C. No indication for antihelminthic therapy given that the 15% 7% appearance of these cysts does not warrant 6% antihelminthic drugs ...... i. y . n h p h i t a it m in r el D. Do not initiate antihelminthic therapy until further e w h lm th y ti e c p n h i ra a ti th e r n n h o a i t f e workup is performed m d n t Del Brutto OH, et al. Journal Neurol Sci 2017;372:202-10. i el o io ia h r t it ti e a in n st ic t a t d o Kori P, et al. Neurology 2013;81:135-6. t r in n r ta a S o o St N D Padhi TR, et al. Survey of Ophthalmology 2017;16:161-89.

Q3: Which antihelminthic drug regimen is Antihelminthic drugs appropriate for a patient with NCC whose brain imaging is notable for >3 calcified cysts?

A. Albendazole 15 mg/kg/day x 7-10 days 56% B. Albendazole 22.5 mg/kg/day x 7-10 days  Albendazole, Praziquantel - Used to treat viable cysts 31% C. Combination therapy Albendazole 15 mg/kg/day x 7-10  Not used for calcified cysts which are already dead days + Praziquantel 50 mg/kg/day x 7-10 days  Worsened inflammation during cyst destruction temporarily worsens symptoms D. Concurrent treatment of Dexamethasone 0.1 mg/kg/day 10% with Albendazole 15 mg/kg/day x 7-10 days to control 1% 2%  Must control symptoms first (if needed, undergo lesion resection, ventricular shunt placement, steroids, etc) There is no rush to initiate antihelminthic drugs! ys ys intracranial inflammation a a .. .. . d d 5 a. 0 0 1 h -1 -1 le et 7 7 o x x z am y y da x a a n e d d e D g/ g/ b f E. None of the above k k l o None of the above / / A t g g y n  Give steroids simultaneously to control inflammation m m p e ra m 5 .5 e t 1 2 h a le 2 t re o le n t z o io t da z t n Gripper. Acta Tropica 2017;166:218-224. n a a re e d in r b n b cu l be m n A l o o A C C Garcia HH, et al. Clin Inf Dis 2016;62: 1375-79.

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Back to our case

 Steroids were initiated right away  Dexamethasone 4 mg TID x 3 days, T2 FLAIR at 4 months then 2 mg TID x 2 weeks, then Prednisone 0.4 mg/kg daily  Clinic follow-up: headaches resolved, R dysmetria resolved T2 FLAIR at 15 months  Ophthalmology: no intra-ocular cysticercosis  Spine MRI with and without Gad: no cysticerci  Cysticercosis IgG Ab: 3.77 H (>0.51 is positive)  Alongside Prednisone, administered Albendazole 15 mg/kg/day x 4 weeks  Ca+Vit D, Famotidine while receiving steroids INITIAL T2 FLAIR  Return precautions given; patient closely monitored, remained asymptomatic

Take home points Thank you  Antihelminthic drug treatment is NEVER the main priority, rather first address patient’s symptoms (seizures, increased ICP). There is no rush to begin antihelminthic drugs.

 Pay attention to cyst stage: there is no role for antihelminthic drugs if only calcified lesions are seen.

 Obtain dilated eye exam prior to initiating antihelminthic drugs; subretinal cysticerci should be surgically resected.

 Administer steroids alongside antihelminthic drugs to limit inflammation that occurs with dying cysts. Happy to answer questions Garcia HH, et al. Clin Microbiol Rev 2002;15:747-56.

7 Disclosures

No disclosures

Recent Advances in Neurology Difficult Diagnosis

Carrie K. Grouse, MD Assistant Professor Division of General Neurology

February 16, 2018

The patient The patient

23 year old man with three weeks of lower extremity In Chicago on vacation, but living in Kona, Hawaii for past year dysesthesias History of developmental delay, no other significant medical Pain started in soles of feet and progressed to feet, ankles, history, no regular medications calves, thighs and shins bilaterally Works at organic produce store in Hawaii, vegan diet for prior Two weeks prior developed severe pruritus in same distribution six months, uses marijuana, no sexual contacts

Denies weakness or bowel/bladder dysfunction

1 The patient The patient

Lab results reveal eosinophilia Neurologic examination: White blood cell count 17.2 cells/µL 15.8% eosinophils, absolute count 2,718 [ref 15-500] Normal cranial nerve examination, normal fundoscopic exam, no 69.5% neutrophils, 8.6% lymphocytes meningismus B12 level 359 Motor exam with normal muscle tone and strength Was diagnosed with gout s/p treatment with Medrol dose pack with no improvement Normal sensation to all sensory modalities

Recently started on Ivermictin for presumed parasitic infection, Deep tendon reflexes 2+ in biceps, triceps, brachioradialis, also with no improvement 3+ in bilateral patellae, and 4+ in ankles with 3-4 beats of clonus

MRI Thoracic spine MRI Lumbar spine

Sagittal T2 sequences Sagittal Post contrast T1 sequences Sagittal T2 sequences

2 MRI Lumbar spine The patient

Further serum studies: chlamydia, HIV, Neisseria, Lyme, Hep C, Hep B (core Ab and surface Ag), RPR, Quantiferon Gold and strongyloides Ab negative

