Neurology Survival guide

Contents Contents.............................................................................................................................................................................1 Differential Diagnosis ...........................................................................................................................................................1 Stroke ................................................................................................................................................................................1 Acute Ischemic Stroke .......................................................................................................................................................1 tPA ...............................................................................................................................................................................4 Stroke trials ..................................................................................................................................................................5 Intracranial Hemorrhage ....................................................................................................................................................5 Subarachnoid Hemorrhage (SAH)........................................................................................................................................6 Herniation/high ICP..............................................................................................................................................................8 Seizure...............................................................................................................................................................................9 Status epilepticus............................................................................................................................................................ 11 Antiepileptic drugs .......................................................................................................................................................... 12 Headache ......................................................................................................................................................................... 15 DHE protocol .................................................................................................................................................................. 17 ALTERED MENTAL STATES: ................................................................................................................................................. 18 HYPOXIC-ISCHEMIC ENCEPHALOPATHY:............................................................................................................................ 19 Hypothermia Protocol: ..................................................................................................................................................... 20 Meningitis ......................................................................................................................................................................... 21 Chronic meningitis .......................................................................................................................................................... 23 CSF ............................................................................................................................................................................... 24 Multiple Sclerosis ............................................................................................................................................................... 26 Acute neuromuscular disorders............................................................................................................................................ 29 MYASTHENIA GRAVIS...................................................................................................................................................... 29 Guillian-Barre Syndrome.................................................................................................................................................. 30 Dizziness .......................................................................................................................................................................... 31 PARKINSONISM................................................................................................................................................................. 32 Serotonin Syndrome .......................................................................................................................................................... 33 Neuroleptic Malignant Syndrome ......................................................................................................................................... 34 Depression........................................................................................................................................................................ 34 Antidepressants .............................................................................................................................................................. 35 Imaging Tips ..................................................................................................................................................................... 35 ICU tips ............................................................................................................................................................................ 35 Opiod Dosing .................................................................................................................................................................... 36 Falls ................................................................................................................................................................................. 36 Lumbar Puncture ............................................................................................................................................................... 37

Differential Diagnosis VITAMIN C, D, and E V= Vascular I= Inflammtory/Infectious T= Trauma/Toxic A= Autoimmune/Allergy M= Metabolic I= Iatrogenic N= Neoplastic/Paraneoplastic C= Congenital D= Degenerative E= Episodic, epilepsy

Stroke Initial questions 1) Hemorrhagic or Ischemic? Risk of hemorrhagic stroke doubled with: coma on arrival, vomiting, severe HA, BP > 220/170, warfarin, glucose > 170 in non-diabetic pt. Obtain STAT head CT (usually already done).

2) Last normal time? If ischemic, within 3 hour window? If less than 3 hours ago, go to section on IV t-PA 3) Candidate for stroke trial? (some eligible 12 hours out-- call stroke pager to be sure-215-452-2793) Description and summary of results of past/ongoing stroke trials: http://www.strokecenter.org/trials/index.aspx 4) Do NIHSS initially rather than entire exam

Acute Ischemic Stroke Sources: Ischemic Stroke AHA guidelines from Chest 2003, Kissela lecture Diagnosis Symptoms: Headache (25%); seizure (10-15%)

Exam: cortical signs (aphasia, neglect, extinction, visual cut, graphesthesia), crossed findings (suggests brainstem) NIHSS 1) LOC: 0 =keenly responsive 1=arousable by minor stim 2=not alert, requires strong stim to respond 3=unresponsive or posturing 1a) LOC ? (month/age): 0=both correct 1=1 correct 2=neither correct 1b) LOC commands (close eyes/fist): 0=both correct 1=1 correct 2=neither 2) Gaze: 0=nl, 1=partial gaze palsy, 2=forced deviation 3) Visual: 0=nl, 1=partial hemianopia, 2=complete hemianopia, 3=blind 4) Facial: 0=nl, 1=minor paralysis, 2=partial paralysis (lower face), 3=complete 5&6) Motor: 0=no drift, 1=drift but doesn’t hit bed, 2=some effort against gravity but falls to bed, 3=no effort against gravity, limb falls, 4=no movement 7) Ataxia: 0=absent, 1=one limb, 2=two limbs 8) Sensory: 0=nl, 1=mild to mod 2=severe or total sensory 9) Language: 0=nl, 1=mild-mod aphasia loss of fluency or comprehension 2=severe aphasia, all communication fragmentary, 3=mute 10) Dysarthria 0=nl, 1=mild to mod some words understandable, 2= severe aphasia, not understandable, 3=intubated or physical barrier 11) Neglect: 0=nl, 1= neglect in one modality 2=profound hemi-inattention in more than one modality Labs: Head CT, electrolytes, CBC (plt), PTT/INR, EKG (can get MI or arrhythmia post-stroke from sympathetic release, esp. rightsided infarct) What to look for on head CT Head CT: look for current bleed or prior strokes CT insensitive with: early stroke, small cortical or subcortical infarct or posterior fossa 3 CT signs of infarct (visible within 6hr in 82% of MCA infarcts): (1) hyperdense (white) MCA -> thrombus; (2) loss of gray-white junction; (3) sulcal effacement DWI sn 88-100% sp 95-100% for detecting ischemia DWI may be negative within the first 3 hours of stroke DDx of stroke: seizure (hx is key), complicated migraine (headache, march of symptoms, young women), meningitis (fever, incr.

WBC, stiff neck, severe HA), hypo/hyperglycemia, SAH, subdural or epidural hematoma, aortic dissection, neoplasm (sometimes presents acutely), abscess Etiology of stroke in a young person (< 50 years). Cardioembolic, vertebral or carotid dissection (ask about trauma, chiropractor), cocaine, hypercoagulable state Complete R. MCA -> NIHSSS 16-20 Complete L. MCA -> NIHSSS 21-24 Acute Treatment (if no TPA) 1) Admit to NSICU (if acute) or floor with CMU 2) Neuro checks q 1-2 hrs x 24 hrs if unstable or unit bed; q 4 hrs if stable/ on floor bed.

3) Head of bed flat 4) IV fluids- Normal saline at 80-100 cc/hr, NO D5 solutions. Watch for fluid overload 5) BP issues. Hold BP meds to allow BP autoregulation: MAP > 100's (Mean Arterial Pressure = Diastolic BP + 1/3 (Systolic BP Diastolic BP); MAP of 140's are not uncommon after large MCA strokes- unless on t-PA, do not aggressively manage for first 10 days. For MAP's > 140's or signs of end-organ damage, try labetalol prn or low-dose IV enalaprilat first, then nicardipine gtt.

HCTZ and ACEI are preferred first line antihypertensives at discharge.

6) If posterior fossa stroke, watch for hemorrhagic conversion- STAT head CT for change in exam, notify neurosurgery if hemorrhage 7) Testing. Order fasting lipids, CBC, coags, panel-10, and U/A. Order TTE for AM, keep NPO post midnight (in case of TEE). If anterior circulation stroke, order carotid dopplers. Consider MRA head and neck if symptoms localize to posterior circulation.

Consider MRI if localization is uncertain. Consider checking ESR, RPR, TSH, type and screen, LFTs, and CXR as indicated.

Consider transcranial dopplers to evaluate for vasospasm if prior SAH is suspected.

8) Diet. NPO if perfusion dependent. Otherwise can start on appropriate diet if speech and swallowing intact. If unsure, keep NPO and order speech and swallow evaluation for AM. Patient will need NG tube in a few days if level of arousal stays low.

9) Keep on sliding scale with FSBG checks q 6 (regardless of whether pt has DM). Keep BG<140.

10) Start antiplatelet therapy if ischemic stroke and not on t-PA 11) Start on statin on the next day (check LFT's) 12) If febrile, pan culture, then start on round-the-clock Tylenol for 48 hours. Fever is associated with poor outcome.

13) GI and DVT prophylaxis- Heparin SQ 5000 U q 12h and TEDS; Zantac 50 mg IV q 8 if in NSICU 14) NEVER use IV heparin in acute stroke (see exceptions below) 15) STAT head CT if any change in exam (rule out hemorrhagic conversion vs. herniation; may need neurosurgery input) Acute Treatment (if got TPA) 1) Same as above, EXCEPT: 2) Admit to NSICU always 3) Neuro checks q15min x 4 -> q30min x 6hr -> q1h x 24hr 4) BP check q15min x 2hr -> q30min x 6hr -> q1h x 24hr 5) Delay placement of tubes (NG, Foley, arterial lines) 6) NO heparin including prophylactic 7) Antiplatelet and heparin prophylaxis after 24-48 hr 8) BP must be aggressively controlled to <180/105. See below for options.

9)

Repeat head CT at 24 hours before transfer out of NSICU

Indications for IV heparin in acute stroke: Extracranial carotid or vertebral artery dissection, central venous sinus thrombosis, stuttering TIA (although no randomized study to support this), basilar artery thrombosis (although no randomized study to support this), stump emboli from carotid occlusion (based on TOAST trial) BP management in stroke Options for uncontrolled hypertension: 1) nicardipine 5mg/hr IV gtt; titrate by 2.5mg q5min; max 15mg/hr (first line) 2) labetolol 10-20mg iv over 1-2 min, repeat q10min (max 200mg) OR gtt 2-8 mg/min a. Contraindications: bradycardia, asthma, bronchitis, cocaine use 3) nitroprusside 0.5mcg/kg/min gtt initial dose (consider if BP > 220/140) 4) Nitropaste 1-2 in If SBP > 230 or DBP > 140 use nicardipine or nitroprusside If SBP 180-230 or DBP 105-140, use labetalol, esmolol, nicardipine, or enalaprilat If SBP < 180 and DBP < 105, defer antihypertensive therapy Options for hypotension: 1. REPLACE VOLUME 2. PHENYLEPHRINE (Neo-Synephrine 0.5-0.1 mg IV q 10-15 min) 3. LEVOPHED (NE) - 2-12 mcg/min IV drip 4. DOPAMINE 2-20 mcg/kg/min 5. MONITOR SEDATING EFFECTS OF MEDS GIVEN (AS ETIOLOGY OF DEC BP) Secondary Prevention 1) Antiplatelet therapy (start with Aggrenox or ASA if cost is an issue; clopidogrel if ASA allergic, do not use ASA and clopidogrel together unless pt has a stent) 2) Indications for long-term anticoagulation: Afib, prosthetic heart valve, Arterial dissection (6 months), Hypercoagulable state, Stroke/TIA + mitral stenosis (ACC/AHA Guidelines; Bonow et al. JACC 1998;32(5):1518-9). Aflutter is controversial. Intracranial stenosis is NOT an indication for anticoagulation (WASID trial) 3) Timing of anticoagulation: no good data exists re: timing of initiating treatment. Our practice is to start ASA within 48 hours, and warfarin in 1-2 weeks. May wait 3 weeks in some large strokes.

4) Lipid lowering agent 5) ACEI if hypertensive (some evidence it reduces recurrence of ischemic stroke) 6) Carotid endarterectomy if symptomatic stenosis >70% (NASCET trial). CEA can be considered in good surgical candidates for moderate stenosis (50-70%). If asymptomatic with >60%, one study (ACAS) reported benefit (ARR 5.9% for stroke over 5 years), but effect was larger in certain subgroups (i.e. men) 7) Intracranial stenting/interventional neuroradiology- usually limited to dire situations- progressively worsening exam in the face of maximal medical therapy; or patients presenting in a locked-in state due to basilar stenosis Aggrenox From UpToDate 4/06 European Stroke Prevention Study-2 (ESPS-2) Stroke rate @ 24 mo with ASA alone 12.9% vs Aggrenox 9.9% (ARR 3.0%, NNT 33) No difference in death rate Prognosis 25% worsen in 24-48 hr If intubation necessary, 50% mortality @ 30 days NIHSS < 10 > 20

Favorable outcome @ 1 yr 60-70% 17%

NIHSS at 3 months All patients Age>75 + NIHSS>20

Group tPA Placebo tPA Placebo

Modified Rankin at 3 months All patients Initial NIHSS>20 Age>75 + NIHSS>20

Modified Rankin Scale 0=normal 1=minor impairment

tPA Placebo tPA Placebo tPA Placebo

NIHSS 0-1 31% 20% 0% 0% MR 0-1 (Good outcome) 39% 26% 10% 4% 0% 5%

NIHSS 2-8 30% 32% 26% 14% MR 2-3 (Moderate disability) 21% 25% 21% 20% 30% 9%

NIHSS >9 22% 27% 26% 41% MR 4-5 (Dependent)

Death 17% 21% 48% 45% Death

23% 27% 21% 38% 22% 41%

17% 21% 48% 38% 48% 45%

2=significant impairment: requires assistance, but independent 3=moderately dependent 4=mostly dependent, uses walker or cane 5=completely dependent

Complications 1) Non-neurologic: Aspiration PNA, PE, UTI, Contractures, Pressure sores, Poor nutrition 2) Neurologic: a) Increased ICP (10-20%) edema peaks 36-72 hours; see ICP section for Rx b) Seizures (4-43%) i) Most likely during early days, esp. first 24 hours ii) Risk recurrent seizures 20-80% c) Hemorrhagic transformation (5%) tPA TIME IS BRAIN: the sooner treatment is started, the greater the odds ratio of favorable outcome When considering tPA, ask about: • recent hospitalization • trauma • bleeding • surgery • prior stroke • oral anticoagulation or anti-plt • recent MI • recent medication problems • seizure (relative contraindication) Requirements to administer tPA: • stroke, not seizure • significant deficit • not resolving • less than 3 hr since onset (better if <= 90 min) o Have to ask “when did you last see them normal?”, NOT “when did this start?”. o If they awoke with symptoms, the clock starts when they went to bed. o ANY focal symptom starts the clock o If symptoms are completely gone and less than a few hours, clock starts again • no recent events (trauma, MI) • no arterial puncture or LP in 7 days • no major surgery within 14 days • no stroke or head trauma within 3 months • no GI or GU bleed within 3 weeks • no hx of ICH • no current bleeding/trauma • not anticoagulated (INR<=1.5, PTT normal, plt > 100) • BG >= 50 and <= 400 • BP < 185/110 o 3 doses of prn antihypertensives, then you’re done o First line: labetolol, enalapril, +/- hydralazine • CT not showing multilobe infarct (> 1/3 hypodensity) • NIHSS > 5 (usually) • No seizure at onset Dose: 0.9mg/kg (max 90mg) given over 60min with 10% given as bolus over 1 min Outcome with tPA 1) Complete or near complete recovery @ 3 mo.: 31-50% vs. 20-35% placebo 2) Mortality similar @ 3 month ~20% @ 1 year ~25% 3) For each 16 people treated, 1 pt who would have been moderately and 1 who would have been severely disabled will have minor or no impairment 4) NNT=8 Risk of symptomatic ICH with tPA Overall 6.4% vs. 0.6% placebo NIHSS < 10 3% NIHSS > 20 17% Risk of asymptomatic ICH with tPA in 24 hours: 4.2% tPA vs. 2.6% placebo Incidence of symptomatic ICH in 36 hours with tPA NIHSS 0-5 6-10

11-15

16-20

>20

% ICH

2

3

5

4

17

Giving tPA At UH, rt-PA is in the pixus, donâ&#x20AC;&#x2122;t wait for pharmacy Give only alteplase/activase, not retavase You can hang the actual bottle up with vented tubing (sometimes needs an extra 18 gauge needle in it) Be careful with time of dose! Pump may not shut off and pt can get too much Only can be reconstituted in sterile water, not NS Stroke trials Heparin in acute embolic stroke HAEST trial 2000 Apr 8;355(9211):1205-10 RCT of 449 patients with atrial fibrillation and acute ischemic stroke Dalteparin 100 IU/kg SC BID vs. ASA 160 mg QDAY No difference in recurrent stroke in 14 days ASA 7.5% LMWH 8.5% No difference in outcome or death at 3 months WARSS Trial N Engl J Med. 2001 Nov 15;345(20):1444-51.

2206 patients with noncardioembolic ischemic stroke Warfarin vs. ASA 325mg -> no difference Death or recurrent stroke at 2 years Warfarin (INR 1.4-2.8) 17.8% p=0.25 ASA 325mg 16.0% WASID Trial NEJM 2005 Mar 31;352(13):1305-16.

RCT of 569 patients with intracranial stenosis by angio or MRA Warfarin vs. ASA 1300mg/d No difference + more bleeding in warfarin group NINDS Trial Double blind RCT of 624 patients with ischemic stroke treated with tPA vs. placebo Carotid Endarterectomy NASCET Trial Stroke 1991 Jun;22(6):816-7 RCT of patients with TIA/CVA + 70-99% stenosis Recurrent ipsilateral CVA at 2 years Endarterectomy + Med Rx 13% (***9%?***) NNT=8 Medical Rx 28% (***26%?***) NASCET II Trial NEJM 1998;339(20):1415 RCT of 2226 patients with TIA/CVA + 50-70% stenosis Recurrent ipsilateral CVA at 5 years Endarterectomy + med Rx 15.7% NNT=16 Medical Rx 22.2% p=0.045

Intracranial Hemorrhage Sources: Shutter lecture, Semin Neuro 2005;25(4):445 Current policy (7/2007) is that neurology and neurosurgery follow patient for first 24 hours. After that, if nonsurgical then neurology assumes care.

Epidemiology Annual risk of ICH in afib patients on warfarin = 0.2-0.6% Risk of ICH doubles for each 0.5 increase in INR above 2.0 Age is risk factor for ICH on warfarin Etiology: Hypertensive vasculopathy (BG, thalamus, pons, CBL), ischemic stroke, warfarin (esp. with older age, HTN, leukoariosis, old stroke), vascular malformation, neoplasm, cocaine, malignant hyperthermia, amyloid angiopathy (usually lobar, 12% of pt age > 85 have mod-sev AA) Treatment 1) Admit to ICU 2) Head CT -> Measure hematoma volume = (A x B x C )/ 2, where A = greatest diameter of hemorrhage, B = largest diameter at 90 deg to A, C = number of cuts showing hemorrhage / 2 (since cuts are usually 5mm each) 3) Head of bed flat unless increased ICP (large ICH, low level of arousal- HOB 30 degrees) 4) Ventilator support

5) 6) 7) 8) 9) 10) 11) 12) 13) 14)

Blood pressure control: Keep SBP<180, DBP<105 (or <160 mm Hg for some attdgs) or MAP <130 (chronic htn). Use pressors for SBP<90. See above on ischemic stroke for BP options.

Hold antiplatelet and heparin. OK to Start DVT prophylaxis 24-48h if hematoma is stable.

If herniating or large mass effect, use 3% hypertonic saline protocol in NSICU (use 2% if pt doesn’t have central access) – see section below “Herniation/high ICP” Tight glucose control Check INR -> Emergently reverse coagulopathy Manage intracranial pressure (see section below entitled “Herniation/highICP”) Call neurosurgery for craniotomy or evacuation if: (1) cerebellar hemorrhage > 3cm diameter, (2) deteriorating young patient with mod-large hemorrhage, (3) ICH associated with surgically accessible structural lesion. If in doubt, call.

