Case 1: History. An Interactive Session: Difficult Diagnosis. Neurologic Examination. Case 1: Past Medical History. Medically refractory epilepsy

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1 Case 1: History An Interactive Session: Difficult Diagnosis S. Andrew Josephson MD Assistant Professor of Neurology, UCSF Recent Advances in Neurology February 13, 2009 A 29F with a hx of epilepsy and mild developmental delay presents to the UCSF ED with aphasia and R sided weakness for 2 days Two days prior, she experienced 2 spells of right-sided shaking followed by a generalized convulsion lasting 2 minutes with associated head trauma Following the spell, she was noted to have decreased verbal output and right-sided weakness with falls to the right while walking Case 1: Past Medical History Medically refractory epilepsy Baseline sz frequency includes 2-3 partial seizures weekly and 1 GTC q 3-4 months Elective abortion at 4 months gestation for unwanted pregnancy 3 weeks prior ROS: +diarrhea x 1 week, no fevers, abdominal pain, vaginal bleeding Neurologic Examination MS: No verbal output but follows commands briskly and nods yes and no appropriately CN: Normal Motor: Moderate R hemiparesis of arm>leg in a pyramidal distribution Sensory: Normal Reflexes: Decreased on R, extensor plantar response on R Coordination: Normal Gait: Falls to right 1

2 Initial Workup Non-Contrast Head CT Presumed Todd s paralysis Normal Chem 7, LFTs, CBC Non-contrast CT of brain What is the most likely etiology of the abnormality on the CT scan? Contrast-Enhanced Head CT A. Tumor 78% B. Infection C. Stroke D. Demyelination E. Congenital 6% 3% 2% 10% T u m o r I n f e c t i o n S t r o k e D e m y e l i n a t i o n C o n g e n i t a l 2

3 Now, what is the etiology of the abnormality on the CT scan? Contrast-Enhanced Head CT A. Low-grade Astrocytoma 68% B. Cerebritis C. Venous Infarct D. ADEM E. CNS Lymphoma 19% 11% 1% 1% L o w - g r a d e A s t r... C e r e b r i t i s V e n o u s I n f a r c t A D E M C N S L y m p h o m a Brain MRI Brain MRV FLAIR FLAIR DWI 3

4 Cerebral Venous Sinus Thrombosis: Associations Hypercoagulable states Genetically-determined Oral Contraceptives Pregnancy Systemic Malignancy Inflammatory Bowel Disease Dehydration/Severe Anemia Direct invasion by Tumor/Infection Idiopathic (25 percent) Treatment of CVT Anticoagulation Based on small studies (less than 50 patients) No good randomized data exists At UCSF we anticoagulate venous sinus thrombosis-associated hemorrhages Endovascular procedures if patient worsens while on heparin AngioJet CVST: Pregnancy Incidence increases in 3 rd trimester and decreases over 2-3 months post-partum Pregnancy changes the levels of many clotting factors (e.g. decreased Protein S) Fibrinolysis impaired with increased plasminogen activator inhibitor (PAI) C-section and instrumentation increases risk Consider CVST in any new seizure, HA, or focal deficit in peripartum period Additional History/Workup Abdominal Ultrasound Normal appearing uterus without fluid collection or signs of retained products of conception Diarrhea Copious since admission Normal abdominal exam Tolerating POs well Fasting Lipids: Tchol 47; HDL 17, LDL 6 Albumin < 1.0 4

5 What is the most likely etiology of this patient s CVST? A. Recent pregnancy B. Dehydration from diarrhea C. Genetically-determined hypercoagulable state D. Infection E. Inflammatory bowel disease R e c e n t p r e g n a n... 13% D e h y d r a t i o n f r... 26% G e n e t i c a l l y - d e... 14% I n f e c t i o n 2% 46% I n f l a m m a t o r y b... Colonoscopy with Biopsy Chronic active colitis with ulceration, crypt abscesses, and moderate crypt architectural distortion Final Diagnosis: Venous Sinus Thrombosis in the setting of Crohn s Disease Cerebral Venous Sinus Thrombosis and IBD More common in Ulcerative Colitis than Crohn s disease Two-hit hypothesis Dehydration Pregnancy Genetically-determined hypercoagulable states Probably more common during flares Case 2: History A 51F with a hx of HTN is transferred to the UCSF Neurohospitalist service with visual changes and weakness for 1 week Her symptoms began with blurred vision and difficulty keeping her eyes open along with lightheadedness 5