Stool Ova and parasites negative

Lumbar puncture was obtained: WBC 695 cells/µL, RBCs 220 cells/µL Lymphocytes 43% Eosinophils 44% Basophils 6%, Monocytes 4% Glucose 43, protein 165.4 Electrophoresis: 5 well defined gamma restriction bands in the Sagittal Post contrast T1 sequences Axial Post contrast T1 sequences CSF not present in serum sample

Audience Question Eosinophilic Meningitis . What is the most common cause of eosinophilic Defined as presence of >10 eosinophils/mm3 in cerebrospinal meningitis? fluid (CSF) and/or eosinophils accounting for >10% of CSF A. A. Medication side effect leukocytes B. B. Ventriculoperitoneal (VP) shunt malfunction Differential Diagnosis C. C. Parasitic infection 61% Infectious etiologies (most common) D. D. Malignancy Inflammatory 28% Malignancy 11% 1%

ct n cy e io n ff ct a e e n e f lig id in a s ic n it M o s . ti a D a ar ic d . P e C . M A B. Ventriculoperitoneal (...

3 Eosinophilic Meningitis: Differential Diagnosis Eosinophilic Meningitis: Differential Diagnosis Causative parasites Less common parasitic causes Other infectious causes of eosinophilic meningitis Borrelia burgdorferi (Lyme) Myocobacterium tuberculosis (TB) Angiostrongylus cantonensis Toxocariasis Gnathostoma spinigerum Cysticercosis Rickettsia Baylisascaris procyonis Paragonimus Rocky mountain spotted fever, Typhus Schistosoma Viral meningitis Strongyloides Trichinella spiralis Coxsackie Loa Loa filariasis Treponema pallidum (syphilis) Echinococcus Fungal Coccidiomycosis, Cryptococcus Prototheca

Eosinophilic Meningitis: Differential Diagnosis Eosinophilic Meningitis: Differential Diagnosis Inflammatory etiologies Malignancy Behçet disease Acute lymphoblastic leukemia Neurosarcoidosis Medication allergic reactions Hodgkin’s disease ibuprofen Non-Hodgkin lymphoma intraventricular vancomycin or gentamycin Glioblastoma ciprofloxacin post-myelography Meningeal carcinomatosis Wells Syndrome VP shunt implantation or malfunction

4 The patient Angiostrongylus cantonensis

Given recent residence in Hawaii, ingestion of local Common name “Rat lungworm” vegetables, and eosinophilic radiculomyelitis, PCR testing for Angiostrongylus cantonensis was obtained Originally identified in Guangzhou region of China, The PCR tested positive for Angiostrongylus hence “cantonensis” cantonensis (81% sensitivitiy, 100% specificity) Image from Barratt, 2006. Metastrongyloid nematode

Leading cause of eosinophilic meningitis worldwide (as of 2012, over 2877 human cases) Image from Lv, 2017

Angiostrongylus cantonensis Audience Question

Image from Barratt J, et al, 2006. . In which of the following US states have there been reports of non-travel related human infection due to A. cantonesis?

A. A. California 39% B. B. Louisiana 38%

C. C. Illinois Has been reported in over 30 countries since identification as a human pathogen in 1945 D. D. New Mexico 15% Initially most prevalent in the tropics and sub-tropics 8%

Has spread to much of Asia, the Pacific Islands, Latin America, Australia, is o o c parts of Africa, Europe, and the United States n xi lli e . I M C ew A. California B. Louisiana . N D

5 Angiostrongylus cantonensis Angiostrongylus cantonensis: Life Cycle Rats are definitive host The United States has had multiple cases of locally acquired angiostrongyliasis Mollusks are intermediate hosts

Hawaii has by far the highest Crustaceans, flatworms, frogs incidence in the US, increasing and monitor lizards are paratenic most in Hawaii and Maui due to (transport) hosts inadvertent mollusk consumption

Image from Cowie, 2017 Humans are infected by Louisiana has had one and Texas three reported cases of local human ingesting hosts or vegetables infection containing infective larvae

A. cantonensis identified in snails and rats in Florida and Louisiana, and Larvae invade intestinal tissue, in accidental mammal/bird hosts in Florida, Alabama, Louisiana, pass to liver, lungs, and CNS Mississippi, Oklahoma, and California

Image from Wang, 2008

Angiostrongylus cantonensis: human infection Angiostrongylus cantonensis: human infection

Worms reach CNS (eye, brain, spinal cord), develop to Most cases are mild and self-limiting, symptoms vary subadult stage, then die; cannot reproduce in humans depending on location of worm - prodromal symptoms: enteritis, cough, or sore throat Peripheral eosinophilia observed in 66-68% of cases, CSF - mild infection can cause headache, neck/shoulder pain, eosinophilia in 70-95% of cases tingling/skin sensitivity, visual disturbance, and fever - protein is usually elevated in the CSF - motor weakness, bowel/bladder dysfunction, coma and - CSF glucose is usually slightly low death can also occur