Seizure prophylaxis (28% seizure within 72 hrs): phenytoin 300mg po qday, levetiracetam 500-1500mg po bid REPEAT HCT if pt has new-onset HA, N/V or photophobia If acute hemorrhagic stroke, no antiplatelet/anticoagulant therapy x 3 months. If acute hemorrhagic stroke in the face of atrial fibrillation/cardiac thrombus- no evidence- can try ASA in 2 weeks, warfarin in 4 weeks, and monitor VERY closely.

Prognosis Overall mortality at 30 d.: 30-50% (ICH score predicts mortality) 20% survivors are independent at 6 mo.

Warfarin doubles mortality in patients with ICH Damage proportional to ICH volume Lobar hemorrhages are more likely to recur ICH Score Factor GCS 3-4 GCS 5-12 ICH volume > 30 IVH extension Infratentorial origin Age >= 80 ICH score 30 d. Mortality (%)

Points 2 1 1 1 1 1 0 0

1 13

2 26

3 72

4 97

5-6 100

Subarachnoid Hemorrhage (SAH) Sources: Lange Neurology, Shutter lecture Determine etiology: Trauma, aneurysm rupture (MCA 29%, ICA 16%, ACOMM 15%, Basilar 14%; multiple in 20%), AVM/vascular malformation, vertebral or carotid dissections, mycotic aneurismal rupture, ICH, coagulopathy Risk factors: ASA, coumadin, ephedra, amphetamines, sympathomimetics Ruptured berry aneurysm: age 40-59 M=F (Lange) Peak incidence ruptured aneurysm between 55 – 60 yrs old M:F=1:1.5-4 (Shutter) Ruptured AVM: M:F=2 age 10-39 but can be later (60s) Incidence berry aneurysm rupture 6/100,000 Symptoms Sudden onset severe HA, LOC, vomiting, neck stiffness Milder but similar HA in preceding weeks HA subsides slowly over 2 weeks Exam High BP Hyperthermia 39 C (102.2 F) x 2 wks Confusion, stupor, coma Nuchal rigidity Brudzinski’s- a few hrs after HA Preretinal globular subhyaloid hemorrhages (20%) Usually nonfocal neuro exam (except CN VI & extensor plantar response in PCOMM or AVM rupture) Tests Head CT with contrast (to see AVM): sn 90% in aneurysm rupture LP if CT is negative (which is 10% of time)-> elevated ICP, gross blood, xanthochromia MRI to find small AVMs in brain stem Xanthochromia develops within several hours, distinguishes traumatic tap Timing of CSF changes: The rule of 1/2s: ½ hour for RBCs to appear, ½ day for xanthochromia to appear, ½ week for RBCs to disappear, ½ month for xanthochromia to disappear Pleocytosis, low CSF glu within 48 hrs Peripheral WBC <= 15.0 EKG -> peaked or deeply inverted T, short PR, tall U 4 vessel cerebral angiogram in surgical candidates DDx: ICH (usu has focal findings), Bacterial meningitis (CSF findings), ruptured mycotic aneurysm (other signs of endocarditis), traumatic tap (no xanthochromia) Treatment

1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25)

Goal: prevent high arterial or ICP to prevent rerupture Admit to ICU Q1h neuro checks Elevate head of bed 15-20 deg Strict I/O, NPO until treatment planned, but then start tube feeding or TPN early Prevent increase ICP (bed rest, mild sedation, antiemetics; Antacids; Stool softeners, Keep room dark and quiet, Analgesia) Avoid hypovolemia Aggressive glu control Caution with hypotonic IVF to prevent cerebral edema; use isotonic with no dextrose BP control. Keep BP < 140-160 until aneurysm secured, then let it self-regulate (J Int Med 2004; 255:257-265). If in vasospasm + surgically corrected -> induce HTN with phenylephrine.

Emergently reverse coagulopathy (FFP, vitamin K) Avoid ASA (inhibits plt function) DVT prophylaxis 24 hr after unless known hemorrhagic lesions or post-op Low Na -> cerebral salt wasting -> NaCl or hypertonic saline Nimodipine 60mg po q4 x 21 days -> reduce vasospasm PHT 300mg/d prophylaxis x 7-14 d (write stop date: 50% discharged on AEDs, only 25% had meds discontinued as out-patient), use LEV if adverse rxn to PHT Check PHT level Steroids provide no benefit If aneurysm -> surgical clipping within 2 days Not surgical candidate if stuporous or comatose If AVM -> removal, ligation or embolization electively (lower rebleeding risk) If deteriorates -> repeat head CT Monitor for complications (see below) Baseline TCDs (transcranial dopplers) PM&R, PT/OT, Speech

Prognosis Mortality (with aneurysm): most deaths occur within first few days. 20% of deaths occur before hospital, 25% from initial bleed, and 20% of deaths occur from rebleeding (if aneurysm not surgically corrected) Mortality ruptured aneurysm @ 30d = 45% (Shutter) Level of consciousness at presentation predicts outcome 50% of survivors have brain injury Recovery from ruptured AVM is 90% Complications 1) Recurrence (20% in 10-14 d with aneurysm) a) 50% mortality with rebleed b) Suspect if change in status (new HA, new N/V, increased BP or ICP) in unsecured pt 2) Intraparenchymal extension 3) Arterial vasospasm (42%) -> ischemic stroke a) Start day 3, peaks day 10-14 b) Cofirm with transcranial Doppler or cerebral angio c) More common with larger bleeds d) Risk: HH Grades III-IV, Fisher Grade 3 or unconscious >1hr e) Treatment of vasospasm i) Nimodipine (may lower BP) ii) Triple â&#x20AC;&#x153;Hâ&#x20AC;? therapy (HHH): (1) Hypertension: SBP 160-200 (2) Hypervolemia: MIVF 150-200ml/hr (3) Hemodilution vs hemodynamic therapy: Decrease blood viscosity, keep Hct 30-35% Increase CBF/CO, decrease ICP, increase CPP iii) Angioplasty, intraarterial papaverine/verapamil 4) Acute or subacute hydrocephalus 5) Seizures (Lange:<10%, Shutter:3-36%) a) Incidence (Neurology 2000; 55:258-65) i) Retrospective study of 95 pts ii) Pre-hospital definitive = 17.9%, questionable = 7.4% iii) In-hospital = 4.1% (3/4 on AED w/ therapeutic level) iv) Post-hospital = 8% (all had seizure early) 6) Myocardial stun syndrome World Federation of Neurological Surgeons (WFNS) Grading Scale Grade GCS Focal deficit 1 15 2 13-14 3 13-14 + 4 7-12 +/5 <7 +/Fisher CT Grade (predicts risk of vasospasm Grade CT findings

Risk of vasospasm

1 2 3 4

Normal <1mm thick blood >1mm IC or IV clot with diffuse or no SAH

0-10% 30% 70% 30%

Hunt-Hess 1) Alert, asymptomatic or minimal H/A & slight nuchal rigidity 2) Alert, mod-severe H/A, nuchal rigidity, no neuro deficit other than CN palsy 3) Drowsiness, confusion or mild focal deficit 4) Stupor, moderate-severe hemiparesis 5) Comatose, extensor posturing, moribund Aneurysm Epidemiology Approximately 1 – 5% of adults have intracranial aneurysms 20% between 15 – 45 Rare in children, uncommon < 20yo.

Risk factors Congenital: polycystic kidney disease, aortic coarctation, Ehlers-Danlos Syndrome, fibromuscular dysplasia, sickle cell, AVM. Modifiable: HTN, arteriosclerosis, hyperlipidemia, smoking, heavy ETOH use, & oral contraceptives Secondary: trauma, infection, drug use Size Small <5mm Medium 6-15mm Large 16-20mm Giant >20mm

Herniation/high ICP Definitions Cerebral perfusion pressure (CPP) = Mean arterial pressure (MAP) - intracranial pressure (ICP) Normal ICP = 0-10mmHg - Elevated ICP >= 20mmHg Autoregulation fails with MAP > 150 or < 50 or in trauma, stroke, status epilepticus Symptoms: Headache, nausea/vomiting, blurred vision, altered level of consciousness, coma, +/- focal deficit Signs of herniation: Deteriorating level of consciousness (GCS), Pupillary asymmetry, Motor asymmetry, Cushing’s triad: hypertension, bradycardia, respiratory irregularity, Uncal: ipsilateral 3rd nerve effects, contralateral cerebral peduncle, Tonsilar: Dysregulation then collapse of respiratory & cardiovascular systems, Subfalcine: Personality change, contralateral leg weakness, ACA infarct DDx of high ICP: Agitation, hypercarbia, hypoxia, TBI (occurs in 40% of severe TBI), SAH, IVH, SDH/EDH, mass lesions, hydrocephalus, stroke, seizures (transient), CNS infections, hepatic encephalopathy, eclampsia, H20 or lead intoxication, HACE, hematoma (occurs in 50-70%) Treatment From Stroke recs Chest 2003, Guidelines for Management of Severe TBI. AANS/BTF 2000 rev, Crit Care Med 2005;33:6, Shutter lecture 1) Initial treatment a) Goals: keep ICP<20-25, keep CPP>60 b) Low threshold for head CT! c) ICP monitoring is controversial in stroke (AANS guidelines say monitor for GCS<=8; consider for hydrocephalus or significant mass effect if sedated) d) Mild fluid restriction e) Head of bed 30 degrees f) Intubate: treat hypoxia, hypercarbia g) CSF drainage (if has ICP monitor) h) Tight glucose control i) Control agitation with diazepam, midazolam, propofol j) Control pain with morphine, fentanyl k) Control fever with scheduled antipyretic because it decreases cerebral metabolism l) Avoid hypotonic fluids or free water m) BP control. Avoid systemic hypotension (SBP < 90 mm Hg). If HTN encephalopathy, lower MAP carefully based to keep CPP>60. Avoid vasodilating BP medications (NTG, nitroprusside, hydralazine). Labetolol is drug of choice, then nicardipine.

2) Further treatment if ICP > 20mmHg, CPP < 60mmHg, signs of herniation present, or progressive deteriorating not explained by extracranial reasons, then: a) Hyperventilate (goal PCO2 35 mmHg) b) Hypertonic saline protocol (can bolus with hypertonic saline 7.5% 2ml/kg) i) Can use mannitol 0.25-1.0 gm/kg over 20 min IV Q6 instead of hypertonic saline (Aim for euvolemia, avoid hypervolemia. Keep S osm < 320. Rebound high ICP 6 hours later.) c) Hyperventilate to PCO2 28-35 mmHg (do not hyperventilate below 25 pCO2)

d)

3) 4) 5)

Barbituate coma (Pentobarbital 10mg/kg over 30 min -> 5mg/kg Q1h x 3 -> 1mg/kg/hr, needs continuous EEG) AND Call neurosurgery for decompressive craniectomy +/- Hypothermia (Shutter) i) Goal: no cough, no response to stimuli, burst suppression on EEG Do not use mannitol or hyperventilation prophylactically because that can increase morbidity or mortality in stroke patients.

Mannitol bolus preferentially shrinks non infarcted brain in ischemic stroke (Neurology 2001; 57:2120-2) Corticosteroids provide no benefit with cytotoxic edema in stroke

TUH Hypertonic Saline Protocol Goal: 1) Patients at risk for increased ICP: Goal = 140 – 150 2) Patients with increased ICP: Goal = 145 – 155 Start with 3% saline at 30 cc/hr via central line Increase in increments of 5 – 10 ml / hr to goal Follow Na & S osm q6h while Na < 150; q4h when Na > 150 Prognosis Sustained episodes of ICP > 25 mm Hg associated with inc. mortality & poor outcome, though prolonged (> 96 hours) elevations can still have favorable outcomes in up to 38%

Seizure From NEJM 1998:970; Lancet Neurol 2006;5:246-56; Epilepsy Research 2006;S77-S82; Ficker lecture; I. E. Lippik, Contemporary diagnosis and management of the patient with epilepsy, 5th ed. 2000 Definitions Seizure = a paroxysmal time-limited event that results from abnormal neuronal activity in the brain.

Epilepsy = a disorder in the CNS whose symptoms are seizures.

Symptomatic = due to secondary cause Idiopathic = congenital epilepsy syndromes Cryptogenic = unclear etiology Status epilepticus = seizure lasting longer than 5 minutes or multiple seizures without return to baseline Simple = no loss of awareness during seizure Complex = has loss of awareness or confusion during seizure Generalized = affecting whole brain Primary generalized = onset begins in the whole brain at once (vs. partial onset secondarily generalized) Partial onset = seizure starts in one part of the brain Seizure Types 1) Partial (Focal seizures) a) Simple partial seizures: no loss of awareness during seizure i) with motor signs ii) with somatosensory or special sensory symptoms iii) with autonomic symptoms iv) with psychic symptoms b) Complex i) simple partial onset followed by impairment of consciousness ii) with impairment of consciousness at the onset iii) duration of one minute or more, an aura, and confusion after the event, temporal slowing or sharp waves on EEG c) Partial w/ secondary generalization i) simple partial seizures evolving to generalized seizures ii) complex partial seizures evolving to generalized seizures iii) simple partial seizures evolving to complex partial seizures evolving to generalized seizures 2) Generalized (Convulsive or Nonconvulsive) a) Typical absence (petit mal) vs atypical i) short duration (10 s), a rapid onseet w/o warning, very rapid recovery, or precipitation of the event by hyperventilation, a pattern of spike and wave at a frequency of 3 Hz b) Primarily generalized tonic-clonic i) onset while the pt is asleep or awake and in any posture, a duration of one minute or longer, increased muscle tone, incontinence, biting of the tongue, flushed color, hot and sweaty skin, stertorous respirations, EEG abnormalities, or a family hx c) Myoclonic d) Clonic e) Tonic f) Atonic seizures 3) Unclassified Epileptic Seizures a) Includes all those seizures that cannot be classified because of incomplete data or b/c they defy classification into the above categories; for example neonatal seizures with swimming movements 4) Status Epilepticus – sz persist > 30 min, or persist 10 min after tx or if seizure recurs frequently enough that full recovery of consciousness/baseline does not occur

History 1) For each patient, determine the seizure classification, including provoked/unprovoked, symptomatic/idiopathic/cryptogenic and simple/complex partial/generalized. Ask about potential causes of symptomatic seizures, such as stroke or tumor.

2) Ask about: Aura? LOC? Duration? Postictal confusion? Description of movements if any? Automatisms like lip smacking or picking movements? Progression of movements? Incontinence? Tongue biting? Signs suggesting syncope such as palpitations, diaphoresis, N/V, lightheadedness? More than one seizure type? Onset of epilepsy? Prior AED use? Current meds? Recent EtOH or other anxiolytic use? Sleep deprivation? Recent illness? Last menstrual period? Missed doses of meds?

3) History from witnesses is crucial!

4) Features suggesting partial onset: Ask about aura, staring with automatisms prior to GTC, Todd’s paralysis, progression from one part of the body 5) Risk factors. Birth complications, previous head trauma with LOC, history of CNS infection, family history of seizures, personal history of febrile seizures. Physical or sexual abuse is a risk factor for pseudoseizures.

Etiology of seizure: •Breakthrough seizure in epilepsy patient (“seizure patients sometimes seize”), •Low AED levels/Noncompliance in epilepsy patient, •Electrolytes (Na, Ca, glu), •Renal failure, •liver failure, •Sepsis, •Anoxia/hypoxia, •Drug withdrawal (barbiturates, benzodiazepines, ethanol, opiates, baclofen), •Drug intoxication (including EtOH, amphetamines, cocaine, phencyclidine, cipro, imipenem, lidocaine, penicillin, theophylline, tricyclics), •acute or remote stroke, •CNS infection, •Head trauma, •Fever/infection, •Tumor, •Vascular malformation, •Congenital, •Mesial temporal sclerosis Mnemonic for seizure etiology – AEIOU TIPS: A-Alcohol, Anoxia E-Endo, Electrolyes, Epilepsy, Encephalitis I-Infection O-Overdose U-Uremia T-Tumor, Trauma I-Insulin P-Psych S-Stroke, SAH, SDH Triggers of seizures: sleep deprivation, missed meds, stress, illness, menstruation, starting a new medication that interacts with pt’s AED or lowers sz threshold Drugs which lower seizure threshold (i.e. don’t give to EMU patients). Bupropion, ciprofloxacin, promethazine, imipenem Labs/Imaging after seizure 1) Electrolytes for Na, Ca, Mg, Glc, BUN/Cr 2) CBC for infection, thrombocytopenia, & hemoglobinopathy 3) LFT (in case starting AEDs and to look for hepatic encephalopathy) 4) Tox screen 5) ANA, ESR in suspected CNS vasculitis, SLE cerebritis 6) HIV 7) CT or MRI with and w/o gad, Consider angio after pt stable; emergency basis if the pt is over 40, has had a partial sz, new focal deficit, persistently altered MS, h/o CA or anticoagulant therapy, & those who may have AIDS 8) EEG after 48 hrs 9) LP 10) Prolactin levels in 20, 60, 120 minutes to check for pseudoseizures Treatment of new onset seizure This can be an outpatient workup MRI brain w/wo gad new onset seizure protocol EEG No driving, working at altitude or swimming alone for at least 3 months Normally no drugs started after first event because risk of recurrence is as little as 24% Consider AED after first event if there is a structural lesion on MRI, EEG abnormalities, family history of seizure Get follow up appointment with new onset seizure clinic How to start AED. When starting AED, increase dose until sz control or side effects occur. Drug levels are not very important except to determine compliance and monitor therapy over time. When reached max recommended dose, add another agent.

Discontinuing therapy -after 2 yrs w/o sz consider discontinuation -if d/c, then reduce dose by 25% every 2-4 wks Treatment of breakthrough seizures Identify and prevent potential triggers (sleep deprivation, missed meds) – stress and illness should not be treated as triggers in that medication should be adjusted for these triggers.