6 Case 2: History (con t) She was admitted to another hospital and subsequently developed respiratory distress and dysphagia and required intubation CXR demonstrated a right middle lobe infiltrate and she was treated for PNA Within 1-2 days, she developed generalized weakness and could not be weaned from the ventilator Case 2: History (con t) Family History Her mother in 1971 remained paralyzed and ventilator dependent after an elective surgery for nearly a week At the time, the mother underwent a genetic test which reportedly demonstrated that she had a disorder which should be treated by avoiding exposure to succinylcholine Her 4 children were also tested at the time and only one daughter (our patient) also tested positive MS: Normal Neurologic Examination CN: Symmetric, reactive pupils, B ptosis with fatigueable upgaze, mild facial diparesis Motor: Moderate weakness of neck flexion and extension with quadriparesis R>L Sensory: Normal Reflexes: Absent in arms and trace in legs; plantar response was flexor bilaterally What is the most likely diagnosis? A. Guillain-Barre syndrome B. Autoimmune Myasthenia Gravis C. Congenital Myasthenia Gravis D. Lambert-Eaton Syndrome E. Botulism 10% 44% 34% G u i l l a i n - B a r r e... A u t o i m m u n e M y a... C o n g e n i t a l M y a... L a m b e r t - E a t o n... 7% 5% B o t u l i s m 6

7 Electrodiagnostic Examination Three weeks following initial symptoms NCS Reduced amplitude of B ulnar and median CMAPs Decremental response to 2 Hz repetitive stimulation No facilitation post-exercise or with high-frequency stimulation EMG Widespread short duration, low amplitude motor unit action potentials Early recruitment throughout No fibrillation potentials Electrodiagnostic Examination (con t) Mother Normal nerve conduction studies with repetitive stimulation at 2 Hz Now, what is the most likely diagnosis? Further Studies A. Critical Illness Myopathy B. Autoimmune Myasthenia Gravis C. Congenital Myasthenia Gravis D. Lambert-Eaton Syndrome E. Botulism 12% 55% 21% 4% 8% CK: 46 Outside hospital Tensilon test: positive AchR: Negative No response to Mestinon or IVIg Normal Chest CT C r i t i c a l I l l n e... A u t o i m m u n e M y a... C o n g e n i t a l M y a... L a m b e r t - E a t o n... B o t u l i s m 7

8 Further History Patient works for a cannery in Northern California She extensively cans at home a variety of vegetables and fruits No other family members or persons at work are sick Further Testing California Department of Public Health conducts extensive search of patient s residence, testing over 20 samples 1 of 20 samples (black olives): positive for Clostridium botulinum Final Diagnosis: Food-Borne Botulism Which of the features of this case is most atypical of botulism? A. No fibrillation potentials B. No pupillary abnormalities 59% C. Rapid onset of the disorder D. No diarrhea 20% E. No other ill contacts 6% 2% 13% N o f i b r i l l a t i o... N o p u p i l l a r y a... R a p i d o n s e t o f... N o d i a r r h e a N o o t h e r i l l c... 8

9 1. Food-borne Adult Botulism 2. Wound-associated 3. Inhalational 4. Iatrogenic (new in 2006) cases in U.S. each year Northern California: Epidemics of black-tar heroin users with wound botulism Adult Botulism: Presentation Symptoms begin hours to a few days after ingestion of contaminated food Cranial nerve palsies followed by decending limb weakness Blurred or double vision early Dysphagia and dysarthria common Respiratory failure Autonomic signs and symptoms Adult Botulism: Myths Pupillary involvement is dependent on serotype: often absent in Western U.S. Fibrillations are not a reliable indicator: present in only 20-30% of reported cases GI symptoms are often not present Usually do not have multiple affected people despite ingesting the same food Adult Botulism: Treatment Equine Serum Antitoxin Call state health department to obtain Must be given early: first 72 hours best 20% serum sickness, 1-3% anaphylaxis Antibiotics: PCN Probably useful in wound botulism, as is debridement Supportive care has dramatically decreased mortality and morbidity 9