CNS damage caused by physical injury from worm Diagnosis can be obtained through real-time PCR from movement and immune response CSF samples

6 Audience Question Angiostrongylus cantonensis: treatment

. What is the recommended course of treatment for confirmed Analgesics for pain cases of meningitis due to Angiostrongylus cantonensis causing severe headaches? Therapeutic lumbar puncture for increased intracranial pressure and to relieve headaches A. A. anthelmintic drugs only 63% B. B. serial lumbar punctures as needed and Corticosteroids are generally used, likely reducing inflammation corticosteroid therapy and associated intracranial pressure

C. C. anthelmintic drugs followed by Use of anthelmintic drugs are controversial corticosteroid therapy 16% 19% - their use may exacerbate the immune response, as rapidly D. D. supportive treatment with analgesics only 2% dying worms provoke a stronger immune reaction

y . - more studies are needed to establish the safety and long- l ...... n e l. . o r o t s tu f n ug c s e r n g tm d u ru a term outcomes of these treatments ic p d e t r c tr n a ti i b n e lm m i iv e lu m rt h l el o t ia h p an r t p . se n u A . a . s B C. D

The patient

Given mild symptoms and duration of infection, he was treated with three days of high dose methylprednisolone, along with a two week oral prednisone taper

He was given gabapentin for symptomatic treatment of his neuropathic pain and pruritus

One week after discontinuation of oral taper, he was found to have recurrence of peripheral eosinophilia, and restarted on prednisone taper

Around this time, he noticed new blurry vision of the right eye with flashers and floaters

Many thanks to Dr. Jack Cohen of Rush Medical Center Ophthalmology for this video.

7 The patient: ocular angiostrongyliasis THANK YOU!

Evaluated by ophthalmology and found to have retinal detachment of right eye

During surgery for repair, found single live worm in the subretinal space

This was killed with a laser and removed

Took 10 mg prednisone taper for additional two weeks, with continued improvement in vision and pruritus

8 2/16/2018

Disclosures

Difficult Case Session . Advisory board to More Health, Inc. Epilepsy . Grant / research support from the U.S. NINDS / DOD.

Robert C. Knowlton, MD, MSPH . Grant support from Medtronics, Inc. University of California San Francisco –Stereotactic laser ablation for temporal Seizure Disorders Surgical Program lobe epilepsy (SLATE) study

Patient NS NS seizures

NS is a 23 yo ambidextrous male (writes with Stereotyped habitual recurrent seizures: right hand, but uses left hand dominantly in . First, "…stomach starts bothering me." He suddenly appears sports). dazed and confused, staring off, and saying things that don't make sense, e.g. "The fingers on the wall are bloody, and . born at 32 weeks gestation as baby B and grass is outside.” He may walk around, fumble with his suffered some hypoxia from meconium clothing, and has no recall of what has happened. aspiration . Duration=15-30 seconds, . Frequency 1-2 per week, . seizures began at age 8 . Longest duration without a seizure was when he was 12-13 and was on a modified ketogenic diet

1 2/16/2018

NS treatment NS pertinent other history

1) Phenytoin (PHT)–gingival hyperplasia • Depression, including SI at age 17 2) Levetiracetam (LEV)–aggression • Learning difficulties 3) Topiramate (TPM)–sedating, mood swings 4) Oxcarbazepine (OXC)–gastrointestinal pain • OCD tendencies 5) Eslicarbazepine (ESL)–gastrointestinal pain • Hearing impairment–left ear–since birth 6) Pregabalin (PRG) • Nephrolithiasis (2016) 7) Gabapentin (GBP) S/P VNS implantation 8) Valproate (VPA) (05/2011)—"no help at all," 9) Zonisamide (ZNS) currently turned off. 10) Lacosamide (LCM)

NS social history NS evaluation

• Works at a pizza restaurant, trying to complete • EEG age 8–left frontal spikes classes in community college • MRIs–left frontal deep WM T2 abnormality • Psychosocial difficulties are large, especially given contrast to his twin sister who "excels at everything, has finished college, drives, works, and pursuing her own life..." • Struggles with mom's close involvement with his cares and needs, and her concerns.

2 2/16/2018

Recall, NS has a VNS–significance?

NS evaluation

• From age 9 to13–numerous VEEG admissions and AEEG studies–no seizures captured. • Do have cell phone videos of seizures

3 2/16/2018

1. What kind of seizures (new terminology)? 2. Localization? 3. Candidate for surgery? 4. Good candidate for surgery? 5. Worth trying seizure monitoring again?

The AAN Practice Parameter for Epilepsy NS presurgical evaluation (VEEG) Surgery supports recommendation for what type of surgery?

72% A. Localized neocortical resection of epileptogenic tissue B. Anteromesial temporal lobe 11% 13% resection 4% C. Corpus callosotomy

.. y b . .. m & e l. o es l t a r a so th l r o o ca po ll B D. Both a & b ti a m c r e s co t u o al p e si r n e Co ed m iz ro al e c nt Lo A

4 2/16/2018

NS surgery treatment option(s)? NS presurgical evaluation (PET)

1. Resection . Where–frontal, temporal, …? . What about language (left hemisphere)? . What about memory (normal hippocampus)? 2. Laser ablation . Indicated for this type of epilepsy? 3. Responsive neural stimulation (Neuropace®) . How effective is this?