Adjust AEDs if no clear trigger even if in therapeutic range Change AED if patient has toxicity Driving restrictions by state: http://www.epilepsyfoundation.org/answerplace/Social/driving/statedrivinglaws.cfm If cluster seizures, increase AED and consider oral LRZ 0.5-1 mg bid/rectal DZP/intranasal benzo for several days Treatment of epilepsy in pregnancy In general, continue on current AED because risk of seizure in switching rapidly may be harmful to the baby (exception is valproate)

Prognosis of New onset seizure Patient Normal EEG + idiopathic sz Symptomatic sz or abnl EEG Symptomatic sz + abnl EEG

Risk of recurrence after 1 event 24% 48% 65%

Risk of recurrence highest in first 3-6 months Chance of seizure freedom in new onset epilepsy From Kwan NEJM 2000;342:314-9 Treatment Seizure freedom (% of original population) 1st AED 47% 2nd AED 13% 3rd AED 1% Duotherapy 3%

Status epilepticus Epidemiology 8% pt in coma without sz hx were in complex partial status 15% of patients with epilepsy will experience status Symptoms Average time of GTC 53-62 sec, none lasted 2 min (5 min = 18-20 std devs) Sx of non-convulsive status: confusion, personality changes, postictal > 30 min, subtle motor movements, nystagmus, coma, psychosis Non convulsive status is common esp. in ICU patients! 198 emergency EEGs -> 74 subclinical status (53 definite, 21 probable) = 37% See Privitera et.al, Epilepsy Research 1994 for details > 50% of patients do not have history of epilepsy Systemic effects Cardiac: tachycardia, or other potentially fatal dysrhythmias (58% of all patients with GCSE), cardiac output decreases, hypotension Hyperpyrexia, acidosis, hypoxia, hypoglycemia Complications Seizure activity lasting 30-45 minutes -> death of neurons via excitotoxicity, probably not excess demand Profound metabolic acidosis (pH < 7.0) in 33% pts -> resolves spontaneously Respiratory acidosis & hypoxia need treatment Hyperthermia in 28-79% so not necessary infection -> passive cooling Drug treatment of status epilepticus Progress through the following algorithm, stopping when status epilepticus terminates: 1) IV Glucose + thiamine, consider naloxone 2 mg IV if overdose is suspected or pupils myotic 2) Use 1 of the following options (at 10-20 minutes) Lorazepam 0.1mg/kg @ 2mg/min Midazolam 0.2mg/kg -> 0.05mg/kg/hr (can be given IM) Diazepam 0.2-0.4 mg/kg @ 5mg/min (can be given as 15-20mg PR [Diastat]).

3) Use 1 of the following options, but fosphenytoin is preferred (at 20-60 minutes) Fosphenytoin @ 150mg phenytoin equivalents/min (if not PME/JME) -> Repeat 5-10mg/kg if needed i. If using standard phenytoin, (1) monitor EKG and BP, (2) do not use with glucose containing solutions, (3) infuse in large vein, (4) total dose is the same but must be given slower at 50mg/min Valproate (Depacon) IV 40 mg/kg (repeat 20 mg/kg if necessary) -> 3 mg/kg/hr PHB 20mg/kg IV @ 50-75mg/min -> Repeat 5-10mg/kg PHB if needed 4) Drug-induced coma, midazolam is preferred (after 1 hour) a. Midazolam 0.2mg/kg slow bolus, then 0.75-10mcg/kg/min b. Propofol 1-2mg/kg, then 2-10mg/kg/hr c. Pentobarbital 10mg/kg at <= 25mg/min, then 0.5-2mg/kg/h d. Continue anesthesia for 12-24hr then withdraw e. Goal: burst suppression (call tech for continuous EEG) ABCs in status Establish multiple IV access (for dextrose and fosphenytoin) Dx/Rx medical problems Control hyperthermia 100% O2 by NC or NRB Oral airway Intubate (vecuronium 0.1mg/kg) if necessary due to hypoxia/resp acidosis Keep SBP > 120 (use pressors for SBP < 90) EKG then telemetry LP if suspect CNS infection.

Labs: glucose, lytes, CBC, AED levels, serum or urine drug screen, EtOH level, ABG, UA

Head CT to look for acute causes pH < 7 + low BP -> bicarb Admit to ICU Resistance to AED is SE develops in time dependent manner. Potency benzos dec by 20x after seizing for 20 min. PHT loses potency more slowly. (Lancet Neurol 2006) EEG indications • long acting paralytic • Unconscious after initial drug treatment • Refractory status Drugs for induced coma Pentobarbital: Load 5 mg/kg Infuse 0.5-3 mg/kg/hr Titrate to burst suppression on EEG Hypotension requiring pressor support in most cases PTB associated with a lower frequency of breakthrough seizures, and higher rate of hypotension than propofol or midazolam (Claassen Epilepsia 2002;146-153) Midazolam 200 µg/kg load (5-10 mg bolus) -> 0.75-10 µg/kg/min (0.05-0.4 mg/kg/hr) infusion SE: Tachyphylaxis Lorazepam (Labar Neurology 1994;1400-1403) Nine cases refractory S.E. (min 24 hours) LRZ 0.3-9 mg/hr infusion S.E. successfully stopped in all cases (This is optimistic in Matt’s experience) Propofol (Stecker Epilepsia 1998;39:18-26): 16 cases refractory S.E. (8 barbiturates, 8 propofol) Seizures controlled (Barbiturate 82% vs Propofol 63%) Time to control longer for barbiturates (123 min) than propofol (2.6 min) No difference in mortality barb vs propofol Midazolam vs propofol (Prasad Epilepsia 2001; 42: 380-6) No difference in clinical and electrographic seizure control Patient survival better with midazolam than propofol with APACHE II score of > 20 IV VLP (Depacon) 15-30mg/kg RCT: PHT (18 mg/kg) vs. VPA (30 mg/kg) in convulsive status successful 42% vs. 66% Absence status Often terminates with GTC Rx: PO benzos vs. PO/IV VLP No Rx necessary if cause identified Prognosis of status Epilepticus From Lancet Neurol 2006 Age Short-term mortality 16-59 14% >= 60 38% Anoxia, multiple medical problems, prolonged status, refractory to Rx -> poor outcome From Ficker lecture Mortality from Status by etiology Etiology anoxia hemorrhage tumor % Mortality

60

47

37

metabolic

infection

stroke

trauma

30

30

27

15

AED withdrawal 5

ETOH 5

Antiepileptic drugs Sources: Ficker lecture Epilepsy Rx; UpToDate 2/06; PDR. Clinical handbook of Epilepsy. 1st edition. 2005.

Initial therapy Seizure Type Partial sz: Partial sz adjunct: Absence Primary Generalized TC

Drug options PHT, CBZ, VPA, LTG, TPM, OXC, GBP ZNS, LEV, TGB VPA, ESM, LTG VPA, LTG, TPM, ZNS, ?LEV, FBM

Contraindicated

CBZ, OXC, GBP, TGB, PB

Young pt/partial sz Older pt/partial sz Young pt/generalized Lennox-Gastaut Myoclonic seizures

PHT, CBZ, LTG, OXC GBP, LTG, LEV VPA if male; LTG, TPM if female LTG VPA

PB CBZ, OXC

Phenytoin [PHT] (Dilantin) 1) Indications: for all partial sz, for tonic-clonic sz, and in the treatment of status epilepticus 2) Dose- Start 5mg/kg/d -> level in 7-10d To load orally, bolus with 3 doses 5mg/kg each Check level 2-3 hours after load AND 5-7 days after each change in dose Level Dose adjustment <7 mcg/ml inc. 100mg/d 7-12 inc. 50mg/d >12 inc. 30mg/d 3) Metabolism: hepatic hydroxylation system; when hepatic hydroxylation system becomes saturated, small increases in dose of phenytoin cause a large increase in plasma conc 4) PK: Nonlinear kinetics, protein bound, long half-life, renal failure increases free levels, INDUCER 5) SE: CNS depression, nystagmus, ataxia, confusion, slurred speech, hirsutism, tremor, nausea/vomiting, gingival hyperplasia, osteoporosis, megaloblastic anemia, confusion, hallucination, and drowsiness, inhibition of ADH and insulin secretion, StevensJohnson syndrome (esp first 8 weeks), neuropathy 6) Drug interactions: a) chloramphenicol, dicumarol, cimetidine, sulfas, and INH inhibit metabolism (increase PHT level) b) carbamazepine increases metabolism (dec PHT level) c) phenytoin increases the metabolism of other AED's, anticoagulants, OCP, quinidine, doxycycline, cyclosporine, mexiletine, methadone, and levodopa 7) Normal level, total: 10-20 mcg/ml 8) Normal level, free: 1-2 mcg/ml 9) Pregnancy category: D 10) Treatment of toxicity a) Hold until pt is asymptomatic (approx total level < 20), then dec maintenance dose by 30-50 mg/d to avoid breakthrough sz b) dec by 25-50% & wait 2 wks until resuming gradually inc doses c) if rash develops gabapentin, divalproex, or levetiracetam can be used to control sz while the offending drug is withdrawn Carbamazepine [CBZ] (Tegretol, Carbatrol) 1) Therapeutic uses: for all partial sz, tonic-clonic sz 2) Dose: start 100mg bid -> inc. 100mg bid q3d -> 600mg bid, check level 10-14 days (OR 3, 6 and 9 weeks, then q2mo until stable level) 3) Normal level: 4-12 mcg/ml 4) PK: Protein bound (70%), liver metabolism, inducible and INDUCER 5) MOA: Na-channel 6) SE: drowsiness/stupor, rash, pruritis, nausea/vomiting, fluid retention, dizziness, cardiotoxicity, respiratory depression, vertigo, ataxia, blurred vision, agranulocytosis, thrombocytopenia, liver toxicity, aplastic anemia (1/287,500), hyponatremia, StevensJohnson/TEN (esp. within 8 weeks) 7) Monitor CBC, LFT initially, 3 mo, then q6 months 8) Drug interactions: cimetidine, diltiazem, erythromycin, ING, propoxyphene decrease metabolism 9) Pregnancy category: D Valproate [VLP] (Depakote); Valproic acid [VPA] (Depakene); IV VLP (Depacon) 1) Therapeutic uses: myoclonic sz, tonic-clonic sz, second choice for absence sz 2) Dose: start 250-500mg/d -> inc. 250mg/d Qwk -> goal 15mg/kg (Check level 1-2 wk after initial dose) 3) Normal level: 50-150 mcg/ml 4) PK: Liver metabolism P450, INHIBITOR 5) SE: weight gain, N/V, hair loss, bruising, tremor, jaundice, VLP-associated hyperammonemia (lethargy, seizures, coma, death), fatal hepatitis (adult c other AED in 1/22,000), sedation, ataxia, dizziness, rash, may cause thrombocytopenia and inhibition of platelet aggregation, hyponatremia 6) MOA: blocks Na-channels; increases GABA 7) Monitor CBC, LFTs 8) Interactions: inhibits the metabolism of Phenobarbital, etc.

9) Pregnancy category: D Phenobarbital [PB] 1) Therapeutic uses: simple partial sz, recurrent tonic-clonic sz, neonatal seizures 2) PK: long acting barbiturate, liver P450 metabolism, INDUCER 3) SE: sedation, ataxia, nystagmus, vertigo, acute psychotic rxn, memory impairment, irritability, hyperkinesias, depression, nausea/vomiting, rash 4) Dose â&#x20AC;&#x201C; 120-250mg or 2-3mg/kg/d. Children 30-100mg daily. Can be given intramuscular and IV and via NG. Gabapentin [GBP] (Neurontin) 1) Dose- Start 300mg qhs -> inc. 300mg/d qday -> 300-600mg tid -> max 3600mg/d 2) Indications: consider in partial sz in elderly and liver dz 3) SE: sedation, rash, nausea, dizzy, wt gain, edema, behavioral changes, no serious toxicity/interactions,

4) 5) 6) 7)

PK: Not protein bound, excreted unchanged in urine Instructions: Take >2 hours after antacids Therapeutic uses: -partial sz, generalized tonic-clonic sz Drug interactions a) increased metabolism by carbamazepine, phenytoin b) decreased metabolism by valproic acid

Lamotrigine [LTG] (Lamictal) 1) Therapeutic uses: partial sz, Lennox-Gastaut, generalized tonic-clonic sz 2) Dose- bid dosing, depends on other AEDs used; total daily dose listed in chart below so divide listed dose bid 3) LTG TOTAL DAILY DOSE Week With PHT/CBZ With VPA Monotherapy 1-2 50mg 25mg QOD 25mg 3-4 100 25 QD 50 inc 25-50/d 5 200 100 Q1-2wk -> 6 300 200 100-150mg/d inc 100 Qwk -> 300-500mg/d 4) SE: Nausea, dizziness, somnolence, rash (1/1,000 or 1/100 with VPA), including Stevens Johnson/TEN (rash less likely with slow titration); mild CNS effect, hypersensitivity reactions, hepatic and renal failure, DIC, arthritis, Tics and insomnia 5) PK: Liver metabolism 6) Drug interactions a) increased metabolism by carbamazepine, phenytoin b) decreased metabolism by valproic acid Levetiracetam [LEV] (Keppra) 1) Therapeutic uses: Partial/generalized seizures. Adjunct or monotherapy.

2) Dose: 500mg bid -> inc. by 1000mg/d Q2wk -> 1-3gm/d -> max 5gm qday 3) PK: Not metabolized by and does not induce P450, adjust dose in renal disease 4) No drug interactions 5) SE: fatigue, dizziness, irritability, anxiety, cognitive effects, somnolence, ataxia, diplopia 6) Pregnancy category: C Toprimate [TPM] (Topamax) 1) Therapeutic uses: Partial/generalized seizures (GTC) 2) Dose: 50mg/d div bid x 1 week -> inc. 50mg/wk -> goal 200mg bid 3) PK: Clearance doubled by inducers (PHT, CBZ) -> need to double TPM dose 4) MOA: blocks Na channels; increases GABA; inhibits NMDA 5) SE: Weight loss, CNS effects (30%), impaired cognition, paresthesia, headache, fatigue, dizziness, depression, mood problems, kidney stones (2-3%), acute myopia, open angle glaucoma, metabolic acidosis (carbonic anhydrase inhibitor). Most side effects improve with time except weight loss and paresthesias.

6) PK: 70% excreted unchanged in the urine, bioavailability is 80% with half-life of 21 hours, does not appear to effects levels of other drugs, however PHT and CBZ decreases topiramate concentrations by 48 and 40% respectively.

7) Pregnancy category: C Zonisamide [ZNS] (Zonegran) 1) Therapeutic use: Partial seizures. Adjunct therapy.

2) Dose: 100-200mg bid (or 2-4mg/kg/d in children) -> inc. Q2wk -> 400-600mg/d 3) Sulfa derivative 4) SE: somnolence, ataxia, confusion, abnormal thinking, nervousness, dizziness, kidney stones (3%, weak carbonic anhydrase inhibitor), irritability, photosensitivity, weight loss/anorexia. Most SEs self-limited.

5) PK: liver metabolism, half-life > 60h but is shortened by drugs that induce hepatic metabolism, significant amount excreted by urine unchanged, low protein binding 6) MOA: blocks Na channel and T-type Ca channels Ethosuxamide [ESM] (Zarotin) 1) Therapeutic uses: absense sz 2) Dose: Start 20-40mg/d in 1-3 divided doses and increase by 250mg q 4 to 7d as needed. (Check level after 1-3 weeks) 3) Level: 40-100mcg/ml 4) SE: N/V, sleep disturbance, drowsiness, hyperactivity, liver failure, Stevens-Johnson 5) MOA: Inhibit T-type Ca channel 6) PK: liver P-450 metabolism; however, it does not induce P-450 synthesis 7) SE: nausea/vomiting, drowsiness, lethargy, dizziness, restlessness, agitation, anxiety, inability to concentrate, Stevens-Johnson sydrome, urticaria, leukopenia, aplastic anemia, thrombocytopenia Tiagabine [TGB] (Gabatril) 1) Therapeutic uses: adjunctive therapy in adults/children > 12 yrs for partial seizures 2) Dose: 4 mg qday -> inc. 4mg/d Qweek -> 24-32 mg/d -> max 56mg/day (adults) 3) SE: Dizziness, asthenia, somnolence, difficulty concentrating, CNS effects (30%), nonconvulsive status, stupor, weakness 4) PK: Metabolism â&#x20AC;&#x201C; CYP 3A isoform subfamily of cytochrome P-450, highly protein bound 5) MOA: GABA reuptake inhibitor Oxcarbazine [OXC] (Trileptal)

1) 2) 3) 4) 5)

Therapeutic use: Partial seizures. 25% crossrxn with (CBZ) Dose: 300mg BID and increased by 300mg q 3rd day to a dose of 1200mg/d -> max dose 1800mg/day.

PK: liver metabolism, metabolized to 10-monohydroxy oxcarbazepine (MHD) with half-life of 9 hours, 40% protein bound SE: hyponatremia, N/V, cross-hypersensitivity with CBZ (25%), rash, etc.

Pregnancy category: C

Primidone [PM] (Mysoline) 1) Therapeutic uses: alternate choice in partial sz and tonic-clonic sz 2) Dose – Initially 125mg qHS x 3d, with the dose increased by 125mg q 3d until maintenance dose of 250mg TID established on day 10.

3) PK: metabolites include phenobarbital (which is usually 2-3 times higher than that of primidone) and phenylethylmalonamide; metabolism is similar to PB but is rapidly and completely absorbed after oral administration with peak concentration in 4 hours 4) SE: see phenobarbital Pregabalin [PGB] (Lyrica) 1) Therapeutic uses – Adjunct for Partial seizures.

2) Dosing – Start 75mg BID or 50mg TID, increase to 300mg/d over one week 3) Metabolism – renal 4) Adverse effects – weight gain, edema, easy bruising, 5) Pregnancy category: C Felbamate [FB] (Felbatol) 1) Therapeutic use: partial and generalized seizure, reduces atonic seizures and improves global assessment scores in children with Lennox-Gastaut syndrome. Increases seizure threshold.

2) Dose – Adults ranges from 1800 to 4800mg/d. Children 15 to 45mg/kg. With monotherapy, larger doses have been tolerated.

3) Metabolism – half-life is 15 to 20 hours with linear pharmacokinetics, time to maximum concentration is 1-4 hours, protein binding is not significant.

4) Adverse Effects: Caution – Relatively frequent aplastic anemia, liver damage. Patient should sign consent. Check CBC, LFTs.

Headache Source: UpToDate, Nicolas lecture, Neurology 2000;55:754-763, Heal Your Headache; Continuum, Lecture notes & AAN Pocket guidelines 2005-2006, Medlink.com 10/06 (for IIH) 1) MIGRAINE a) IHS criteria for diagnosis i) At least 4 episodes, lasts 4-72 hours ii) 2 of 4: unilateral, throbbing, moderate to severe, worse with head movement iii) 1 of 3: N/V, Sensitivity to light/sound. b) Patients may have prodrome unique to individual: food craving, increased energy, fluid retention, yawning. Occasionally aura (scintillating scotomata) followed by the headache. c) Treatment. See below.

2) ACEPHALIC MIGRAINE a) Migraines without headache. b) Abnormal transient neurologic dysfunction. e.g. - visual symptoms such as "fortification scotomata" (vary in size, frequently bilateral). c) Treatment. indomethazine 3) CLUSTER HEADACHE a) Clinical features. Occur daily for several weeks, then stop for a long period of time. Often wake pt in AM or in the evening. may start in REM sleep. Can set clock by it. "Ice-pick", "Hot poker", sharp periorbital or retroorbital pain. The worst pain known! Peaks early (5-10 minutes ), shortlived (usu 30-45 min, up to 2 hours). May have ipsilateral Horner syndrome, tearing, rhinorrhea. b) Epidemiology. Usually male (M:F=10:1), often drinkers and smokers. Usually tall and thin. 65% hazel eye colour! Leonine facies. c) Prophylactic Treatment. One of the following: verapamil is drug of choice or prednisone taper (40 mg start) or lithium. d) Acute Abortive Treatment. Try one of the following: Oxygen 8-10 L/min, 4% lidocaine nosedrops, fast-acting ergotamine, sumatriptan.

