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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. Please see section below entitled “tPA” for contraindications.

3) Candidate for stroke trial? (some eligible 12 hours out-- call stroke pager to be sure-513-844-7686)

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. right-sided infarct)

What to look for on head CT

Look for current bleed or prior strokes. Acute hemorrhage is bright on CT scan, may be within the parenchyma, subarachnoid at base of brain and/or subdural/epidural or subtentorial and all of these areas need to be examined.

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/encephalitis (fever, incr. WBC, stiff neck, severe HA), hypo/hyperglycemia, SAH, subdural or epidural hematoma, aortic dissection, neoplasm (sometimes presents acutely), abscess, multiple sclerosis/transverse myelitis

Etiology of stroke in a young person (< 50 years). Cardioembolic, vertebral or carotid dissection (ask about trauma, chiropractor), cocaine, hypercoagulable state, vasculitis, complicated migraine

Complete R. MCA -> NIHSSS 16-20

Complete L. MCA -> NIHSSS 21-24

Acute Treatment (if no TPA)

1) All acute strokes without tPA should use the “TIA/stroke-no tPA” order set

2) Admit to NSICU (if acute) or floor with CMU

3) Neuro checks q 1-2 hrs x 24 hrs if unstable or unit bed; q 4 hrs if stable/ on floor bed.

4) Head of bed flat

5) IV fluids- Normal saline at 70/cc/hr or 1cc/kg/hr and usually order it for 1-2 liters total. NO D5 solutions. Watch for fluid overload. Caution with Afib or CHF.

6) 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. Goal: to lower SBP by no more than 20 mmHg and DBP to less than 105 for the first several days.

7) If posterior fossa stroke, watch for hemorrhagic conversion or delayed edema (72-96 hours) which can compress the brainstem or cause hydrocephalus- STAT head CT for change in exam, notify neurosurgery if hemorrhage or significant swelling.

8) Testing. Order fasting lipids, CBC, coags, panel-10, and U/A. Low threshold for cardiac enzymes, esp. in patients with risk factors. 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.

9) 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.

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

11) Start antiplatelet therapy if ischemic stroke and not on t-PA

12) Start on statin on the next day (check LFT's)

13) If febrile, pan culture, then start on round-the-clock Tylenol for 48 hours. Fever is associated with poor outcome.

14) GI and DVT prophylaxis- Heparin SQ 5000 U q 12h and TEDS; Zantac 50 mg IV q 8 if in NSICU

15) NEVER use IV heparin in acute stroke (see exceptions below)

16) 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) All acute stroke with tPA should use the “TIA/stroke-with tPA” order set

3) Admit to NSICU always

4) 2 large bore IVs

5) Neuro checks & BP checks q15min x 6hr -> q1h x 24hr

6) Delay placement of tubes (NG, Foley, arterial lines)

7) NO antiplatelet, heparin or warfarin including prophylactic until stable for 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

10) If got IA tPA, look, feel and listen to groin site for signs of hematoma or bruit

Possible indications for IV heparin in acute stroke: Extracranial carotid or vertebral artery dissection, central venous sinus thrombosis, very high-grade carotid stenosis with mild stroke/TIA. Always call attending before starting heparin gtt. More controversial indications are 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/ICH

Options for uncontrolled hypertension:

1) nicardipine 5-15mg/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, recent cocaine use

3) esmolol 250 mcg/kg IVP load, then gtt 25-300 mg/kg/min

4) enalaprilat 1.25-5 mg IVP q6h, first test dose 0.625mg since it can precipitously drop BP

5) nitropaste 1-2 in

6) nitroglycerin gtt 20-400 mcg/min

7) nitroprusside 0.1mcg/kg/min gtt initial dose, max: 10mcg/kg/min (consider if BP > 220/140, labile response)

8) hydralazine 5-20mg IV q30min (last choice, unpredictable response)

If SBP > 230 or DBP > 140 use nicardipine or nitroprusside

If SBP 180-230 or DBP 105-140, use nicardipine, labetalol, esmolol, or enalaprilat

If SBP < 180 and DBP < 105, defer antihypertensive therapy

Options for hypotension:

1. REPLACE VOLUME (Prefer NS 250cc bolus over 30-60 minutes depending on situation, sometimes 500ml. Can also place in reverse

trendelenburg.)

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), venous sinus thrombosis, 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) Statin (High cholesterol has not been consistently shown to be a risk factor for ischemic stroke. Statins may have effects on microcirculation and nitric oxide which is why it shows a benefit while other lipid lowering medications would not and are not proven to lower the risk of stroke.)

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). Asymptomatic CEA is more controversial.