NS presurgical evaluation NS presurgical evaluation (Wada) (language lateralization) • RIGHT hemisphere dominant language Right handers with right hemisphere language representation. dominance? • Left carotid injection (RIGHT hemisphere Neurologically normal right handers: memory) was INTACT (7/8). . 0-2% based on aphasia following stroke • Right carotid injection (LEFT hemisphere . Zero based on fMRI memory) was POOR (2/8). Non neurologically normal right handers: . 10-20% with lesions before age 5 . 6-15% based on Wada studies in epilepsy patients†

† Less language transfer in patient with long-standing temporal lobe epilepsy

5 2/16/2018

NS presurgical evaluation NS presurgical evaluation (VEEG) (advance EEG analysis)

Source localization/imaging (ESL, ESI)

NS presurgical evaluation (ESL) NS presurgical evaluation (ICEEG)

6 2/16/2018

NS outcomes What percentage of adult patients is likely to remain seizure free with planned withdrawal of • Seizure control anti-seizure medication following successful • Memory function–better or worse? epilepsy surgery? • Behavior and personality–any changes? 50% A. 25% • Mood–improvement or worsening? B. 50% • Quality of life 30% C. 75% – Driving 15% – Employment D. 95% 5% – Independence

5% 0% 5% 5% 2 5 7 9

7 2/16/2018

History

Recent Advances • 32 y/o female referred to our clinic for an in Neurology increase in headaches for the past three months

Case Presentation • History of headaches since childhood – provoked by hunger or lack of sleep Rebecca L. Michael, MD • In adolescence, frequency increased with onset February 16, 2017 of menses and then again with onset of using OCPs

History continued History continued

• Location was unilateral frontotemporal region, • She endorsed a preceding visual aura alternated sides equally – alternating wavy lines and black spots • Quality is described as pressure and at times – evolved into her entire visual field over 30 minutes throbbing – occurred 75% of the time • Associated with nausea, photophobia, phonophobia and osmophobia. • She stopped OCP’s at age 28 with improvement in HA frequency to only 2-3 days/month

1 2/16/2018

History continued History continued

• Prior three months, headaches increased • Past Medical History • 18 headache days per month and 8 days of “headache – menorrhagia s/p thermal ablation and eventual hangover” hysterectomy • Quality of pain is similar – hyperthyroidism s/p thyroidectomy • Worse in the morning – anxiety • Worse with valsava and bending over – obesity

• Visual ‘aura’ now however is “blacked out” central vision • Review of Systems – snoring • Only clear precipitant is stress with her upcoming wedding – insomnia

History continued Question 1 Based on the history, what is the most likely • Headaches are minimally responsive to tylenol diagnosis? and advil A. Chronic Migraine 44% • Rizatriptan and intranasal sumatriptan caused B. Sleep Apnoea Headache 37% side effects C. Idiopathic Intracranial • Has never been on a preventive medication Hypertension, IIH 11% D. Chronic Tension Type Headache 5% for migraine 3% E. Cerebral Venous Sinus Thrombosis e e n h . . .. ai c .. .. . r a H e T ig d l H s a a e u M e i in c H n yp S i a ra T s n e c u ro o a n o h n tr io n C p In s e A n V p ic Te l e th c ra le a i b S p n e o ro r i h e Id C C

2 2/16/2018

Chronification of Migraine Neurological Exam

• usually develops from episodic migraine BP: 115/73 HR: 78 BMI 32.94 (annual conversion rate of about 3%) • CN intact, visual acuity normal • Visual fields: enlarged blind spot bilaterally • optic discs blurred bilaterally • Risk factors – obscuration of all borders – Non-modifiable • remainder of neurological exam normal • age, female sex, low education status – Modifiable • MOH, ineffective acute treatment, obesity, depression and stressful life events

May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment Nature Reviews Neurology 12, 455–464 (2016)

Question 2 IIHTT The most common headache phenotype (according to ICHD-3) described in patients with • Largest randomized controlled trial on IIH ever IIH in the Idiopathic Intracranial Hypertension conducted Treatment Trial, IHTT, is which of the following • 38 neuroophthalmology centers in US 49% • 165 subjects A. Migraine – Bilateral papilledema, mild visual field loss, lumbar puncture with elevated OP B. Probable migraine 27% • acetazolamide w/ diet (70) vs. placebo w/ diet (69) C. Tension-type headache 14% 9% • Primary outcome D. Probable tension-type headache – Perimetric mean deviation (PMD) at 7 months

e e • Numerous secondary outcomes n i h .. ra c . g da e i a p M e y h -t e n p o y si -t n n e o t Probable migrainesi e n l e ab T b ro P

3 2/16/2018

Headache Characteristics at Baseline

• HA present in 84% at baseline • Locations of headache Frontal 68% Global 36% Ocular 47% Posterior 39% Nuchal 47% Unilateral 30% • Characteristic of pain pressure like 47% throbbing 42%