10 So what s the deal with mom? Pseudocholinesterase Deficiency Inherited enzyme deficiency leading to slow metabolism of succinylcholine and other similar drugs Increases paralysis after these drugs from 5 minutes to usually a few (<8) hours Occasionally can last days if enzyme activity very low Can test with enzymatic assay or genetic testing Case 3: History A 60M was transferred to the UCSF Neurohospitalist Service with foot pain and progressive confusion for 10 days Symptoms began with burning pain in the soles of the feet noticed while playing golf 24 hours later, he began to have subjective fevers, fatigue and malaise Over the next week, at another hospital, he became progressively agitated, confused, hypophonic, and developed right-sided weakness Case 3: Past Medical History Asthma Sinus disease History of PNA 10 years previously, a similar episode of bilateral leg pain and encephalopathy that resolved over a three month period Medications: prednisone 10mg, montelukast, and antihypertensives Neurologic Examination MS: Alert following variable commands, MMSE 8/30, speech slow and hypophonic CN: Decreased blink rate and left HH Motor: Moderate pyramidal weakness in right arm and leg with rigidity throughout R>L Sensory: Decreased temperature in B legs to mid-shin Reflexes: Hyperreflexive and symmetric, extensor plantar responses B 10

11 MRI Brain What test would you next like to perform? FLAIR DWI A. EMG/NCS B. Lumbar Puncture C. Cerebral Angiography D. Echocardiogram E. Urinary Porphyrins 5% 62% 16% 11% 5% E M G / N C S L u m b a r P u n c t u r... C e r e b r a l A n g i o... E c h o c a r d i o g r a m U r i n a r y P o r p h y... Further Studies CBC WBC 28K, 67% Eosinophils Lumbar Puncture (OSH): 0 WBC, Protein 36, Glucose 80 (serum 110) EMG/NCS: Normal CT Angiogram with mild narrowing of intracranial vessels ESR=7 ANA +1:160 RF, p-anca, and c-anca negative Eosinophilia: NAACP Neoplastic: Eosinophilic leukemia, lymphoma Allergic rhinitis, asthma, medication allergy Adrenal Insufficiency Collagen Vascular Disease Parasitic Infections 11

12 What test would you next like to perform? 1. Cerebral Angiogram 2. Bone Marrow Biopsy 3. Brain Biopsy 4. Cultures and Serologies for Parasites 5. Empiric Trial of Steroids C e r e b r a l A n g i o... 25% B o n e M a r r o w B i... 12% B r a i n B i o p s y 3% C u l t u r e s a n d S... 39% 20% E m p i r i c T r i a l... Further History 2-3 months prior had started montelukast and weaned steroids slowly from 60mg daily to 10mg daily Final Diagnosis: Churg-Strauss Syndrome with likely CNS vasculitis Patient improved dramatically with empiric steroid treatment and eosinophilia completely resolved Churg-Strauss Syndrome (CSS) A small to medium sized necrotizing vasculitis allergic granulomatosis Average age at diagnosis is 48, equal men and women Churg-Strauss Syndrome (CSS) Diagnostic Criteria (ACR): 4 of 6 1. Asthma 2. Eosinophilia > 10% 3. Neuropathy 4. Transient pulmonary infiltrates 5. Paranasal sinus disease 6. Biopsy showing extravascular eosinophils 12

13 CSS Neurologic Complications Neuropathy Usually starts as painful dysesthesias Progresses to mononeuritis multiplex Distal polyneuropathy which may be asymmetric CNS medium and small vessel vasculitis Ischemic optic neuropathy Cranial mononeuropathies (V) CSS Triggers Vaccinations Infections Drugs such as macrolides and carbamazepine Leukotriene receptor antagonists Controversial if due to medication itself or weaning off steroids that occurs concurrently Cerebral Vasculitis Diagnosis: Our Approach Vasculopathy vs. Vasculitis LP important including IgG Index and OCBs Ultimately, tissue diagnosis key Search for evidence of systemic involvement Both for clinical and pathologic diagnosis Rarely treat empirically 13