4) TENSION HEADACHE a) Etiology. Due to chronic muscle contraction; may be maintained by vascular component. b) Clinical features. Chronic, bilateral, constant, daily, NON-THROBBING, feeling of a tight band around the head. c) Prophylactic Treatment. One of the following: Tricyclics, NSAIDs, Beta-blockers (maybe). d) Acute Abortive Treatment. Muscle relaxant (don't give habituating drugs to person with daily headaches).

5) COITAL HEADACHES a) Clinical features. Occur near/at orgasm. Benign. b) Treatment. indomethacin or propranolol.

6) POST-TRAUMATIC HEADACHE a) Usually of vascular origin; treat with same medications as migraine.

7) TEMPORAL ARTERITIS a) Clinical features. Patients >55 years old. History of recent onset of headache. Pain with chewing. Jaw gets tired with chewing. b) Exam. Temporal artery tenderness. DO NOT MISS THIS DIAGNOSIS! c) Labs. ESR, temporal artery biopsy.

8) 9)

d) Treatment. Corticosteroids.

THALAMIC PAIN a) Clinical features. Severe, debilitating, refractory pain (head or otherwise) following WEEKS to YEARS after thalamic infarct (often has total hemianesthesia).

PSEUDOTUMOR CEREBRI (better known as idiopathic intracranial hypertension) a) Epidemiology. Usually occurs in premenopausal, obese women. 90% of pts are obese. Age<44. More likely to occur with pregnancy. b) Drugs that can cause pseudotumor cerebri: glucocorticoids, tetracycline, vitamin A, lithium c) Etiology. Mnenomic - "Coatails": Calcium, Oral Contraceptives, Addison's disease, Tetracycline, Vitamin A toxicity, Idiopathic, Lung disease (chronic), Steroid withdrawal d) Differential diagnosis. analgesic rebound headaches, cerebral venous sinus thrombosis, depression, increased intracranial pressure, infection, malignancy, migraine, papilledema, tension-type headache e) Clinical features. Severe, daily, pulsatile headache (90%). Back/shoulder pain. Horizontal diplopia. Peripheral visual field loss (asymptomatic - severe irreversible visual loss occurs in 10%). Transient visual obscurations (75%) when changing position. Pulsatile tinnitus (specific). f) Exam. Abducens palsy (25%). Visual acuity. Visual fields. Fundoscopic exam -> Papilledema, elevation and blurring of disc margins, a peripapillary halo, venous congestion and tortuosity, retinal exudates, nerve fiber layer hemorrhages, and retinal infarcts (also known as “cotton wool spots”). g) Labs/imaging. CT or MRI brain w/wo+MRV, LP shows CSF pressure >250 mmH2O (normal 50-180) with normal fluid, serial visual field testing h) Treatment. Weight loss, low salt diet. Progress through the following: Acetazolamide (drug of choice), Furosemide, Prednisone for severe cases with impending visual loss, optic nerve sheath fenestration to prevent blindness, lumboperitoneal shunt for cases refractory to medications. i) Prognosis. Permenant loss of visual fields (25-30%). Loss of visual acuity (10%). Many have continued headache despite treatment

Treatment of severe headache in pregnancy: Stadol, fiorcet, metaclopromide + acetaminophen, tylenol with codeine, phenergan, Dilaudid suppositories (also oxycodone or morphine), Prednisone 20 mg PO QID x 2 days or methylprednisolone 4 mg PO 21 tablets over 6 days. Do not use NSAIDs in third trimester. Consider MRV/MRI to look for venous thrombosis.

Worriome Headache Red Flags Mnemonic – SNOOPS: Systemic symptoms (e.g., fever, weight loss), Neurologic symptoms or signs, Onset: sudden, abrupt, or split-second, Older: new onset or progressive headache in patient over 40 to 50yrs old (e.g. giant cell artertitis), Previous headache hx: first, different, or worsening headache at any age; Secondary risk factors (e.g., HIV, history of cancer) Differential diagnosis of thunderclap HA. SAH, sentinel headache (unruptured aneurysm), venous sinus thrombosis, cervical artery dissection, spontaneous intracranial hypotension, coital HA, pituitary apoplexy, retroclival hematoma, ischemic stroke, acute hypertensive crisis, colloid cyst in 3rd vent, CNS infection, idiopathic.

Migraine prophylaxis Drug Propranolol Nadolol

Useful with HTN, heart disease

Amitriptyline Nortriptyline

Depression, anxiety, insomnia

Verapamil Diltiazem

HTN

VLP

Seizures, bipolar disorder

Dec. HA frequency by 50%

125-250mg qhs or ER 500mg qhs -> 1000mg bid or level > 200mcg/ml

GBP

Neuropathic pain

2.7 HA/mo vs. 3.5 46% had 50% dec.

HA frequency

2400mg/d

Cyproheptadine (anti-histamine) TPM ($$$)

Allergies Obesity

Efficacy 60-80%

Dose (propranolol) 4080mg qd -> 160mg bid (nadolol) 20-40mg qd -> 80mg bid 10-25mg qhs -> 100-200mg qhs or level > 200250ng/ml 120mg qd-bid -> 240-360 bid

50% had 50% dec.

HA freq

2-4mg qhs -> 8mg tid 25mg qhs -> 100mg bid

SE Fatigue, insomnia, depression

Nortrypt has fewer SEs; Dry mouth, sedation, constipation, increased appetite Well-tolerated; possible constipation, leg edema, palpitations Increased appetite/weight gain, hair loss, nausea, tremor, sedation, liver toxicity

Sedation, increased appetite Paresthesias (50%), wt loss (10%), dizziness, confusion

Contraindications Asthma, low BP, low HR, DM, PVD, ED, sinus dysfcn, depression, insomnia, fatigue

Beta-blockers

Pregnancy

CoQ ($$$)

Riboflavin

47% had 50% dec HA at 3 mo. (based on 1 study) 54% had 50% dec.

HA at 2 mo. (based on 1 study)

100mg tid

400mg/d

Treatment of acute headache or status migranosus in ER Start IVF and try these, roughly in suggested order 1) IVF 2) Sumatriptan 6mg SC (Nonsedating, contraindicated with vascular disease) 3) Prochlorperazine 10mg IV + diphenhydramine 25mg IV (risk of EPS effects, hence the Benadryl, and sedation) a) Alternatively, with diphenhydramine to prevent EPS: i) Metoclopramide 10mg IV (risk of extrapyramidal side effects) ii) Promethazine 25-50mg IV (risk of EPS or sedation) iii) Ondanstron 4-8mg IV (nonsedating anti-nauseant) – doesn’t need diphenhydramine 4) Ketorolac (Toradol) 30mg IV or 60mg IM (nonsedating) 5) Dexamethasone 4-10mg IV (nonsedating) OR Medrol dose pack 6) Valproate 500-1000mg IV (nonsedating) 7) Magnesium 2gm IV (nonsedating) 8) Stadol 9) Droperidol 2.5-5.0mg IV Q30min x 3 doses (Risk of QT prolongation, EPS in 1/20 and sedation, needs cardiac monitoring) 10) DHE protocol (see below) 11) Narcotics (rarely should use because causes rebound and makes other acute therapies ineffective) Triptans 1) MOA: (5-HT1B/1D agonists) 2) Contraindications: Ischemic heart disease/angina, Coronary vasospasm (including Prinzmetal’s angina), Multiple risk factors for coronary artery disease, unless workup is fully negative, Hemiplegic or basilar migraine, Uncontrolled hypertension, Pregnancy category C, Concomitant use of MAO inhibitors (or use within 2 weeks); specifically rizatriptan, sumatriptan, and zolmitriptan, Use within 24 hours of an ergot 3) SE: Tingling, Warmth, Flushing, Chest discomfort, Sensations of pressure, Dizziness, somnolence. The SC form of sumatriptan has more Ses 4) Dosing: take at onset of headache, may repeat in 2 hours if necessary Suma 25-50mg PO, max 200mg daily Suma 5-20mg intranasal, max 40mg daily Suma 6mg SC, max 12mg daily *Ele 40-80mg – no major SEs Nara 2.5mg – no major SEs, slow acting *Riza 10mg (dec. dose if on propranolol) – SE: dizziness, fatigue, nausea Zolmi 2.5mg – SE: nausea, dizziness, fatigue, tingling *Best choice Preventing Rebound Prefer non-combination analgesics up to 2 days/week APAP (without caffeine) up to 1000mg q4h (max 4000mg/d) ASA (without caffeine) up to 1000mg q4h Ibuprofen 200-800mg q4-6h Naproxen 220-660mg q6-8h Use non-medication measures (lie down, eat something, relax, quiet room, sleep, ice/heat, massage, neck stretches, exercise) Other meds up to 2 days/month

DHE protocol 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13)

Place hep lock Order DHE-45 and metoclopramide (Reglan) to the floor stat.

Give 10mg metoclopramide IV followed immediately by 0.5mg DHE IV given over 2 minutes If nausea appears or headache disappears within 1 hour, order DHE 0.5mg IV Q8 + metoclopramide 10mg IV Q8 If no nausea and headache persists, give additional DHE 0.5mg IV with no metoclopramide 1 hour after first DHE dose, then order DHE 1mg IV Q8 + metoclopramide 10mg IV Q8. Keep to schedule of 6am – 2pm – 10pm.

After 5 doses given, d/c metoclopramide Prophylaxis begun after step 4 or 5 After pt is headache free, substitute DHE 1mg IM or SC Q8 for IV form Lomotil is usually necessary for diarrhea or codeine withdrawal; the average dose is 2-3 tablets Q6h prn.

Chlorpromazine 10mg IV q30 min, up to 3 doses (total 30mg) is useful for pain control or sleep. This sequence may be repeated up to 4 times in 24 hours.

Morphine 4mg IV once only may be ordered for the first 24 hours in the event that IV chlorpromazine fails.

Naproxen 500mg PO q6h prn may be used for headache control 48 hrs after all analgesics have been d/c’d.

At discharge, order 20 DHE ampules, 3ml syringes both #25 x 5/8 and #23 x 1” needles, prophylactic medications and naproxen for prn use.

ALTERED MENTAL STATES: Definitions 1. Coma = total or near-total unresponsiveness. Not arousable to any stimuli.

2. Stupor = state of severely impaired arousal. Some responsiveness to vigorous stimuli.

3. Obtundation = some responsiveness to touch or voice 4. Lethargy/Somnolence = state in which pt has diminished arousal but is able to maintain arousal spontaneously or with repeated light stimulation.

5. Acute Confusional State = inadequate arousal to perform a coherent thought or action (inattention, disorientation) 6. Delirium = state of confusion w/periods of agitation, irritability, hallucinations. Typically alternates with periods of decreased arousal.

Localization: Results from damage to components of reticular activating system (midbrain and rostral pons to thalamus to cerebral cortex) Etiology: 1) Common causes: medications, infection/sepsis, renal failure, hepatic encephalopathy, uremia, respiratory failure, acidosis, alkalosis, HTN encephalopathy/PRES, drug intoxication (EtOH, cocaine, sedatives, methanol, ethylene glycol), drug withdrawal, hypoxic-ischemic, nutritional deficiency (Wernicke’s, B12, niacin), sundowning, dehydration, ICU psychosis, hypotension 2) Neurologic causes: seizure, postictal state, ischemic stroke, head injury/trauma, concussion, nontraumatic ICH, SAH, SDH, epidural hematoma, CNS infection, brain tumor, demyelination (MS/ADEM), paraneoplastic syndrome, basilar migraine, transient global amnesia, abscess, right parietal lesion, tertiary syphilis, Lyme, leptomeningeal carcinomatosis, Creutzfeldt-Jakob disease, pituitary apoplexy, locked-in syndrome 3) Uncommon causes: Myxedema, thyrotoxicosis, Addison’s disease, Cushing’s disease, hypo/hyperparathyroidism, HIV, lupus cerebritis/vasculitis, TTP, catatonia, severe depression, psychogenic coma, porphyria, Reye syndrome, Wilson’s disease, hypothermia, occupational exposure (carbon monoxide, cyanide, organic solvents, heavy metals [Pb, Ar, Mg]), hypervisocisity syndrome (polycythemia vera, multiple myeloma, Waldenstrom’s) History: Time course? Medications? History of trauma? Headache, Hemiparesis, Ataxia, Vomiting? (suggests neuro cause) EtOH or recreational drug use? History of psych illness? History of seizure? Recent surgery? Occupational, environmental exposures?

Exam: Vitals, jaundice, spider angiomas, signs of anemia (pallor), signs of hypothyroid (dry skin, brittle hair, edema), needle tracks, hot dry skin (anticholinergic), asterixis, rashes, nuchal rigidity, Brudzinski’s sign, Battle’s sign, raccoon eyes, oto-/rhinorrhea, murmur (endocarditis), coma exam (see below), check language function since sometimes “mental status changes” is really aphasia Medications causing acute confusional states (partial list): acyclovir, amantadine, amphetamines, anticholinergics, anticonvulsants, antidepressants, antihistamines, antipsychotics, baclofen, benzodiazepines, cephalosporins such as cefepime (rare), chloroquine, clonidine, cocaine, corticosteroids, cyclosporine, digoxin, ergot, ethanol, ganciclovir, isoniazid, levodopa, lidocaine, methylphenidate, opiods, selegiline, thyroid hormones, lithium, TCAs Plan: 1) Minimize sedating medications (use low dose quetiapine if absolutely necessary) 2) Consider empiric naloxone, thiamine, CIWA protocol 3) Rule out or treat infection (fever, vitals/SIRS criteria, WBC, CXR, UA, blood cx) 4) Treat medical causes 5) Check Na, Ca, HCO3, Mg, glucose, BUN, anion gap, liver profile, CBC, ammonia, urine or serum tox, coags (if liver disease), ABG, TSH, B12, B1, RPR/FTA 6) Low threshold for EEG since many ICU patients are in nonconvulsive status epilepticus 7) LP if any signs of meningitis (fever, nuchal rigidity, immunocompromised) – send for HSV, VDRL. CSF glutamine is specific for hepatic encephalopathy (but not sensitive) 8) Head CT or MRI if there are focal findings or if concern for SAH 9) If above workup is negative, consider ESR, CRP, ACTH stim test, HIV, PTH, serum Cu, ceruloplasmin, imaging for cancer screening 10) Call poison control if concern for intoxication 11) AED levels if on AEDs COMA EXAMS: 1. Goal of exam is to distinguish coma caused by damage to brain tissue or from secondary mechanism affecting the brain (metabolic, toxic) 2. Purely unilateral cerebral lesions usually do not produce coma (must have increased pressure/shift of a single lesion to produce true coma) 3. Glasgow Coma Scale: used mostly in traumatic injuries a. Eye Opening: 4=spontaneous, 3=to speech, 2=to pain, 1=none b. Verbal: 5=oriented, 4=confused, 3=inappropriate, 2=unintelligible, 1=none c. Motor: 6=obeys commands, 5=localizes to pain, 4=withdraws to pain, 3=flexion to pain/decorticate, 2=extensor response to pain/decerebrate, 1=none d. Score less than 8 is indicative of comatose state

4. Coma Exam: a. All components of exam may be impaired by hypothermia, drug intoxication, sedative medications, making exam unreliable b. Level of consciousness: describe what level of stimulation pt responds to if any. c. Nuchal rigidity d. Pupillary exam (CN II): describe size, reactivity, shape, and symmetry e. Fundoscopic exam: look for papilledema (increased ICP), retinal hemorrhage (HTN), subhyaloid blood (massive SAH), retinal infarcts (stroke, vasculitis) f. Gaze deviation: •tonic horizontal deviation towards side of lesion/away from weakness=stroke or other cerebral hemispheric damage •tonic horizontal deviation away from side of lesion/towards weakness=seizure or brainstem process (“wrong way eyes”) g. Roving eye movements: may be conjugate or dysconjugate. Good prognostic sign in post-anoxic injury. h. Ocular bobbing: fast downward or upward movement w/slow return to mid-position (pontine lesions or metabolic coma) i. Corneal reflex (CN V, VII) j. Vestibulo-ocular reflex (CN III, VI, VIII) •do not perform in pts w/neck injury or unstable C-spine •absence of reflex indicates destruction of brainstem or severe metabolic depression •Calorics: elevate head to 30 degrees. Inject 50-100ml or more of ice water into auditory canal until nystagmus or tonic deviation of eyes occurs. In comatose state eyes deviate towards side of cold stimulation, no nystagmus/fast phase seen. In awake pt see both slow and fast phases. In brain death have no movement of eyes at all. COWS refers to direction of fast phase. k. Motor exam: Observe for spontaneous movement or subtle movements that may indicate nonconvulsive sz. Evaluate tone and response to noxious stimuli.

•Decorticate posturing: Indicates damage to mesencephalic region with lesion above the red nucleus, facilitation of rubrospinal tract, disinhibition of vestibulospinal tract.

•Decerebrate posturing: Indicates damage below level of red nucleus, facilitation of vestibulospinal tract l. DTRs and plantar responses BRAIN DEATH EXAM: 1. Prerequisites must be met prior to examination: a. Rule out presence of medical condition that may confound assessment (electrolyte disturbance, acid-base, endocrine) b. Absence of severe hypothermia (body temp must be >32 degrees C) c. SBP must be equal to or > 90mmHg d. Absence of drugs that may interfere with examination e. Interpretation of neuroimaging to assess for cause of brain death f. Performance of any confirmatory lab tests deemed necessary to evaluate pt g. Often need period of observation (6-24hrs) if possibility of drug-induced or hypothermic depression of CNS may be contributing factor, or if cardiac arrest is cause of brain death.

2. Requirements: a. Coma of known cause b. Absence of motor responses c. Absence of pupillary responses, pupils mid-position and 4-6mm. d. Absence of corneal reflex e. Absence of caloric response f. Absence of gag reflex g. Absence of coughing in response to tracheal suctioning h. Apnea Test: Absence of respiratory drive at a PaCO2 that is at least 60mmHg or 20mmHg above baseline values.

•Must pre-oxygenate w/100% O2, remove ventilator and watch for respiratory effort.

•Check ABG after approximately 8 minutes and reconnect ventilator.

•If SBP reaches <90, O2 sats drop markedly, and/or cardiac arrhythmias occur immediately draw ABG and connect ventilator. Test is + if above conditions met.

3. Neurologic states that can mimic brain death: Locked-in syndrome, Guillian-Barre syndrome, hypothermia, sedative/anesthetic agents, drug intoxication 4. Confirmatory Tests: Can use EEG, transcranial dopplers, nuclear imaging for metabolic function assessment (not often used in our experience).