Friedman DI et al. Headache 2017; 57, 1195-1205

Headache Characteristics at Baseline Headache Characteristics at Baseline • “Migraine” associated symptoms common • Headache phenotype (ICHD-3 beta) photophobia (70%), phonophobia (52%), nausea (47%), Migraine 52% Probable migraine 16% vomiting (17%), worsened with physical activity (50%) Tension-type 22% Probable tension-type 4% Not classifiable 7% • IIH-related symptoms • Constant visual loss (34%) • 50% of migraine or probable migraine subjects (n=94) had a • Transient visual obscurations (68%) history of migraine • Diplopia (22%) • 29% of the other headache types (n=45) had a history of • Dizziness (53%) migraine • Headache with none of the above (14%)

Friedman DI et al. Headache 2017; 57, 1195-1205 Friedman DI et al. Headache 2017; 57, 1195-1205

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Back to our case… MRI brain wwo contrast

• 32 y/o female w/ increase in headache frequency and papilledema • Referred for urgent evaluation/imaging • Ophthalmology exam

MR venogram • Lumbar Puncture – initial opening pressure was 25cm

5 2/16/2018

Criteria for IIH Diagnosis Criteria for IIH Diagnosis Initially defined by Dandy and modified by Diagnosis without papilledema Friedman et. al – if B-E are satisfied in addition to a bilateral or 1. Required for the diagnosis unilateral abducens palsy A. Papilledema – Diagnosis can be suggested if B-E and three of four B. Normal neurological exam except for cranial nerve neuroimaging are satisfied abnormalities i. Empty sella C. Neuroimaging (MRI brain wwo contrast for typical ii. Flattening of posterior aspect of the globe patients and MRV for others) iii. Distention of perioptic subarachnoid space with or D. Normal CSF composition without a tortuous optic nerve E. Elevated lumbar puncture OP (≥25 mm in adults, ≥28 iv. Transverse venous sinus stenosis mm in children)

Friedman DI et al. Neurology 2013 Friedman DI et al. Neurology 2013

Neuroimaging Findings Back to our case…

• Diagnosis of Idiopathic Intracranial Hypertension was made • Initiated on acetazolamide 500mg BID • Was seen by nutritionist • Referred for sleep medicine evaluation

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Follow Up Optical Coherence Tomography, OCT

• Lost 12 lbs • Retinal Nerve Fiber Layer (RNFL) Thickness • Headache reduced to prior frequency of 2-3 days/month • Denied further TVO’s • Repeat ophthalmology exam – Papilledema no longer present – Optical Coherence Tomography, OCT, normal • Repeat LP with opening pressure 30cm – CSF normal

Mollan et al. J Neurol Neurosurg Psychiatry, 2016

Question 3 Management OCT, optical coherence tomography, is unreliable in which of the following scenarios? • Instructed on slow taper diamox • Naratriptan given for acute treatment A. significant disc edema 39% 32% • Encouraged continued weight loss B. crowded disc • Called three weeks later with increase in C. pseudopapilledema 16% 12% headache frequency and severity D. answer choices A and B • Initiated on topamax 25 100mg E. answer choices A, B and C 1%

a c a C • s Currently doing well m i m d e d e n d d d a e e le B c d il , is w p d o a A t r p s n c o ce a d i ic u o if e ch n s r g p e si answer choicessw A and B an

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Management Management

• In the IHTT, acetazolamide + weight loss program improved visual outcomes – more so than weight loss program alone • acetazolamide is safe up to 4 g/day • alternatives – Topiramate – Zonisamide – Furosemide – Indomethacin, Iron ?

Friedman DI et al. Headache 2017; 57, 1195-1205 Friedman DI et al. Headache 2017; 57, 1195-1205

Conclusion Thank You • UCSF Headache Center Referrals: • IIH is a condition important to recognize because it may lead to progressive loss of vision over time, which may be – Intractable migraine, cluster headaches, post-traumatic permanent headaches and other unusual or difficult headache disorders • Diagnosis can be challenging – Outpatient treatment – Overlap with migraine – Nerve blocks – May present with papilledema or without – Neurostimulation • OCT may help aid in the diagnosis of mild cases or in the – Telemedicine monitoring of response to treatment – Research – Inpatient treatment • Additional headache treatments should be undertaken

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9 2/16/2018

Patient Summary

Recent Advances in Neurology 2018  71 year-old right-handed man with HTN and hyperlipidemia referred for progressive numbness  Had bilateral CTS  underwent bilateral releases with success Difficult Diagnosis:  In the last 18-months: A Polyneuropathy That Made a Turn for the Worse  Numbness in the soles of the feet  When it reached the ankles, he noticed numbness in the lateral right hand and forearm  In time, the numbness extended up to the knees  He then developed mirror symptoms in the left hand and forearm  15-20 lbs. weight loss over the past year  Negatives:  No pain or radicular symptoms  No bowel or bladder control problems  No fevers, chills, or night sweats  Up to date on cancer screening Jeffrey W. Ralph, MD

Testing From Care Everywhere

 HgbA1c: 5.4; SPEP/IFE: Normal; ESR: 2; RPR: NR; GM-1AB: Negative; TSH .98

“Suspicion of ______given  EMG 1/2016: the sequence of events to date.” IMPRESSION: 1) a moderate distal axonal sensorimotor polyneuropathy 2) a severe right median neuropathy at the wrist (carpal tunnel syndrome). Dr. Raymond Stephens Similar to those obtained by Dr. R. Stephens on 7/8/2015.