HYPOXIC-ISCHEMIC ENCEPHALOPATHY: 1. The longer the duration of the coma, the less likely a patient will awaken and the higher likelihood of having neurologic deficits.

Studies show vast majority (90-92%) of pts that will awaken do so within first 3 days.

2. Prediction criteria based on findings of Levy et al (NEJM, 1985): 210 pts with serial neuro exams after cardiac arrest. a. Total of 13% regained independence within 1st year after arrest. b. 52 pts had absent pupillary reflex on initial exam, and none of these regained independent function after 1 yr. c. Presence of pupillary reflex, motor response of extention, flexion, or withdrawl, and development of spontaneous eye movements that were roving/conjugate or better predicted recovery of independent function in 41-63% of pt with these exam findings. These exam findings held their predictive value up to day 14 after arrest.

3. Overall literature review has found that absent pupillary response, absent corneal reflexes, extensor or absent motor response to pain at 72hrs, and myoclonic status epilepticus were all strongly predictive of death or poor neurological outcome following cardiac arrest (motor response has been shown to be most reliable). However, use of clinical exam alone for prognosis is compromised by frequent presence of reversible states that affect consciousness.

4. EEG: Generalized epis, status, and burst suppression predict poor outcomes but with insufficient prognostic accuracy.

5. SSEP: Bilateral absent cortical responses at 72hrs predicted poor outcome.

6. Serum neuron-specific enolase (NSE): Levels >33 mcg/L on days 1-3 indicate poor prognosis.

7. Imaging may show loss of gray-white differentiation, diffuse cortical necrosis, changes in hippocampus, basal ganglia, hypothalamus, thalamus, watershed infarcts 8. Prognosis in anoxic injury + myoclonic status: Hui et al. (Eur Neurol. 2005;54(1):10-15) performed a meta analysis of 134 cases in which 89% died, 8% PVS, 1% severe disability, 2% good outcome. In this study by itself, there were 18 cases. 16 of these died, of which all but 2 died within 8 days.

Hypothermia Protocol: 1. Advisory statement of International Liaison Committee on Resuscitation: Unconscious adult pts w/spontaneous circulation after out-of-hospital arrest should be cooled to 32 to 34 degrees C for 12 to 24 hrs when initial rhythm was V fib.

2. Evidence. Multiple trials done on comatose patients following out-of-hospital cardiac arrest show improved functional outcome in patients with induced mild hypothermia (to 32 degrees C). a. What is done. Patients received active cooling with external measures (blankets/ice packs) as soon as possible after arrest (up to 4-6 hrs post-arrest). Cooling continued for up to 24 hrs with passive rewarming. b. Efficacy: One trial showed favorable neurological outcome (able to live independently and work part-time) in 55% of pts tx w/hypothermia vs 39% of those not tx (RR1.4, NNT=6). Other trials with good outcome in 49% of pts tx vs 26% of those not tx (RR1.85, NNT=4) 3. Mechanism. Proposed that hypothermia reduces cerebral metabolic rate for oxygen and suppresses many chemical reactions associated w/reperfusion injury (free radical production, electrolyte shifts, amino acid release) 4. Potential risks include arrhythmias, infection, coagulopathy 5. Contraindications. Not recommended for use in pregnancy, children, pts with severe cardiogenic shock or life-threatening arrhythmias, pts with primary coagulopathy. Thrombolytic therapy does not preclude use of hypothermia.

6. Initiate cooling ASAP but restore normothermia slowly/passively as rebound hyerthermia can occur.

7. University Hospital Hypothermic Protocol: a. Inclusion criteria: •Age 18 or older •If women are 50 years of age or less must have negative pregnancy test •Cardiac arrest with return of normal sinus rhythm. Preferred initial rhythm of Vfib or pulseless Vtach. Can be considered for PEA, asystole as well.

•Persistent coma following arrest as evidenced by no eye opening to pain after resuscitation (no waiting period required) •SBP of at least 90mmHg (spontaneously or with fluid/pressor support) •No limit on duration of resuscitation effort, but “down time” of less than 1 hour desirable. b. Exclusion Criteria: •Pregnancy •Presence of another condition that may be cause of comatose state (drug overdose, head injury, storke, status epilepticus) •Known terminal illness preceeding arrest (as per primary treating physician determination) •Pre-existing DNI status (if pt not intubated during resuscitation efforts) •Refractory cardiogennic/non-cardiogenic shock despite fluids/pressors c. Protocol Specifics/Orders: (goal temperature 33O C as to be achieved as soon as possible): •Patients should be enrolled as quickly as possible. For out-of-hospital arrests, ED attending will make decision to implement protocol. For in-hospital arrests, CCU resident in charge of completed code will make decision.

•Page Neurology at 0904 or Dr. Daniel Woo at 249-3112 for immediate initial neurologic assessment prior to pharmacologic paralysis. Do not delay initiation of hypothermia pending this assessment.

•Immediately place ice packs under the armpits, next to the neck, on the torso and the limbs.

•Temperature sensing Foley catheter should be placed if available, otherwise rectal or tympanic temperatures should be used (in that order).

•Two cooling blankets should be used, one under and one over the patient.

•Page the ICU Resident to manage the ventilator and sedation.

•The ventilator humidifier should be turned off and a Heat Moisture Exchanger (HME) should be used.

•The room thermostat should be turned off if set to heat.

•Administer midazolam 2-6 mg/hour and fentanyl 25-75 mcg/hour •Once sedation is started, give vecuronium 0.1 mg/kg bolus, then start a drip of 1 mg/hour. Titrate the drip 0-5 mg/hr to keep 1/4 twitches.

•Patients should be on insulin drip if glucose > 180 mg/dl, daily aspirin, on pressors and or nitrates to maintain blood pressure, and any anti-arrythmics necessary.

•Patients may receive other cardiac interventions including systemic thrombolysis, anticoagulation, and urgent cardiac cath interventions as needed. Hypothermia should proceed concurrent with these interventions.

•Once the patient reaches 33O C (bladder, rectal, or tympanic), keep patient at 33O C by removing ice packs and top cooling blanket if necessary.

•Begin passive rewarming 24 hours after the beginning of cooling (not 24 hours after target temperature is reached):

-Turn room thermostat up to normal.

-Turn on heater on ventilator.

-Turn off cooling blanket.

-May use regular blankets.

-Do not use warm air blanket unless temp not 36O C after twelve hours of passive rewarming.

•Paralysis, then sedation, may be discontinued during or after rewarming, based on shivering and other critical care issues.

NEJM 2002;346(8):557 Randomized, unblinded trial of 77 patients with out-of-hospital witnessed VF or VT cardiac arrest (head trauma, stroke patients excluded) in which patients had core body temperature reduced to 33 C within 2 hours of restored circulation and maintained for 12 hours Discharge to home or rehab Mortality @ 30d.

Hypothermia 49% (21/43) p=0.046 51% p=0.145 Normothermia 26% (9/34) OR=5.25 68%

Meningitis Sources: Kleindorfer lecture, Neel lecture,Lange’s Clinical Neurology Symptoms: Fever > 38 or hypothermic, Nuchal rigidity, Altered mental status (22% respond only to pain), Photophobia, Headache (50%), Rash, Symptoms present < 24h, 33% do not have all three (fever, AMS and nuchal rigidity), Acute is < 4 weeks Exam Kernig’s sign: supine patient, hip flexed 90 degree -> extend knee -> positive if resistance at =< 135 degree or pain in lower back/thigh Brudzinski’s sign: supine patient -> passive neck flexion -> positive if knee or hip flexes Look for infection (ears, sinuses, lung) Otorrhea/rhinorrhea -> halo testing Labs LP (see “CSF” section for tests to order) Etiology: Bacterial Organism Age < 60 N. meningitidis 20%

Age > 60

Risk factors

Other

3-4%

childhood-mid 20s

pneumococcal bacteremia, cribriform plate fracture, complement deficiency, hypogammaglobulinemia, splenectomy, diabetes, sickle cell, alcoholism, thalassemia, skull fractures, CSF rhinorrhea defects in cell mediated immunity; Immunosuppressed, elderly and young

High mortality 5-10% Waterhouse-Friderichsen syndrome a massive, usually bilateral, hemorrhage into the adrenal glands Culture + in 80% Meningococcal rash Chemoprophylaxis Precedent illnesses: pneumonia,acute otitis media,sinusitis

S. pneumoniae

60%

70%

L. monocytogenes

6%

20%

S. epidermidis S. aureus

surgery/foreign body endocarditis, surgery/foreign body

Group B strep GNR

4%

H. influenzae

10%

Legionella Mycoplasma

Site of entry: GI tract (cheese, ice cream, lunch meats) Rhombencephalitis VIIth and VIIIth palsies High mortality

3-4%

3-4%

advanced medical illness, neurosurgery diminished humoral immunity (Old age, Young age, splenectomy, acquired immunodeficiency) Acute febrile illness, often epidemic Pneumonia, encephalopathy, HA, confusion Mycoplasma Implicated in meningitis (sometimes aseptic), guillain-barre, transverse myelitis CSF findings highly variable, from purulent to aseptic to GBS like

Etiology: Viral 1) Enteroviruses (80%, summer) a) Coxsackie virus A and B i) Coxsackie viruses have prodrome of mild-mod fever, HA, abdominal pain ii) CSF with 25-250 cells, 10-50% PMN iii) Coxsackie Virus A: myositis and flaccid paralysis, herpangina (hand-foot-mouth), aseptic meningitis iv) Coxsackie virus B: encephalitis, myocarditis, aseptic meningitis, pancreatitis, pleurodynia b) Echovirus i) Symptoms: gastroenteritis, macular exanthems, URI, cerebellar ataxia ii) CSF usually 100% lymph within 48 hours c) Enterovirus 68 to 71 2) Poliomyelitis 3) Mumps virus (in 50-60% of patients with mumps) 4) HSV 2 5) CMV, EBV, VZV, HHV 6 Complications Seizures (15-30%) Focal deficits (20-33%) Hearing loss (late) Increased ICP (altered mental status and 6th nerve palsy) Subdural effusions (in kids) Arteritis, septic venous thrombophlebitis, or cerebritis -> focal deficits CSF findings in Meningitis Meningitis

Pressure (mm H20)

WBC

Protein

Glucose

Acute bacterial

Usually elevated

Usually 100-500, 5-40 in most Sev. Hundredcases >60,000, usually occ > 1000 a few thousand, PMNS

Tuberculous

Usually elevate, 25-100, rarely >500, lymphs but can be low with spinal block (except early)

Usually 100-200, Usually low, < 45 in 75% can be higher with block

Cryptococcal

Usually elevated

0-800, avg 50, lymphs

20-500, usually 100

Viral

Normal to mod elevated

5-few hundred, nl or sl elevated, nl (except may be up to <100 mumps, HSV or 1000, lymphs CMV, which is except within 48h low in 25%)

Acute syphillis

Usually elevated

Avg 500, usu.

Lymphs

Cystercircosis

Reduced, avg 30

Avg 100

Nl

Often inc. but can Increased, with be low with block eos in 50%

50-200

Reduced in 20%

Sarcoid

Normal to considerably low

0-100, mononuclear

Sl to mod elevation

Reduced in 50%

Carcinomatosis

Nl to incr

Elevated, often 0-sev hundred, very high mono + malignant Minor pleocytosis Usually nl (20%)

Legionella Mycoplasma

Nl to low in 75%

Highly variable

From UpToDate in Kleindorfer lecture 8/06 Glucose < 10 mg/dl Bacterial, TB or fungal meningitis Glucose 10-45 Bacterial, syphilitic, or some viral (mumps) meningitis Protein > 500 mg/dl Bacterial or TB meningitis Protein 50-500 Viral, Layme or syphilitic meningitis WBC > 1000/mcl Bacterial or sometimes mumps WBC 100-1000 Bacterial or viral meningitis, or encephalitis (e.g. West Nile) WBC 5-100 Early bacterial, viral, syphilitic, TB meningitis or encephalitis (e.g. HSV) PMNs > 50% Bacterial meningitis PMNs < 10% Viral meningitis

From Kleindorfer lecture 1,232 cases in Chicago study of acute purulent meningitis Test Sens for bacterial meningitis WBC > 100 91% PMN < 50% 90% Abnl Glu 76% Abnl prot 86% Treatment Start IV antibiotics/dexamethasone immediately (i.e. before LP) Source: Lange Clinical Neurology, UpToDate in Kleindorfer lecture 8/06 Situation Antibiotics Empiric Rx for age 3 mo-50 yr CEF [+ VANC*] Empiric Rx for age > 50 yr or < 3 mo CEF + AMP [+ VANC*] AMP + TAZ [+ VANC*] Impaired cellular immunity (HIV, Malignancy, Chemotherapy, Chronic steroids and immunosuppression) Head trauma, neurosurgery, CSF shunt, nosocomial VANC + TAZ Gram-positive cocci If dexamethasone: RIF + CEF If neonate: VANC + TAX Otherwise: VANC + TRI Gram negative cocci/N meningitides PCN x 7 days Gram positive rods [AMP or PCN] + GENT Gram negative rods If neonate: TAX + GENT Otherwise: [TRI or TAZ] + GENT S pneumoniae VANC + CEF x 10-14 d H influenzae TRI x 7 d L monocytogenes AMP + GENT x 14-21 d S agalactiae PCN x 14-21 d Enterobacteriaceae CEF + GENT x 21 d P aeruginosa, acinetobacter TAZ + GENT x 21 d Consider meropenem * Add vancomycin if there is high prevelance of cephalosporin resistant pneumococcus in the community.

AMP = ampicillin 4gm IV Q4 (adult) OR 100 mg/kg IV Q8 (children) TRI = ceftriaxone 2gm IV Q12 (adult) OR 50-100mg/kg IV Q12 (children) TAX = cefotaxime 2gm IV Q6 (adult) OR 50mg/kg IV Q6 (children) CEF = TRI or TAX VANC = vancomycin 15mg/kg IV Q6 (max 4gm/d) TAZ = ceftazidime 50-100mg/kg IV Q8 (max 2gm Q8) PCN = penicillin G 300,000 units/kg/d IV (max 24,000,000 units/d) RIF = rifampin 600mg/d GENT = gentamicin 1.5mg/kg IV load -> 1-2mg/kg IV Q8 Consider acyclovir 12 mg/kg IV q 8 hours Dexamethasone IV 0.15 mg/kg or 10mg Q6 x 4 days (NEJM 347(20):1549-1556) -Measure GCS (see “Altered Mental status” section) -Given 15 minutes before or at the time of antibiotics in suspected bacterial meningitis with GCS 8-11 -Discontinue if Gram stain/culture does not show pneumococcus RTC in adults of intravenous dexamethasone vs. placebo At 8 weeks significant reductions in mortality (14% vs. 34%) and the combined end point of death or neurologic disability (26% vs.

52%) seen only in patients with S. pneumoniae meningitis only in those with an intermediate neurologic deficit on admission

Chronic meningitis Sources: Neel lecture ‘06, Continuum 12(2) April 2006 Etiology: Chronic meningitis 1) Infectious a) MYCOBACTERIAL: Mycobacterium tuberculosis b) FUNGAL: Coccidiodes immitis (CSF eos), Cryptococcus neoformans (50% of fungal meningitis), Histoplasma capsulatum, Blastomyces dermatitidis, Candida, Apergillus c) PARASITES: Amoebas (Acanthamoeba, Naeglaria), Taenia d) ATYPICAL BACTERIA AND SPIROCHETES: Brucella, Leptospira, Nocardia, Actinomyces, Borrelia burgdorferi , Treponema Pallidum e) RICKETTSIA: Ehrlichia chaffeensis, Coxiella burnetti 2) Non-infectious: Chronic subarachnoid, Sarcoid, Leptomeningeal metastasis, neoplastic (Breast, lung, leukemia, melanoma), Chemical meningitis, IVIG, craniotomy, Dermoid cyst, Vasculitis, Giant cell arteritis, Wegener’s, Amphetamines and cocaine abuse, Connective Tissue diseases, Lupus, Rheumatoid 3) No etiology in 15-25%

Common causes 1) TB (PPD sn 50%, high-volume CSF culture & PCR x 3 sn 50-80%, otherwise 20-40% on routine LP, CXR->Ghon complexes, h/o active TB) 2) Crytococcus neoformans (cryptococcal Ag, fungal cx sn 75%) 3) Coccidiodes immitis (CSF > 10% eos, fungal cx sn 50%) 4) Histoplasma (CSF fungal cx sn 50%, high serum histoplasma Ab titer) 5) Neurosyphilis (CSF-VDRL, FTA Ab, RPR) 6) Lyme disease (CSF anti-B. burgdorferi Ab) 7) HIV (low-grade lymph pleocytosis, normal-slightly high protein, normal imaging, serum HIV-PCR) 8) VZV (immunosuppresed, MRI-multiple focal area white matter demyelination/infarctions, CSF VZV-PCR) 9) Enteroviruses (rarely chronic, hypogammaglobulinemia, CSF enterovirus PCR) 10) Rickettsia (travel/residence in endemic area, serum indirect immunoflourescent Ab test showing high titer or 4-fold increase) 11) Cysticercosis (residence/travel Latin America, MRI-parenchymal/meningeal cysts, CSF & serum cysticercosis Ab) 12) Neurosarcoidosis History in chronic meningitis Travel 1) Southwest US = coccidiodes 2) Midwest = Histoplasma, Blastomyces, Ehrlichia 3) Northeast, Northwest = Borrelia, Babesia 4) Mexico, Latin America = Taenia, Tyrpanosoma cruzii Animal exposure 1) Goats, unpasteurized milk = Brucella, Listeria 2) Cats = Bartonella 3) Rabbits = Francisella TB meningitis Symptoms: Low Temp, HA, then slow development of focal neurologic deficits (CN, seizures) Risk factors: previous pulmonary infection, AIDS and immunosuppression Diagnosis Tuberculin positive in only 50% CXR seldom shows active pulm infection CSF PCR - Specificity 56%, sensitivity 98% (!!)

CSF Mycobacterial culture needs large volume (20-40 ml), high speed centrifuge for â&#x20AC;&#x153;CSF pelletâ&#x20AC;?, 3 successive taps, like for cytology Cryptococcal meningitis 50% of all fungal meningitis Risk factors: Immunocompromised>immunocompetent Symptoms: Meningeal signs are less common, cognitive, fever, HA, chronic and insidious Diagnosis: CSF culture, India ink or Crypto antigen Treatment Daily LPs for <25 cm H2O Amphotericin x 10 weeks, then oral fluconazole Exam Look for extrapulmonary fungal infection (bone, bone marrow, skin, joints, sinuses, liver, GU system) Labs If CSF PMNs & fungal infection, likely Blastomyces, Aspergillus, Zygomycetes (Cx sn < 5%) Fungal PCR not sn or sp Candidemia doesn't imply Candidal meningitis Antibody tests may be (-) if immunocompromised Treatment of chronic meningitis Difficult isolation of organism: Requires multiple taps, cultures, meningeal biopsy Antituberculous drugs and anti-fungal drugs ID consult Repeated lumbar punctures and ventricular drains/lumbar drains for increased protein and hydrocephalus

CSF Source: Kleindorfer lecture Indications for head CT before tap: Focal neurological deficit, New onset seizure, Papilledema, Abnormal consciousness, Immunocompromised Total CSF volume = 140ml Formation/absorption = 0.35ml/min, or 500ml/day Rate of absorption is directly proportional to pressure difference between CSF and dural venous sinuses.

Tests to order Processing CSF fluid:

Tube 1: Cell count, diff, gram stain, culture (bacterial, fungal, TB, viral) Tube 2: Glucose, protein, protein electrophoresis (need concurrent serum study) Tube 3: Save the fluid until further notice Tube 4: Cell count and diff Consider additional tests tube 4 a. Bacterial cultures b. N meningitides, H influenza, S pneumoniae antigens c. Cryptococcal antigens in immunocompromised pts d. Oligoclonal banding, IgG index and assay for myelin basic protein are useful to dx MS e. VDRL for syphilis f. AFB stain, TB culture, and PCR for TB (needs >20ml) g. India ink for cryptococcus h. Lyme titer i. Fungal or viral cultures j. Cytology (at least 20ml) k. HSV PCR l. MS serology m. lactic acid/pyruvate (mitochondrial disorders), n. rapid antigen testing for beta-Streptococcus, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae Send serum simultaneously (for glucose and IgG if testing IgG index)!

CSF appearance Should be clear, colorless, non-viscous Cloudy =200 WBC or 400 RBC Greenish = purulent Viscous: fungal, epidural fat, mucin Clots and/or pellicles = Froin’s syndrome c block -> protein >1.5g Bilirubin: yellow (xanthochromia) Oxyhemoglobin: pink or orange Methemoglobin: brown or dark yellow Rule of halves ½ hour: for RBC to appear after SAH ½ day for xanthochromia to appear ½ week for RBC to disappear ½ month for xanthochromia to disappear DDx of xanthochromia: SAH, Systemic jaundice (serum bilirubin 10-15 mg/dL), High protein, Betacaroteinemia, Rifampin, Malignant melanomatosis Cell counts + diff Normal WBC <= 5 cells/mm3 1 WBC for every 700 RBCs (assuming nl CBC) If leukocytosis or anemia: Corrected WBC = WBCF - (WBCB x RBCF / RBCB) WBC should be lymphocytic Can include small round cells (most common), B and T cells, monocytes, macrophages Should NOT include: plasma cells, multinucleated giant cells DDx of Eosinophils in CSF: Parasitic infections, TB meningitis, Neurosyphillis, SSPE, Granulomatous meningitis, Viral meningitis, Fungal, Idiopathic eosinophillic meningitis, Malignant lymphoma/Hodgkin’s disease/leukemia, Multiple sclerosis, Penicillin therapy, ICH/SAH, Myelography CSF Protein Normal 23-38 (depend on lab + age of patient) Gradient of protein: ventricle<cisterna magna<lumbar Correction: 1 mg/100ml of protein for every 1,000 RBC (only if done on same tube) DDx of high CSF protein: Myxedema (25% of myxedema), AIDP/CIDP, Diabetic polyneuropathy, Neurofibroma in cerebral or spinal subarachnoid space, Resolving SAH, Meningitis and meningoencephalitis, CNS vasculitis, Gliomatosis Cerebri, Radiculopathy Mild elevations common and non-specific: (Vasogenic brain edema, Breakdown of blood-brain barrier) Very high protein (>500) uncommon: (Meningitis, Spinal block, Froin’s syndrome, tumor, carcinomatous or infections meningitis, epidural abcess, large midline disc protrusions, Arachnoiditis with SAH) DDx of low CSF protein: Young children 6mo-9yrs, Large volumes removed (Replaced by cisterna magna fluid), CSF leaks Benign intracranial hypertension (1/3rd), Acute water intoxication, Hyperthyroidism, NOT often with serum hypoproteinemia unless <4.0gm/dL IgG Index = (IgGCSF / IgGserum) / (AlbCSF /Albserum) Easily thrown off by bloody taps DDx of High IgG index: MS, Neurosyphyllis, Viral menigoencephalitides, TB meningitis, Sarcoid, Cystercercosis, Carcinomatosis, Paraneoplastic, SSPE, Bloody tap Oligoclonal Bands One band is common in normal CSF, but rarely is it unique to CSF (serum sample run simultaneously) 83-94% sensitive for MS 100% sensitive for SSPE 25-50% of other inflammatory disease: Infections, carcinomatosis, GBM, AIDP, SLE, Behcets, sarcoid, ataxia telangectasia, adrenoleukodystrophy, cystercercosis CSF Glucose Normal 45-80 (if serum glucose normal) < 40 is abnormal Normal CSF:Blood ratio 0.6 (but longstanding diabetics can be as low as 0.3) Takes 2 hours to equilibrate with blood (look at recent insulin usage) Glucose may stay low for up to 10d after infection is properly treated

DDx of Low CSF glucose: Acute purulent meningitis (can be <5), TB/fungal (usually 20-40), Sarcoid, Carcinomatous meningitis, Chemical meningitis (usually 30-40), SAH, Hypoglycemia, Rheumatoid meningitis, Lupus myelopathy, Usually NOT with viral meningitis - Exceptions: mumps (25%), HSV and zoster (occasional) DDx of normal glucose with purulent CSF: Consider FOCAL septic process: Brain abcess, Epidural or subdural abcess, Venous sinus thrombophlebitis Opening pressure Normal = 5-15 mm Hg or 65-195 cm H2O (10-100 cm H2O in children) Unreliable in sitting position, straighten legs is possible Level of right atrium is zero DDx high opening pressure: Elevated CVP, Meningitis/encephalitis, Pulmonary insufficiency, Mechanical ventilation, Postanoxic encephalopathy, Hepatic encephalopathy/Reyeâ&#x20AC;&#x2122;s syndrome, Lead encephalopathy, Water intoxication/hyponatremia, Dural venous sinus occlusion, Spinal cord tumors, AIDP, Pseudotumor cerebri

Multiple Sclerosis Sources: see below, Practical Neurology, Rob Neelâ&#x20AC;&#x2122;s lecture 2006 Diagnosis Define phase of illness: relapsing remitting, secondary progressive, primary progressive Barkhof Criteria for dissemination in space by MRI MacDonald et al. Ann Neurol 2001; 50(1): 121-7.

Barkhof et al. Brain 1997 Nov;120 ( Pt 11):2059-69 Tintore et al. AJNR Am J Neuroradiol. 2000 Apr;21(4):702-6 Need 3 of 4 1) One gadolinium-enhancing lesion OR nine or more T2-hyperintense lesions 2) At least one infratentorial lesion 3) At least one juxtacortical lesion 4) At least three periventricular lesions Sens and spec From Tintore # criteria 1 2 3 4

of Barkhof criteria for predicting MS sn 91% 82% 73% 45%

sp 50% 62% 73% 82%

acc 62% 68% 73% 72%

MacDonald criteria for diagnosing MS Situation # Dissemination in time 1 2+ attacks 2 2+ attacks 3 4

1 attack + dissemination in time by MRI 1 attack + dissemination in time by MRI

5

Insidious neurological progression suggestive of MS > 1 year or dissemination in time by MRI

PPV

NPV

55%

85%

Dissemination in space Objective clinical evidence of 2 lesions Objective clinical evidence of 1 lesion + Barkhof criteria or (2+ MRI lesions + positive CSF) Objective clinical evidence of 2 lesions Objective clinical evidence of 1 lesion + Barkhof criteria or (2+ MRI lesions + positive CSF) Positive CSF + Dissemination in space ([9+ T2 lesions in brain OR 2+ spinal cord lesions OR 4-8 brain lesions + 1 cord lesion] OR [abnormal VEP + (4-8 brain lesions OR <4 brain lesions + 1 cord lesion)]

MRI criteria for dissemination in time: 1) new GdE lesion >= 3 mo after onset of attack OR 2) new T2 lesion >= 6 mo after onset Positive CSF = 5+ unique oligoclonal bands or high IgG index Abnormal Visual evoked potentials = delayed but well-preserved wave form An attack must last at least 24 hours Separation in time = at least 30 days from onset to onset Visual evoked potentials -> delayed but well-preserved wave form CSF -> lymphocytic pleocytosis <= 50/mm3, high IgG index, 5+ oligoclonal bands not present in serum Optic Neuritis Treatment Optic Neuritis Treatment Trial (N Engl J Med. 1992 Feb 27;326(9):581-8)

RCT with 457 patients Methylprednisolone 1gm IV qday x 3 days, then prednisone 1mg/kg x 11 days caused faster recovery of visual loss and slightly better visual fields and color vision (but not acuity) at 6 months compared to placebo. Oral prednisone alone increased risk of recurrence.

Prognosis 10-year risk of MS Optic neuritis -> 38% Optic neuritis and 1+ typical MRI lesion -> 55% Optic neuritis and no MRI lesions -> 22% Atypical features, including no light perception or absence of pain, were protective When to admit MS patient 1) New onset urinary incontinence 2) Optic neuritis 3) Inability to walk (treat with steroids, rehab) When not to admit MS patient 1) No objective neurologic finding (i.e. more than pain) 2) Symptoms due to infection or anamnestic response 3) Patient can be treated at home with IV steroids Treatment 1) For exacerbations a) IV steroids i) Indication for IV steroids: definite change in function affecting vision, motor or cerebellar systems, not recrudescence of old symptoms due to infection ii) Methylprednisolone 1000mg IV Qday x 5 days, followed by prednisone 60mg qday x 3 days, then decreased by 10mg/day Q3days iii) Improves rate of recovery but not final outcome iv) SEs: mental changes, unmasking of infections, gastric disturbances, anaphylactoid reactions, arrhythmias v) Contraindicated by pregnancy b) Plasma exchange (if steroids fail) 2) Disease modifying treatments a) Glatiramer acetate (Copaxone) i) Dose: 20mg SC Qday ii) Most effective for patients with minimal disability iii) Efficacy: Lowers 2-year relapse rate 1.19 vs 1.68; reduced disability (decrease 1.5 EDSS) in 140 weeks, 22% vs 41%; reduces new T2 lesions ( Neurology 1995 Jul;45(7):1268-76.; Neurology 1998 Mar;50(3):701-8.; Ann Neurol 2001 Mar;49(3):290-7.) iv) Fewest side effects (local injection reactions, chest pain, flushing, dyspnea, palpitations, anxiety) v) Pregnancy B vi) No lab monitoring vii) MoA: mixture of random polymers of four amino acids, which is antigenically similar to myelin basic protein; glatiramer is thought to suppress T-lymphocytes specific for a myelin antigen b) Interferon (Avonex, Rebif) i) IFN-beta-1a = Avonex, Rebif; IFN-beta-1b = Betaseron ii) Avonex dosing: 30mcg IM qweek iii) Rebif dosing: 8.8mcg sc 3x/wk x 8 week -> 22mcg x 8 week -> 44mcg x 8 week iv) Betaseron dosing: 0.0625mg SC QOD -> inc by 0.0625mg qweek -> goal 0.25mg QOD v) Efficacy (1) Betaseron: Reduces freq of relapses 0.84/year vs 1.27/year; reduced disease progression at 5-yr 35% vs 46%; 5yr MRI burden remained the same whereas it increased 30% for placebo (Neurology 1993 Apr;43(4):655-61.; Neurology 1995 Jul;45(7):1277-85.)

(2) Avonex: Reduces freq of relapses 0.61 vs 0.9/yr; a decrease in MRI lesion volume (mean 74 versus 122), and less disability of decreasing 1 point on EDSS (22% versus 35%). (Ann Neurol 1996 Mar;39(3):285-94.)

(3) Rebif: Reduction in relapse rate over 2 years 27% vs 33%; reduced MRI burden 3.8% vs 10.9% (Lancet 1998 Nov 7;352(9139):1498-504.) vi) Instructions: Take APAP or ibuprofen prn before each dose to reduce flu-like symptoms; if missed a dose, take it ASAP, but not within 48 hours of another dose, report depression or SI, report black and blue at injection site vii) Caution in psychiatric illness because can cause severe psychosis or depression viii) Side effects: flulike symptoms, fever, myalgia (reduced by premedication with ibuprofen); injection site reactions, mild lymphopenia, hepatotoxic/elevated LFTs (rarely requires discontinuation) ix) Pregnancy C x) Interactions Rebif/Avonex: ACEI (monitor CBC), hepatoxic drugs, warfarin (increased effect), zidovudine (increased levels) xi) Interactions Betaseron: theophylline (increases levels) xii) Monitor CBC/LFTs at 1, 3, and 6 mo, then periodically -> if high LFTs or low WBC, reduce dose 20-50% xiii) Monitor TSH if has thyroid disease c) Mitoxantrone i) Indicated in RR or progressive MS not responding to other therapy ii) Side effects: cardiotoxic (use limited to <3 years, check EF before starting, donâ&#x20AC;&#x2122;t start if EF<50%), leukemia iii) Dose: 12mg/m2 q3 months over 5-15 min iv) Monitor CBC, LFTs prior to each dose v) Contraindicated in pregnancy

d) e) f) g)

Nataluzamab Naltrexone Pulse steroids Immunosuppresants

Treatment of symptoms 1) Spasticity a) Treatment can exacerbate ambulation if spasticity compensates for weakness b) PT (stretching, ROM exercises, aerobic) c) Baclofen 10mg qhs-bid, titrate weekly by 10mg/d, max 200mg/d (SE: weakness, sedation, dizziness, confusion; must be tapered) d) Tizanadine 2mg qhs, max 32mg/d div tid (SE: liver toxicity, orthostatic HoTN, somnolence, dry mouth, asthenia; lower dose in elderly, hepatic clearance, lower dose with oral contraceptives; monitor LFTs for a couple months) e) Diazepam (alone) 1-2mg bid-tid, max 20-30mg/d (with baclofen or tizanadine: 0.5-1mg bid-tid) f) Clonazepam g) Dantrolene 25mg/d, titrate slowly, max 100mg qid (use in preserved strength with severe spasticity; SE: liver toxicity, diarrhea, pericarditis, pleuritis; monitor LFTs) h) Baclofen pump i) Botox j) Phenol nerve blocks 2) Weakness 3) Fatigue (occurs in 80-97%) a) Worse with heat (Uhthoff phenomenon) b) Rx i) Brief (20 min) nap/timed rest ii) Drink cool liquids iii) Light dress iv) Keep rooms cool v) Treat fever vi) Amantadine 100mg QAM + Qnoon vii) Modafinil 50-400mg QAM (lower doses in elderly, hepatic cleared, SE: HA, N/V, nervousness, anxiety, insomnia; interacts with oral contraceptives) viii) Methylphenidate 4) Sensory Symptoms/Pain a) Identify type: positive or negative symptoms, secondary (contractures, arthritis, wounds, osteoporosis, fractures) b) Non-drug treatment: PT/OT, massage, TENS, trigger point injections, acupuncture, exercise c) NSAIDs, opiates, GBP, CBZ, LTG, TPM, nortriptyline, duloxetine d) Back pain: NSAIDs, aggressive PT e) Burning/dysesthetic pain: GBP (up to 2400mg/d div tid), amitryptiline (up to 100mg/d), TPM, capsaicin 5) Imbalance a) Includes tremor, ataxia, postural instability, impaired righting, vertigo, gaze instability, gait abnormality, loss of proprioception 6) Cognitive symptoms a) Neuropsych testing b) Donepezil 7) Depression (in 25-50%) and Mood Symptoms a) Group therapy b) Stress management/biofeedback c) Bupropion d) SSRI/mixed receptor agents (sertraline, venlafaxine, mirtazapine, duloxetine) e) ECT 8) Bladder symptoms a) Evaluate for UTI b) Postvoid residual and urology consult to define type of bladder dysfunction: flaccid neurogenic bladder, overactive bladder, detrusor-sphincter dyssynergia c) Overactive bladder i) Bladder retraining: Timed voiding, biofeedback, Kegel exercises ii) Intermittent self-cath iii) Oxybutinin: 2.5 mg to 20 mg/day; XL: up to 30mg/day (SEs: dry mouth, drowsy, constipation, blurry vision) iv) Tolterodine: more bladder selective, easier to tolerate v) Propiverine, trospium chloride, darifenacin, solifenacin vi) Suprapubic catheter vii) Sacral nerve stimulation d) Flaccid bladder i) Terazosin, doxazosin, tamsulosin ii) Bethanacol iii) Intermittent self-cath 9) Bowel symptoms a) Incontinence i) Timed/Planned Voids ii) Bulk forming agents (metamucil) iii) Anti-motility agents (lomotil, loperamide) iv) Biofeedback, bowel retraining b) Constipation

i) Bulk forming agents ii) Laxatives (lactulose, polyethylene glycol, docusate) iii) Prokinetic agents: metoclopramide, erythromycin iv) Biofeedback, bowel retraining 10) Sexual dysfunction 11) Paroxysmal symptoms 12) Visual Systems

Acute neuromuscular disorders MYASTHENIA GRAVIS 1. Acquired autoimmune disorder caused by immunologic attack against postsynaptic NMJ. a. Antibodies directed against acetylcholine receptor (AchR) or against muscle-specific tyrosine kinase receptor (MuSK).

Antibodies cause accelerated turnover of receptors, blockage of active site of receptor, and damage to postsynaptic muscle membrane. b. Affects all age groups, peaks of incidence in women in their 20’s and 30’s and men in their 50’s and 60’s. Female to male ratio 3:2. c. Osserman criteria: •Group 1: ocular, 15-20% •Group 2A: mild generalized, 30% •Group 2B: moderately severe generalized, 20% •Group 3: acute fulmiating, 11% •Group 4: late severe, 9% d. Up to 70% of patients with MG have thymic hyperplasia, up to 10% have thymomas (can be malignant and invasive) e. Can result from treatment with penicillamine (for scleroderma or RA). Treatment with aminoglycosides or procainamide can lead to exacerbations of weakness. f. Associated syndromes include hyperthyroidism (common), and less commonly SLE, Sjogren, sarcoidosis, scleroderma.

2. Clinical Features: a. Fluctuating motor weakness with abnormal fatigability that improves with rest. b. Limb weakness is often proximal and asymmetric. DTRs are preserved. c. Ocular MG: shifting diploplia and ptosis. Sustained upgaze at a fixed target for 30 to 60 seconds may cause worsening of sx and a dysconjugate gaze. d. Facial musculature may be affected, causing impaired activation (“myasthenic snarl” when asked to smile) e. Diaphragmatic and intercostal weakness can lead to dyspnea, progressive hypoventilation, CO2 retention. Respiratory failure can develop rapidly over hours without any prior sx. Be prepared for elective intubation if needed.