1 2/16/2018

Six Months Later… Recent Exam cont.

 Speech now slurred; numbness up to the  Moderate weakness in proximal muscle groups in UEs + thighs; numbness in the anus and perianal LEs; severe weakness of distal muscles in UEs + LEs  No reflexes; flexor plantar responses bilat region; could not open bottles.  LT and pain sensation diffusely, severely impaired in the  CN: moderate lingual dysarthria; tip of limbs tongue numb; tongue-scalloped  Vibration sensation intact at fingers; absent in RLE; appearance w/ fasciculations absent distal to knee in LLE  JPS very impaired at toes  Fasciculations seen in the shoulders and  HKS clumsy with eyes closed quadriceps  Wide based gait; could not walk on heels or toes; Romberg-moderate sway  Atrophy of the hand and leg muscles

Which of the following genetic What would you do next? neurological disorders has an effective medical treatment? A. Repeat EMG/NCS 55% B. Nerve Biopsy A. Pompe disease 55% C. Lumbar Puncture 21% B. Familial amyloidosis 32% D. Genetic testing 17% 4% E. No more testing… 3% C. Spinal Muscular Atrophy 5% 8%

S y g . C s re n .. time for IVIG trial. N p u ti o / io ct s f D. All of the above e e G B n t M e u c im e s E v P ti t s si y e t r r e a o h v a e a … e d p o e N b n g is i ro ab p e n d lo t m G ti e y A e e u s p m r th R L e a la f t om l u o e P ia sc ll r il u A o m a M m F al o n N pi S

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Back to the patient… Genetic testing

 Left gastrocnemius and sural nerve  TTR gene biopsies: Congo red: deposits of salmon-  c.250T>C heterozygous pink material that demonstrate apple-  p.Phe84Leu green birefringence on polarization  MUTATION  Transthyretin stain is positive; amyloid A, kappa, and lambda stains negative.  Dx: amyloid myopathy; amyloid neuropathy

Transthyretin: the transporter Amyloidosis for thyroxine and retinol

 Binds: Thyroxine (20%); Retinol binding protein  4 exons & 127 amino acids  Extracellular deposition of soluble precursor protein that aggregates in the form of insoluble  Normal configuration: tetramer fibrils  Amyloidogenesis: tetramer  dimers   Molecular β-pleated sheet structure with peptides monomers dissociate & may fold aberrantly in antiparallel configuration aberrantly folded monomers aggregate to form  Serum amyloid P, a glycoprotein, is a constituent amyloid of all amyloid  Damage mainly secondary to tissue infiltration and swelling

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Both Wild-Type and Mutant TTR Cause Familial Transthyretrin Amyloidosis Amyloidosis Mutant TTR; ATTRM Wild-type TTR (no AND mutation); ATTRWT Age > 30 AND  >150 mutations Age > 70  Almost all missense point mutations Familial Transthyretin Senile Amyloidosis Amyloidosis  Autosomal dominant  de novo mutations occur, but Cardiac TTR amyloid Amyloidosis neuropathy TTR (TTR-FAP) leptomeningeal/CNS frequency not known amyloidosis Poly- Carpal tunnel neuropathy syndrome (?) TTR cardiac amyloidosis

True or false: The absence of a family history makes transthyretin familial amyloid DISEASE PHENOTYPE DEPENDS ON TTR MUTATION, GEOGRAPHIC REGION, AND GENETIC MILLEAU polyneuropathy unlikely.  Penetrance and age of onset is variable 94% A. TRUE  Val30Met mutation  In Portugal, 80% by age 50, and 91% by age 70 B. FALSE  In French, 13% by age 30, 50% by age 70  In Sweden, 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90.

E LS TRUE FA

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TTR-Familial Amyloid TTR Familial Amyloid Polyneuropathhy Neuropathy

 In the US  Neuropathy  Late onset is common and family history often  Usually starts in the lower extremities negative (50%)  Sensory symptoms—burning, shooting pains  21 % have Val30Met variant (In Portugal, 90-100%)  Loss of small > large fibers (but sometimes small and large fiber dropout are =)  Epidemiology-Prevalence  Motor symptoms—Foot drop, wrist drop, and  Worldwide disability of the hands and fingers common  TTR-FAP prevalence 0.87-1.1 / 1,000,000  Autonomic neuropathy—Constipation, constipation  Endemic areas altering with diarrhea, delayed gastric emptying,  Portugal , 1:909 people anhidrosis, and urinary incontinence  Japan, Nagano prefecture, 1:1108 people