3. Diagnosis: a. Clinical evaluation b. Tensilon test: Injection of edrophonium (Tensilon) which acts as an Ach acetylcholinesterase inhibitor, resulting in transient increases in ACh at the NMJ that clinically improves weakness.

•Patient should ideally be off any AChE inhibitors for at least 24hrs •Assess objective sign of weakness prior to administration and after. Any improvement will likely last less than 30min.

•Inject 2mg test dose of edrophonium via peripheral IV. Assess for strength improvement after 1 minute. If no response inject another 8mg IV over the next 1 minute.

•Monitor pulse and BP. Have atropine at bedside in case of severe bradycardia.

•Side effects include fasciculations, bradycardia, nausea, vomiting, lacrimation, salivation.

•Test is only positive if objective improvement occurs, not just subjective improvement from patient’s perspective. c. Labs •AChR antibodies (3 types-blocking, binding, modulating) positive in 80-90% of patients with generalized MG. Present in 70% in patients with ocular form.

•Antibody levels do not necessarily correlate with disease severity in the individual patient.

•Anti-MuSK antibodies: positive in 30-40% of patients without AChR Ab. MuSK Ab is not present in pts with + AChR Ab testing or pts with ocular MG only.

•Anti-striatal muscle Ab (antititin Ab) positive in 30% of patients with MG •often find abnormal ANA, TSH associated with MG. d. Electrophysiology •Repetitive stimulation: give 2-3 Hz repetitive stim. with patient at rest. Normal = less than 10% decrement.

Patient then exercises muscle for up to 1 minute and repetitive stim. test performed again at 2-3 Hz. If no abnormal decrement is seen then perform single fiber EMG •Single fiber EMG: increased jitter and blocking of transmission.

3. Myasthenic crisis a. Patients must be monitored in ICU with frequent pulmonary function testing. When NIF is less than -30cm H2O or FVC is less than 15ml/kg consider elective intubation. Can also try bipap for patients who are not hypercapnic. b. When FVC is less than 10ml/kg patients need emergent intubation. c. Treated with plasma exchange or IVIG. 4. Treatment a. Acetylcholinesterase inhibitors: Most commonly Mestinon (pyridostigmine) •usually used patients with mild, stable weakness or ocular sx only •Start at 30-60mg po q6hrs. Dose titrated gradually. Most adults require 60-120mg q4-6hrs.

•Side effects: nausea, vomiting, abdominal cramping, diarrhea, increased oral/bronchial secretions, bradycardia, confusion, psychosis b. Corticosteroids (Prednisone) •Start low, increase slowly: start with 15-20mg daily, increase by 5mg/day every 3-4 days until symptoms improve. Generally gradually taper dose after at least 1 month to alternate-day dosing, with continued tapering after another month.

•May take weeks to months to see symptomatic improvement.

•Some patients may experience initial worsening of weakness if high-dose daily steroids are used at onset of treatment (sources vary, ranges from 5% to 30% of patients) •Increased risk of infection, diabetes, HTN, glaucoma, cataracts, osteoporosis. Prior to initiating therapy consider obtaining CXR, PPD, fasting blood glucose, PFTs, DEXA scan, BP check, eye exam. Patient should receive calcium/Vit D supplementation, have routine DEXAs and eye exams, periodic checks of BP and fasting blood sugar. c. Immunosuppresive Drugs: Used when patients have not responded to prednisone and mestinon. May take months to see benefit.

•Azathioprine: start at 50mg/day, increase by 50mg/wk to total dose of 2-3mg/kg/day. Systemic reaction may occur with fever, abdominal pain, nausea, vomiting, anorexia (occurs in 15% of patients) requiring discontinuation.

Monitor CBC, LFTs. •Cyclosporine: start at 3-4mg/kg/day in two divided doses, increase gradually to 6mg/kg/day as necessary.

Monitor BP, electrolytes, renal function, cyclosporine levels.

•Mycophenolate mofetil: demonstrates earliest improvement in sx. Start with 1g po BID, increase by 500mg/month up to 1.5g BID. Does not cause GI or renal impairment. d. IVIG and Plasma Exchange: Used for patients in myasthenic crisis or to maximize function prior to surgery. Some studies have shown these tx to be equivalent, some have shown PE to be more efficacious.

•IVIG given as a total of 2gm/kg over 5 days (400mg/kg/day) in general. May repeat weekly or monthly depending on sx severity.

•Risks of IVIG include possible anaphylaxis (in IgA deficiency), flu-like symptoms, aseptic meningitis, fluid overload, renal failure.

•PE requires placement of dialysis catheter. Exchanges occur every other day (2-3 L exchanged) for total of 5 treatments e. Thymectomy •Indicated for patients with thymoma.

•In patients without tumor, thymectomy may be useful in generalized MG for patients between puberty and age 55. Up to 85% of patients have symptomatic improvement, and of these 35% are able to remain drug-free.

Guillian-Barre Syndrome 1. Four major subtypes: a. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) b. Acute motor-sensory axonal neuropathy (AMSAN) c. Acute motor axonal neuropathy (AMAN) d. Miller-Fisher syndrome (characterized by ataxia, opthalmoplegia, areflexia) 2. Clinical Features: a. Typically presents as weakness beginning distally in lower extremities with progressive, symmetric, ascending paralysis. b. Areflexia occurs within first few days of onset c. May have tingling dysesthesias in extremities, muscle aches and back pain. d. Can involve cranial nerves producing facial weakness, bulbar symptoms, respiratory impairment (30% of patients require ventilatory assistance at some point). e. Sensory disturbances are variable, but often large fiber function (touch, vibration, proprioception) are impaired more than small fiber function (pain and temperature). f. Autonomic instability may be prominent, leading to fluctuations of BP, postural hypotension, cardiac arrhythmias.

These features require intensive monitoring, usually in an ICU setting, and can be fatal. g. Symptoms generally progress over 2-4 weeks, and if longer than 8 weeks, is more likely to be another entity (such as CIDP). h. Exam: Count in one breath, Cough, Reflexes, No sensory level, Cranial nerve palsy (esp VII), Atrophy, Motor weakness, Sensory loss 3. Pathophysiology: a. Up to 75% of patients describe preceding acute infectious process, usually respiratory or GI. Association with recent infections with Campylobacter jejuni (30% of cases), CMV (13%), EBV (10%), Mycoplasma pneumonia (5%), hepatitis A, B, C, HIV, Lyme disease, sarcoidosis. b. Appears to be autoimmune process. Proposed mechanism of molecular similarity between glycolipids expressed on bacteria and/or viruses and myelin epitopes. May lead to antibody formation that cross-react to antigens on Schwann cells or axolemma. c. Antibodies identified: •Anti-GM1 (most commonly seen in AIDP and most closely associated with C. jejuni infection).

•Anti-GD1a (most commonly seen in AMAN form) •Anti-GQ1b (most commonly seen with Miller-Fisher syndrome) 4. Diagnosis: a. Clinical features and history most helpful in diagnosis b. CSF shows elevated protein levels with normal cell counts (may have slightly elevated WBC in 10% of patients) and no evidence of pleocytosis. c. EMG: May show no abnormalities in early stages.

•In AIDP there is evidence of multifocal demyelination: Sensory and motor distal latencies are markedly prolonged, conduction velocities are slow, amplitudes may be reduced. Conduction block and temporal dispersion may be apparent. F-waves and H-reflexes are delayed or absent.

•In AMSAN sensory and motor nerve conduction studies show absent or reduced amplitudes with normal distal latencies, normal conduction velocities.

•In AMAN the nerve conduction studies show same motor findings as in AMSAN but sensory studies are normal.

•In Miller-Fisher syndrome reduced amplitude action potentials are most prominent. May have abnormal blink responses. d. Differential diagnosis. Sarcoid radiculopathy, Carcinomatous radiculopathy, Lymphoma, Spinal cord compression, HIV radiculopathy, Paraneoplastic syndromes, Diabetic amotrophy 5. Treatment: a. Both plasma exchange and IVIG have been demonstrated to be equally effective for treatment of AIDP. There has been no benefit shown to combination of treatments together.

•IVIG given as 2mg/kg total dose with equal infusions over 5 days (400mg/kg/day) •Treatment should begin as soon as possible, preferably within 7-10 days for best results •Mean time to improvement in studies ranged from 6 to 27 days with both treatment types.

•Up to 10% of patients receiving IVIG or PE may have relapse of symptoms within several weeks necessitating repeat treatments with IVIG or PE. b. Patients should be monitored in ICU until they have reached a plateau in the progression of their symptoms. c. Must have telemetry if on floor to evaluate for autonomic dysfunction d. Consider checking Camylobacter jejuni Ab (this is a worse prognostic sign) e. Frequent monitoring of NIF and FVC should be done (Q6h for at least 24h).

•FVC and NIF will decline prior to development of clinical signs of respiratory distress or abnormalities on ABG. Decline may be rapid.

•Consider elective intubation when FVC is less than 15ml/kg or NIF is less than –20 to –30. Emergent intubation should occur at FVC equal to or less than 10ml/kg.

•For FVC 15-20mg/kg, check NIF & FVC Q2h. f. Other treatments to keep in mind include early physical therapy, frequent repositioning, DVT prophylaxis, treatment of depression, neuropathic pain control. g. There is no benefit of corticosteroids in AIDP. 6. Prognosis: a. Most patients (up to 85%) have good functional recovery within several months to one year. Between 5-10% of patients have continued disabling motor or sensory symptoms. Little recovery occurs after 2 years. b. Mortality rate is 5%. Major complications leading to death include respiratory failure, pneumonia, pulmonary embolism, cardiac arrhythmias, sepsis. c. Poor prognosis associated with age older than 50, C. jejuni, axonal form, rapid onset of symptoms and distal CMAP amplitudes less than 10-20% of normal on EMG.

Dizziness Clarify type: vertigo, lightheadedness or dysequilbrium Localize: peripheral vestibular vs. sensory ataxia vs. central Peripheral Severe Horizontal-rotary nystagmus (peripheral>central) Nystagmus improves with visual fixation in primary gaze Nystagmus increased by gaze toward fast phase 2-10 second onset of nystagmus after Dix-Hallpike <30 second duration of nystagmus after Dix-Hallpike Fatiguable Central Continuous dizziness months to years Direction changing nystagmus Vertical nystagmus Gaze has no effect on nystagmus Immediate second onset of nystagmus after Dix-Hallpike >45 second duration of nystagmus after Dix-Hallpike Not fatiguable History. Assoc with position? Worse when lying with affected ear down? Recent cold or flu? Onset (Rapid onset with head movement, after viral illness, when anxious, upon standing, with head positioning)? Duration of attacks (seconds=BPPV, hours=Meniere’s, days=vestibular neuronitis)? Frequency of attacks (many times daily=BPPV, weekly=Meniere’s, continuous=central)? Draining ear? Past surgery? Tinnitus? Change in hearing? Fullness? Trauma? Nausea/vomiting?

Family Hx. Familial ataxia? Neurodegenerative disorders? Meniere’s?

Exam Cardiac: irreg pulse, orthostatics Otoscopic: otitis media, cholesteoma

Acuity (uncorrected refractive problem) Nystagmus (direction of fast phase, points away from lesion in unilateral labyrinthine lesion) Saccadic pursuits (CBL lesion, medication, inattention) CN V dec facial sensation (schwannoma, petrous apex lesion) CN VII spasm or droop (schwannoma, petrous apex lesion, trauma, Ramsay-Hunt) Dix-Hallpike: describe latency, symptoms, direction, duration, fatiguability Peripheral neuropathy Romberg & tandem Romberg (more sensitive): falls toward lesions with acute vestibular lesion Ataxia: FTN, HTS, RAM, Gait DDX Vertigo: BPPV, Meniere’s, vertebrobasilar insufficiency, acoustic neuroma Light headedness: Orthostatic hypotension, vasovagal episode, cardiac arrhythmia, hyperventilation Dysequilibrium: Peripheral neuropathy (sensory ataxia), stroke, cerebellar atrophy, NPH Physiologic: motion sickness, height vertigo Testing ENG, audiogram, consider ENT referral MRI brain to look for acoustic neuroma, brainstem/cerebellar infarct Check orthostatics If lightheaded, telemetry, EKG, TTE

PARKINSONISM 1. Classified into 2 types based on pathologic findings of abnormal protein accumulation in neurons (alpha-synuclein or tau proteins).

Most common is Parkinson’s disease but can have atypical forms that are characterized by more severe symptoms with more rapid progression, poorly responsive to typical PD medications.

2. Alpha-Synucleinopathies a.Parkinson’s disease: •Epidemiology: affects >1 million persons in the US (1% of those over age 55, 3% of those over age 85). Age of onset 35-85 (average 60’s) and incidence increases with age. More commonly seen in males. Disease progresses over 10-25 years.

•Etiology: felt to be related to environmental and genetic factors. Most cases sporadic but can be genetic (5% of all cases, earlier age of onset). Pathology shows gross loss of melanin pigment from midbrain and degeneration of dopaminergic cells in the substantia nigra pars compacta area (symptoms develop when dopamine depletion reaches >50%). Remaining neurons in this area often have Lewy bodies that stain + for a-synuclein.

•Clinical features: Symptoms usually unilateral at onset and progress asymmetrically.

-Bradykinesia (typically most disabling feature) -Resting tremor (4-6 Hz, “pill-rolling”) -Rigidity (cogwheeling) -Postural instability: usually in later stages of disease, (stooped posture, balance problems, frequent falls, retropulsion on “pull test”) -Gait abnormalities: shuffling, decreased arm swing, turning en bloc, festinating gait, freezing of gait.

-Other motor sx: hypomimia, hypophonia, micrographia, mask-like facies -Can have autonomic dysfunction -Other associated features can include anxiety, depression, sleep disturbances, variable sensory complaints, cognitive impairment, psychotic sx (often related to medication) -Progression of disease and symptoms is generally followed using clinical measures, most commonly via the Unified Parkinson disease rating scale (UPDRS—found at www.wemove.org). The motor subscale is a convenient way to measure change in exam over time.

-Can have associated dementia (PD patients have up to six times higher likelihood than general population of developing cognitive impairment; 25% of PD patients will develop Alzheimers-type dementia) •Treatment: -Dopamine Agonists (non-ergots: Ropinerole, Pramipexole; ergots: Pergolide, Bromocriptine). Direct stimulation of post-synaptic receptors. Can be used alone or as supplement to levodopa. Titrate dose slowly, not well tolerated in patients with underlying psychiatric disease or in the elderly. Side effects include nausea, psychotic symptoms, daytime somnolence, sleep attacks. Ergots can cause pulmonary/retroperitonial fibrosis and restrictive valvular heart disease (esp w/pergolide).

-Levodopa: Most effective treatment for PD, increases dopamine precursor availability. Paired with carbidopa to prevent peripheral breakdown of levodopa. Comes in IR and CR formulations. Start with low doses (25/100mg, ½ tab po TID) and titrate slowly. Side effects include nausea, postural hypotension, psych sx. At least 50% of patients treated with levodopa for 5 years will develop significant motor fluctuations (on-off symptoms, dyskinesias, freezing) -COMT inhibitors:(Entacapone, Tolcapone): Used only in conjuction with levodopa, acts to block catabolism of dopamine at pre-synaptic terminal. May increase amount of “on” time and diminish severity of motor fluctuations. Tolcapone is more potent but used less frequently due to risk of fatal hepatotoxicity and hematologic abnormalities (requires informed consent and frequent monitoring of LFTs).

-Amantadine: NMDA glutamate antagonist. May help reduce dyskinesias in more advanced patients.

-Selegiline: MAO-B inhibitor. May have mild symptomatic benefits in early PD. Previously thought to have some neuroprotective benefits but now it is generally felt this is not the case.

-Anticholinergic drugs (trihexyphenidyl, benztropine): Rarely used now but may still see some patients on these from earlier years.

•Management of mental status changes in PD: Can occur as mild confusion, cognitive difficulty, behavioral disturbance, delirium, psychosis. General approach is to rule out infectious or metabolic process, and review any recent medication changes. Symptoms most commonly managed with low doses of seroquel, can use clozapine if inadequate response to seroquel. Risperdone and olanzapine are generally avoided. Avoid haldol and use ativan as a last resort in acute situations. Often see some improvement if doses of dopamine agonists can be reduced.

•Surgical Treatments/DBS: -Indicated for patients with idiopathic PD, patients with good response to levodopa (need to undergo documented on/off evaluation), and patients who have significant intractable symptoms and/or significant drug-induced dyskinesias and wearing-off.

-Contraindicated in patients with atypical PD, cognitive impairment, major psychiatric disease, poor response to levodopa, and multiple medical comorbidites.

-Generally, symptoms that don’t respond to levodopa will not respond to surgery.

-Most patients can reduce their anti-Parkinsonian medication doses, most commonly see a 50% dose reduction.

-Prior surgeries focused on ablation of BG or thalamic regions. Now most commonly see placement of deep brain stimulators (DBS) with targets for lead placement in subthalamic nucleus (most common) or internal segment of globus pallidus. b. Multiple system atrophy (MSA): atypical Parkinsonism characterized by varying degrees of destruction of nigrostriatal system, cerebellum, autonomic system (usually 3 phenotypes as below). Average age of onset around 50, rapid progression with death in 5-10 years.

•MSA-P (previously striatonigral degeneration): prominent parkinsonian features at onset •MSA-C (previously olivopontocerebellar atrophy): prominent cerebellar signs at onset •MSA-A (previously Shy-Drager syndrome): progressive autonomic failure c. Diffuse Lewy body disease: characterized by prominent visual hallucinations, parkinsonism, fluctuating mental status (episodic confusion with lucid intervals), dementia (typically with severe impairment of visual-spatial deficits with memory less affected), behavior disturbance. Pathology shows Lewy bodies (intraneuronal cytoplasmic inclusions that stain with PAS and ubiquitin) throughout cortex, amygdala, cingulated cortex, SN. May respond to anticholinesterase medications.

3. Tauopathies a. Progressive supranuclear palsy (PSP): usual age of onset in 60’s or 70’s, progression to death in 5-10 years. Characterized by akinetic rigid parkinsonism with prominent early balance problems (postural instability occurs much earlier than in classic PD), frontal-type cognitive impairment. Also see abnormalities of voluntary eye movements, initially in vertical planes, with normal VOR. b. Corticobasal degeneration (CBD): age of onset in 60’s or 70’s. Have parkinsonian symptoms, apraxia, aphasia, cortical sensory loss, “alien limb” phenomenon, frontal-type dementia. c. Frontotemporal dementia: age of onset 50-70. Behavioral symptoms predominate in early stages (disinhibition, apathy, compulsions) but later develop dementia (usually affects higher functions with relative sparing of memory), parkinsonism, apraxia. If left hemisphere more affected referred to as primary progressive aphasia. Pick’s disease appears to be a subtype of this with distinctive pathologic findings of Pick’s bodies (inclusions that stain with silver).

4. Other Causes: vascular (usually due to lacunes in BG or multiple subcortical infarcts), neuroleptic exposure, other meds (metoclopramide, prochlorperazine, reserpine, alpha-methyldopa), toxins (MPTP, carbon monoxide, manganese, disulfides, cyanide, methanol). Removal of offending agent usually improves symptoms. Medication-induced cases may respond to anticholinergics.

Serotonin Syndrome Source: NEJM 2005;352;11:1112 History and Exam Spectrum of severity from very mild to life-threatening Rapid onset (present within 6 hours) Ataxia, myoclonus, hyperreflexia more common in SS than in NMS Hyperthermia and rigidity milder in SS than in NMS Fever, diarrhea, vomiting common in prodrome of SS unlike NMS Tremor, clonus and akathisia without other EPS is suggestive History of offending agent, including OTCs, herbal and drugs of abuse Mental status changes, autonomic hyperactivity, neuromuscular abnormalities Delirium, agititation, hypervigilance, pressured speech Autonomic signs: tachycardia, shivering, diaphoresis, mydriasis, hyperthermia, HTN, diarrhea/hyperactive bowel sounds Tremor, myoclonus, hyperreflexia (worse in lower extremities), ocular clonus Seizures Poorly treated hyperthermia -> metabolic acidosis, rhabdomyloysis, high LFTs, renal failure, seizures, DIC Exam: Reflexes, Clonus, Muscle rigidity, Pupils, Dryness of oral mucosa, Bowel sounds, Skin color, Diaphoresis Offending medications: MAOIs, TCA, SSRI, opiods, OTC cough medicines, antibiotics, weight reduction agents, antiemetics, antimigraine agents, drugs of abuse, herbal products, meperidine, MDMA (“ecstasy”), dextromethorphan, trazadone, nefazadone, buspirone, clomipramine, venlafaxine, phenelzine, valproate, fentanyl, tramadol, pentazocine, ondansetron, metoclopramide, sumatriptan, sibutramine, linezolid, ritonavir, LSD, tryptophan, St. John’s wort, ginseng, lithium Diagnostic criteria (sn 84% sp 97%) Has exposure to serotonergic drug in last 5 weeks AND any one of the following 1) tremor + hyperreflexia 2) spontaneous clonus 3) muscle rigidity + T > 38 C + (ocular clonus or inducible clonus) 4) (ocular clonus or inducible clonus) + (agitation or diaphoresis)

Labs: coags, LFTs, ck, pan culture, CXR, Head CT, +/- LP Treatment 1) Remove precipitating drugâ&#x20AC;Śusually resolves within 24 hours 2) Supportive care: IVF, correct vital signs 3) Control agitation: benzodiazepines (lorazepam 1-2mg, then titrate to eliminate agitation), no restraints 4) Control autonomic instability a) norepi or phenylephrine for hypotension b) esmolol or nitroprusside for hypertension 5) Control hyperthermia: a) Eliminated excessive muscle activity with benzos (moderate cases) or neuromuscular paralysis (severe cases T > 41.1 C) b) No role for antipyretics 6) If above measures fail, try 5HT2A antagonists a) First line: Cyproheptadine 12mg PO x 1, then 2mg Q2 if symptoms persist, maintenance dose 8mg Q6 b) Olanzapine 10mg SL c) Chlorpromazine 50-100mg IM (not if hypotensive or if has NMS) 7) Propranolol (5HT1A antagonist) not recommended because of hypotension + bradycardia 8) Bromocriptine not recommended because may worsen NMS or serotonin syndrome 9) Dantrolene not recommended because no effect on survival in animal models

Neuroleptic Malignant Syndrome Idiopathic reaction to dopamine antagonists Slow onset (over several days) Bradykinesia, lead pipe rigidity, hyperthermia, fluctuating consciousness, autonomic instability *Ask what meds they got, get vital signs, what has been done so far *Results from dopaminergic blockade, usually assoc. with haldol, can also be seen with PD patients when holding their dopamine agonist or sinemet (known as NMS-like syndx) *Clincally: Fever, rigidity, elevated CK, rhabdomyolysis, mental status change, dysautonomia *Needs comprehensive lab w/u, *TX: Stop offending agent. May try bromocriptine 5 mg TID or dantrolene 0.5-3 mg/day, amantidine 100 mg/q12H is alternative to bromocriptine

Depression Epidemiology 10-15% prevelance 2:1 F:M, onset age 30-40s Diagnosis DSM IV criteria 2 weeks of depressed mood or anhedonia plus 4 of SIGECAPS Sleep disturbance Interest decreased Guilty Energy decreased Concentration impaired Appetite changes Psychomotor retardation/agitation Suicidal thoughts Rule out other causes: substance use (EtOH, sedative, cocaine withdrawal, steroids, Acutane, beta-blockers, hypothyroid, syphilis, mono, HIV) Neuro disorders causing depression: MS, PD, seizures, CVA, trauma, tumors Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Lancet Neurol 2006;5(5):399 Choose the best answer of the following: 4=Always or often 3=Sometimes 2=Rarely 1=Never 1) Everything is a struggle 2) Nothing I do is right 3) Feel guilty 4) Iâ&#x20AC;&#x2122;d be better off dead 5) Frustrated 6) Difficulty finding pleasure Score > 15 suggests depression (range 6-24)

Antidepressants Ask about mania before starting antidepressants Efficacy for all of them 60-75% SSRIs SEs: headache, stomach upset, loose stools, serotonin syndrome, sexual side effects (1/3, most likely decreased libido or delayed orgasm), alopecia, hyponatremia, decreased plt aggregation Citalopram/Escitalopram: Fewest side effects, sedating for some people, escitalopram requires ½ dose compared to citalopram Sertraline: generic available, fewest side effects Paroxetine & fluoxetine inhibit 2D6 -> increased beta blocker, TCA, antipsychotics Paroxetine: weight gain, sedation Flouxetine: better for noncompliant, longest half-life (30 hrs, 2-3 weeks for metabolite) SNRI (5HT & NE reuptake inh) Venlafaxine: can increased BP at higher dose (has more NE effect @ higher dose), SEs include HA, GI upset, sexual SEs Duloxetine (Cymbalta): also indicated for diabetic peripheral neuropathy, dose 30mg x 7 days, then 60mg qday, can increase BP OTHERs Mirtazapine (Remeron): MOA: blocks alpha-2 receptor on presynaptic increasing 5HT/NE release, sedation and weight gain occur at lower doses Buproprion: NE/DA reuptake inhibitor, decreases seizure threshold, contraindicated in eating disorders, is activating “like having too much caffeine”, don’t use in agitated depression, good in amotivational depression, fewer sexual SEs, SE includes anxiety Tazadone: 5HT reuptake inhibitor & 5HT2A blocker, SEs include sedation, orthostasis, priapism, better for insomnia than depression Fewest sexual SEs: bupropion, mirtazapine, nefazadone

Imaging Tips Blood on MRI Timing Hyperacute (0-24hr) Acute (1-3 d) Subacute (3-7 days) Chronic (<2 wk) Chronic (>2 weeks)

Type of hemoglobin oxyhemoglobin deoxyhemoglobin intracellular methemoglobin extracellular methemoglobin hemosiderin

T1 Isodense Isodense Bright

T2 Bright Dark Dark

Bright

Bright

Dark

Dark

Bright on T1: fat, methemoglobin, calcium, enhancement, proteinaceous fluid DWI positive: infarct, hypercellularity (some tumors), demyelination

ICU tips Fever workup in NSICU (per Dr. Shutter): Cult blood, urine, BAL (no sputum); ABG; CXR; LP; LE Dopplers; Echo; LFTs - chole is forgotten cause of ICU fever b/c tube feeds Antibiotics in ICU (per Dr. Shutter) When to start abx: (Must have >2) 1) Fever 2) Leukocytosis 3) HR > 90 4) RR > 30 5) Hypotensive (MAP < 70) or Altered Mental Status + Abnormal CXR PaO2/FiO2 < 300 Purulent secretions For ventilator PNA: Vanc 1.5 gm q12 hrs + Cefepime 2 gm q12 hrs +/- tobramycin (7 day course or 14 days if drug resistant- put stop date in when writing order) For meningitis: Vanc + CTX For UTI: Nitrofurantoin 7 days Bacteremia: Vanc and cefepime Bugs needing double coverage: SPACE: Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter

Pressors in ICU 1) No pressors until you have given at least 2 L 2) Levophed 2 mcg/min; max 10 mcg/min 3) Consider adding vasopressin .04 u/min 4) Add inotrope- dobutamine, epinephrine 5) Consider hydrocortisone 50 mg dose

Opiod Dosing Opioid

Parenteral Equivalent dose (mg)

Oral Equivalent dose (mg)

Duration of analgesia (hours)

Onset (min)

Morphine

10

30

3-4

PO 15-60

Oxycodone

NA

30

3-4

PO 10-15

Hydromorphone (Dilaudid)

1-1.5

6

3-4

PO 15-30

Fentanyl

0.1

NA

IV 0.5-1 TM 1-2.5

IV 1-2 TM 5-8

Patch: 25, 50, and 75 mcg

Meperidine (Demerol)

75-100

300

2-3.5

SC 10-15

Avoid in seizure patients

Hydrocodone

NA

30

3-4

PO 10-20

Codeine

120-130

200

3-4

PO 30-60

Notes

Safe in renal insfx.

Falls Etiology 1) Central processing: dementia 2) Neuromotor: Parkinson's disease, stroke, myelopathy, cerebellar degeneration, peripheral neuropathy 3) Vision: cataracts, glaucoma, age-related macular degeneration 4) Vestibular: PPV 5) Proprioception: peripheral neuropathy, vitamin B12 deficiency 6) Musculoskeletal: arthritis, foot disorder, muscle weakness 7) Systemic: postural hypotension, metabolic disease (thyroid), cardiopulmonary disease, other acute illness 8) Medications a) Reduce alertness or retard central processing: analgesics (narcotics), psychotropics (TCA, benzo, phenothiazine) b) Impair cerebral perfusion: antihypertensives, antiarrhythmics c) Direct vestibular toxicity: AMG, high dose loop diuretics d) Extrapyramidal syndromes: phenothiazes Plan -evaluate pt to get details of fall -assess for any trauma (esp any abrasions, cuts, localized pain, ROM at hip) and do quick neuro check -check serum osm & calculate serum osm, if gap present then hidden substrate -XRAY limbs/pelvis or head CT if indicated by exam -consider if new organic cause (MI, Sz, agitation from pain, MS changes, over sedation) -make sure to leave a cross-cover note

Lumbar Puncture Indications: Suspected CNS infection (meningitis, encephalitis) Suspected SAH (HCT 1st to exclude increased ICP. Pseudotumor cerebri (therapeutic) or NPH (diagnostic) Guillian-Barre syndrome (very high protein level > 200mg/100ml) Multiple sclerosis (elevated IgG index and OCBs present on electrophoresis) Spinal analgesia SLE Acute demyelinating disorders (encephalomyelitis, transverse myelitis) Dementia Meningeal carcinomatosis Staging of lymphoma Diagnosis of tertiary syphilis Unexplained neurologic disorders if CT is negative Contraindications: Local skin infections (absolute CI) Raised ICP (ok for pseudotumor or suspected NPH) Suspected venous sinus occlusion Supratentorial mass lesions (HCT 1st) Severe bleeding dithesis, coagulopathy, or anticoagulated patient (relative CI) Platelet count les than 50,000/mm3 Precautions: Pt w/ coma, focal neurological findings, or papilledema should have a CT w/ IV contrast prior to the procedure Imaging rarely indicated in pts w/ suspected acute meningitis, esp if pt is immunocompetent w/ no h/o CNS lesions, a normal neuro exam, & no clinical evidence of ICP (no papilledema & nl SBP) Instituting antibiotic therapy one to two hrs before LP will not decrease diagnostic sensitivity if the culture of the CSF is done in conjuction w/ testing of CSF fluid for bacterial antigens and w/ blood cultures Risks/Complications: 1. Post-LP headache: HA occurs in 10-25% of pts and is usually self-limited. The HA usually lasts for a few days, but may last longer than a week and can be debilitating. Spinal HA usually occurs w/I 48 h following dural puncture, but it may occur up to 12d later. It is exacerbate by sitting upright and is relieved by lying down. The incidence is reduced by using a 20- gauge or smaller needle; by keeping the bevel of the needle oriented parallel to the long axis of the ts spine, thereby spreading rather than cutting the fibers of the ligamenta flava; by telling the pt to remain at bed rest following the procedure. Oral and IV caffeine benzoate can be used to treat refractory HA. IV doses of 500mg are given over a few minutes. A repeat dose can be given in an hour for an 85% chance of alleviating symptoms. Epidural blood patch can be performed for those refractory to caffeine. This is done by injecting 15 ml of autologous blood into the dural space.

2. Epidermoid tumors have been associated with LP performed in the neonatal period, when needles are used w/o stylus.

3. Seizures reported on a small percentage of pts with post-dural puncture headaches.

4. A traumatic or “bloody” tap from inadvertent puncture of the spinal venous plexuses is possible. This is self-limiting in the majority of pts, but could lead to a spinal hematoma in pts with bleeding disorders. Some uthorities recommend sending the first and fourth tubes for cell ct (RBCs and WBCs with diff) if a traumatic tap is suspected. The RBC ct will decrease from tube one to tube four in the case of a traumatic ta. A correction can be made for SDF leukocytes and CSF protein if the tap is traumatic. For each 700 RBCs, CSF leukocytes increases by one and CSF protein rises 1mg/100ml.

5. Brain herniation from a suptratentorial mass or increased ICP is another complication. Always check the fundi for papilledema before performing LP. If a tumor, an intercranial bleed, or marked increased ICP is suspected, an emergent HCT should be done before LP to reduce changes of herniation.

6. Paresthesias in the lower extremities are usually transient, but rare cases can last for more than a year.

7. Local pain in the back may be due to injury of the periosteum or the spinal ligaments.

8. Nerve root aspiration is possible. Replacing the stylus before withdrawing the needle may prevent aspiration of nerve roots.

Very rarely, nerve root diverticula can rupture as a result of LP, causing a brief CSF leak and a spinal headache.

9. Infection/meningitis Procedure: 1. Position pt near edge of bed/exam table in the lateral recumbent or sitting position. Slightly flex the neck anteriorly. If lying, ask pt to “roll up into a ball: with knees drawn up to the abdomen. Shoulders and pelvis should be aligned vertically w/o forward or backward tilt. Identify L3-L4 interspace ( a line drawn b/w the superior aspect of the iliac crest intersect the body of L4). If necessary, the L2-L3 or L4-L5 interspaces can be used.

2. Open spinal ray in a sterile manner. Put on sterile gloves and reassemble the manometer. Open numbered test tubes and placed them upright, in order, in the slots provided in the plastic tray.

3. Prepare the skin at the selected interspace with an antiseptic solution. Cover the area with fenestrated drape.

4. Draw 3 ml of 1% lidocaine into the syringe with the 0- to 23- gauge needle.

Administer local anesthetic with the skin needle and raise a wheal over the L3-L4 interspace. Inject a small amount deeper into the posterior spinous region, in the direction that the spinal needle will follow.

5. Palpate the posterior spinous process. Using this and the umbilicus s landmarks, insert a 20- or 22- gauge spinal needle through the skin. Angle the needle about 15 degrees cephalad, toward the umbilicus, keeping it level with the sagittal midplane of the needle parallel to the longitudinal is of the sine. If bone is encountered, withdraw the needle slightly and change its angle. Depending on the size of the patient, after the needle has advanced about 3 to 4 cm, stop, withdraw the stylus and check the hub for fluid. If there is no fluid, replace the stylus and advance another fraction before repeating this again. Usually a slight “pop” is felt as the spinal needle penetrates the dura. Advance the needle 1 to 2 mm farther and withdraw the stylus. Rotating the needle 90 to 180 degrees is sometimes helpful if no fluid returns. If the patient experiences pain radiating down one leg or the tap is “dry” remove the needle completely and make an attempt at a different interspace. A “dry” tap is more often due t a poorly positioned patient or an improperly placed needle than to an obliterated subarachnoid space. Reposition the patient from lying to sitting or vice versa.

6. Once fluid is obtained, place the end of the stopcock with the attached manometer on the hub of the needle. Have the patient straighten their legs and relax so that the opening pressure is not artificially elevated. The CSF should rise in the manometer to the level of the OP. Note the color of the fluid and the OP. CSF pressure should oscillate slightly with the pulse and with respiration.

7. In case the fluid is bloody and does not clear after the first few drops of fluid (bloody tap), replace the stylus and remove the spinal needle. Select an alternative lumbar interspace above or below the current level and re-attempt. Bloody CSF due to SAH will not clot. Also, after spinning in a centrifuge, the supernatant is xanthochromic.

8. Turn the stopcock to allow the CSF to flow into the test tubes. Keep track of the order in which they are filled. Fill at least three test tubes with 2-3ml of CSF each. Label each tube in the order it was collected. A 4th tube can be filled and frozen in case further studies are needed.

9. Once you have obtained enough CSF, replace the stylus and withdraw the needle. Cover the puncture site with a sterile dressing.

Have the pt turn to the supine position and remain there for the next 2 hours.

10. For a therapeutic LP, remove enough spinal fluid to reduce the closing pressure to 100 mm H20) or less (usually 25-35 ml of CSF). For diagnostic table, removal of 3-50 ml may result in transient improvement in gait or cognition for suspected NPH. Processing CSF fluid: Tube 1: Cell count, diff, gram stain, culture (bacterial, fungal, TB, viral) Tube 2: Glucose, protein, protein electrophoresis (need concurrent serum study) Tube 3: Save the fluid until further notice Tube 4: Cell count and diff; Optional studies (VDRL, India ink, cryptococcal antigen, cytology, oligoclonal bands, myelin basic protein, countercurrent immunoelectrophoresis, serologic and genetic tests for other microorganisms) Consider additional tests a. Bacterial cultures b. N meningitides, H influenza, S pneumoniae antigens c. Assay for cryptococcal antigens in immunocompromised pts d. Oligoclonal banding, IgG index and assay for myelin basic protein are useful to dx MS e. VDRL for syphilis f. AFB stain, TB culture, and PCR for TB g. India ink for cryptococcus h. Lyme titer i. Fungal or viral cultures j. Cytology k. HSV PCR l. MS serology Role of repetitive LPs for f/u 1. Aseptic meningitis 2. Subacute/chronic meningitis of proven etiology 3. Bacterial meningitis which does not respond to Rx Normal CSF values: Opening pressure 50-200mm H20 WBC < 5/mm3 Neutrophils none Glucose 60-70 blood glucose levels Protein level 15-45mg/100ml REF: Pfenninger & Fowler, Procedures for Primary Care, 2nd ed. 2003.