Diagnosis: Tissue is the Issue Management

Abdominal fat  Neurologist  Clinical examination Gastric or rectal  Disability scores Deposition of mucosa  Cardiologist – early diastolic dysfunction and Amyloid – Immuno- later systolic failure Sural nerve Congo Red histochemistry  Interventions Staining Cardiac  Carpal tunnel release for CTS  Pacemaker implantation for second-degree or third- Van Selby, MD Peritendinous fat degree AV block OR Mass Spectrometry- Based Proteomics

If TTR  Sequence the gene

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Treatments for Slowing Progression of TTR-FAP Liver Transplantation  Purpose: Removes the source of mutant TTR   Liver transplantation Stabilizes polyneuropathy – little objective improvement  TTR Stabilizers  Until recently, the “Standard of Care” treatment for TTR- FAP  Tafamadis (Europe only)  OLTX for early onset V30M-ATTR: 10 year survival  Diflunisal (US) 100% vs. 56% for nontransplanted patients  TTR Gene Silencing (Yamashita et al. Neurology 78:637-643)  Antisense Oligonucleotides (ASOs) – Inotersen  Small Interfering RNA (siRNA) – Patisiran  Immune-Mediated Amyloid Clearance  Anti-SAP Monoclonal Antibodies (hu-SAPMab)

Liver Transplantation II TTR Stabilizer: Tafamidis

 Eligibility  Function  Age younger than 60 years  Inhibits dissociation of TTR tetramers in vitro  Safe and well tolerated  Disease duration less than 5 years  Pivotal study*  Either polyneuropathy that is restricted to the  Intention to treat analysis – benefit not significant lower extremities or autonomic neuropathy  87/128 patients evaluated – benefit significant alone  Regulatory Status  2012 – Approved in Europe for stage I ATTR polyneuropathy  No significant cardiac or renal dysfunction  Must be biopsy proven  OLTX not effective in non-neuropathic TTR amyloidosis  Not approved in the US  Cardiac amyloidosis – may progress; even accelerate after OLTX in non Val30Met patients

Coelho T et al., Neurology 2012;79:785–792

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Formation of Disease-Causing Proteins TTR Stabilizer: Diflunisal  NSAID, 250mg twice daily Gene RNA Disease-Causing  Randomized, double blind study of 130 patients TRANSCRIPTION TRANSLATION Protein  Patients had different mutations  Endpoint – difference in neuropathy progression as measured by Neuropathy Impairment Score + 7 nerve tests  87 patients completed year 1 and 68 completed year 2  Results:  NIS+7 Score difference 6.1 @ 1 year (p 0.02) and 16.3 @ 2 yrs (<0.001)  Adverse events  4 stopped treatment (GI bleeding, CHF, glaucoma, and nausea)  Promising drug for TTR-FAP, and it’s cheap. Courtesy of Ionis

Inotersen Addresses the Underlying Cause of Small Molecules & Biologics Target Proteins All Forms of ATTR

SMALL MOLECULES Gene TRADITIONAL MEDICINE Gene ANTISENSE DRUG Inotersen DISEASE mRNA RNA MODIFICATION (Mutant and wild-type) Prevents Formation of Blocks All Types of TTR Protein Disease-Causing Translation Protein

DISEASE TRANSLATION TRANSCRIPTION TRANSCRIPTION

Designed to Cause DISEASE Destruction of RNA MODIFICATION Less RNA = Less PROTEIN

Courtesy of Ionis BIOLOGICS Courtesy of Ionis ANTIBODIES 27 28

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Inotersen Produced Robust and Sustained Lowering of TTR Levels in hATTR Patients What are we doing?

Percent TTR Reduction from Baseline

0  Now: Diflunisal

-10

-20  Near Future: ASO (Inotersen) -

-30

SE) Placebo ± Expanded Access Program -40 TTR Inotersen S ( LSM -50  Symptomatic therapies: -60 hnefo Baseline from Change % -70  Florinef -80 0 10 20 30 40 50 60 70 Study Week

TTR Reduction (nadir) : -79% (median), -74% (mean)

Courtesy of Ionis 30 29

Genetic Counseling Final Points

 50% chance of getting the mutation  Include TTR-FAP in your differential for  But the risk of getting the disease lowish axonal polyneuropathy, particularly if there  What would you recommend if his is autonomic involvement or heart failure daughter has the mutation:  Put this on your list of potentially treatable  Surveillance  Start diflunisal? neuropathies  Stabilization of multimers using small molecules FREE GENETIC TESTING IS AVAILABLE INVITAE COMPREHENSIVE NEUROPATHIES  ASOs and siRNA approaches to reduce TTR PANEL – 79 GENES INCLUDING TTR expression www.invitae.com/alnylam-act THANKS FOR YOUR ATTENTION

8 DISCLOSURES

. No relevant disclosures

RAIN 2018 - Difficult Cases A case of migrating leukoencephalopathy

Nicole Rosendale, MD 2/16/18

Zuckerberg San Francisco General Zuckerberg2 Presentation San Title Francisco General

Patient MJ – Initial Presentation Patient MJ – Initial Presentation

. She presented to a local hospital and was admitted for evaluation

. 42 year old woman with episodic migraine and hypothyroidism who developed new, intractable right-sided headaches . Headaches were refractory to her typical over the counter abortive . Her husband also witnessed a few episodes of shaking with decreased responsiveness concerning for seizure

Zuckerberg3 Presentation San Title Francisco General Zuckerberg4 Presentation San Title Francisco General

1 Patient MJ – Initial Presentation Patient MJ – Second Presentation . After a few months, she developed a new, intractable left-sided headache followed by rapidly progressive bilateral vision impairment and hearing loss . CSF: - 1125 WBC (81% L, 13% N) - protein 125 mg/dL - glucose 69 mg/dL

. Treated with IV acyclovir and levetiracetam . Her headache improved, and she was discharged home

Zuckerberg5 Presentation San Title Francisco General Zuckerberg6 Presentation San Title Francisco General

Patient MJ – Second Presentation Question The serum assay for aquaporin 4 antibody detection is:

. She was treated with methylprednisolone 1g IV for 5 days A. A. more sensitive than specific followed by an oral prednisone taper with no significant B. B. more specific than sensitive improvement in her symptoms 44% C. C. equally sensitive and specific . During her treatment course, a serum NMO test returned 35% positive, so she was referred to UCSF Neuro-Immunology D. D. neither sensitive nor specific Clinic for further evaluation

11% 10%

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2 Patient MJ Patient MJ – Admission Examination

. GENERAL: well appearing, comfortable, neck supple . NEURO: . On initial evaluation in the UCSF Neuro-Immunology Clinic, - MS: Awake, alert, not clearly hard of hearing but had difficulty she reported progression in her symptoms, as well as new comprehending what was being said, able to name “pen”, episodes of nausea and vomiting. ”thumb” and ”glasses” but not “knuckles”; followed 1-step . She was admitted to the hospital from clinic for further commands inconsistently and was unable to perform digit span or management. calculations - CN: able to count fingers and detect movement bilaterally, blink to threat was intact bilaterally, pupils were equal and briskly reactive to light with no rAPD, fundoscopic exam was normal bilaterally, extraocular movements were full, facial sensation and strength were intact, able to hear finger rub bilaterally (L

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Patient MJ – Inpatient Evaluation Patient MJ – Inpatient Evaluation . CSF . Serum – all negative - 7 WBC (91% L, 9% M), protein 24 mg/dL, glucose 67 - Aquaporin-4-Ab mg/dL - HIV - IgG index 0.6 - Treponema - No unique oligoclonal bands - Coccidiodes - Negative: - Brucella . HSV PCR - Bartonella . VZV PCR, IgG & IgM - Leptospira . CMV PCR - ANA, dsDNA, ANCA, . WNV IgM/IgG C3/C4, beta-2- . AFB & fungal culture glycoprotein, lupus . VDRL anticoagulant screen . Cytology & flow cytometry . Universal microbial DNA screen

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3 Question Patient MJ – Inpatient Evaluation What would be the next step?

A. A. Repeat large volume LP for cytology . Steroids were held to increase the diagnostic yield . She underwent an uncomplicated brain biopsy of the left B. B. Finish steroid taper and monitor clinically 55% with no further diagnostic studies inferior parietal lobule . The neurosurgeon described the tissue as friable with frank C. C. CT angiogram 34% overlying subarachnoid hemorrhage D. D. Brain biopsy

9% 2%

Zuckerberg San Francisco General 13 Presentation Title Zuckerberg14 Presentation San Title Francisco General

Patient MJ – Biopsy Results Question The treatment for primary angiitis of the central nervous system 1. H&E stain with is: inflammatory infiltrate of leptomeningeal vessels. 2. Verhoeff’s (EVG) stain 36% A. A. prednisone demonstrating arteriolar wall breakdown B. B. cyclophosphamide 23% associated with 21% inflammatory infiltrate C. C. azathioprine 3. A CD3 stain highlighting D. D. rituximab small round T-cells that 11% E. E. A, B & C predominate 5% 3% 4. CD45 stain confirms F. F. all of the above paucity of B-cells within the inflammatory component

Zuckerberg15 Presentation San Title Francisco General Zuckerberg San Francisco General 16 Presentation Title

4 Primary angiitis of the central nervous Patient MJ- Treatment & Follow-Up system (PACNS)

. A rare and challenging diagnosis . She was started on steroids and azathioprine

. One month later, she presented to a local hospital with . Differential is often broad, and includes: recurrent seizure and worsened aphasia - Infectious etiologies of CNS vasculitis . Levetiracetam dose was increased and she was switched - Reversible cerebral vasoconstriction syndrome (RCVS) from azathioprine to cyclophosphamide - Systemic vasculitides with CNS involvement . She has continued to do well on cyclophosphamide with near full recovery of language and improvement in her vision to 20/30 OU . Brain biopsy remains the gold standard - Recommendation to increase yield: open wedge biopsy of leptomeninges, cortex and subcortical white matter from a radiographically active area

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Thank you for your attention!

Acknowledgements:

Megan Richie, MD Arturo Montano, MD Patrick Hullett, MD, PhD Giselle Lopez, MD, PhD Bruce Cree, MD, PhD Maulik Shah, MD

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