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

Asymptomatic Carotid Stenosis

http://stroke.ahajournals.org/cgi/content/full/35/10/2425

ACAS Trial

47% RRR ipsilateral stroke/periop death with CEA

2.7% ARR of disabling or fatal stroke (NNT ~ 40) with CEA

5-year risk ipsilateral stroke wo CEA = 11%

Criticized because of unrealistically low periop complications

Only best surgeons participated (40% applicants rejected) -> 1.5% periop stroke/death, 0.4% periop death

Metaanalysis of case reports of asymptomatic CEA show 4.3% periop stroke/death, 1.1% periop death

ACST trial

3120 pt with >60% asymptomatic stenosis (12% had symptoms >6 months previously) based on ultrasound

Surgeons had to have <= 6% periop risk

2.5% ARR of disabling or fatal stroke at 5 year (NNT ~ 40)

5.3% ARR of any stroke at 5 year

30-day op risk of death 1.1%

30-day op risk of stroke/death 3.0%

5-yr risk any stroke in medical group 11.8%

No gradation of benefit for more stenosis

More benefit in men (less benefit in women with 70-99%, no benefit with 50-69%)

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

Risk of recurrent stroke ~8% in 14 days in pts with afib (HAEST trial 2000)

NIHSS Favorable outcome @ 1 yr

< 10 60-70%

> 20 17%

NIHSS at 3 months	Group	NIHSS 0-1	NIHSS 2-8	NIHSS >9	Death
All patients	tPA	31%	30%	22%	17%
All patients	Placebo	20%	32%	27%	21%
Age>75 + NIHSS>20	tPA	0%	26%	26%	48%
Age>75 + NIHSS>20	Placebo	0%	14%	41%	45%
Modified Rankin at 3 months		MR 0-1 (Good outcome)	MR 2-3 (Moderate disability)	MR 4-5 (Dependent)	Death
All patients	tPA	39%	21%	23%	17%
All patients	Placebo	26%	25%	27%	21%
Initial NIHSS>20	tPA	10%	21%	21%	48%
Initial NIHSS>20	Placebo	4%	20%	38%	38%
Age>75 + NIHSS>20	tPA	0%	30%	22%	48%
Age>75 + NIHSS>20	Placebo	5%	9%	41%	45%

Modified Rankin Scale

0=normal

1=minor impairment

2=significant impairment: requires assistance, but independent

3=moderately dependent

4=mostly dependent, uses walker or cane

5=completely dependent

Complications of stroke

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%)

Hemorrhagic Transformation

Types of radiographic hemorrhagic transformation

HI-1 (Hemorrhagic infarction): small petechiae around margins

HI-2: confluent petechiae, but no mass effect

PH-1 (Parenchymal hematomas): hematomas, space-occupying, <= 30% of infarcted area

PH-2: hematomas, space-occupying, >30% infarcted area

Timing of hemorrhagic transformation

From Stroke 1986;17(2):179-185

65 stroke patients prospectively followed with CT for 28 days

Treated with prophylactic heparin +/- ASA

Day	% with any HT
3	6.2
7	16.9
14	40
21	43.1
28	43.1

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 last normal

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 unless it’s a compressible site (e.g. femoral)

· 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 or SAH ever

· 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, don’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	Stroke and death at 30 days	Major or fatal ipsilateral stroke at 2 years
Endarterectomy + Med Rx	9%	5.8%	2.5%
Medical Rx alone	26%	3.3%	13.1%
	NNT=8; p<0.001		P<0.001

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

Vascular Territories

Source: Neuroanatomy through Clinical Cases

Intraparenchymal 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 in cm, B = largest diameter at 90 deg to A in cm, C = number of 1.0cm cuts showing hemorrhage (CT cuts are usually 0.5cm each)

3) Head of bed flat unless increased ICP (large ICH, low level of arousal- HOB 30 degrees)

4) Ventilator support

5) Blood pressure control: (a-c is from Broderick Stroke 2007;38:2001-23)

a) If SBP>200 or MAP>150, use IV infusion and monitor q5min

b) If SBP>180 or MAP>130 with suspicion high ICP, use IV infusion or intermittent IV meds to keep CPP>60-80, consider ICP monitoring

c) If SBP>180 or MAP>130 without suspicion high ICP, goal MAP=110 or BP=160/90 using intermittent or continuous IV meds, clinically reexamine q15min

d) Use fluids then pressors for SBP<90. See above on ischemic stroke for BP options.

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

7) 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”

8) Tight glucose control

9) Check INR -> Emergently reverse coagulopathy

10) Manage intracranial pressure (see section below entitled “Herniation/highICP”)

11) 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.

12) Seizure prophylaxis (28% seizure within 72 hrs): phenytoin 300mg po qday or levetiracetam 500-1500mg po bid

13) REPEAT HCT if pt has new-onset HA, N/V or photophobia

14) Re-starting anti-platelets or anti-thrombotics is largely a judgment call based on need and size of hemorrhage.

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	Points
GCS 3-4	2
GCS 5-12	1
ICH volume > 30	1
IVH extension	1
Infratentorial origin	1
Age >= 80	1

ICH score	0	1	2	3	4	5-6
30 d. Mortality (%)	0	13	26	72	97	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 (Lange)

Peak incidence ruptured aneurysm between 55 – 60 yrs old M:F=1:1.5-4 (Shutter)

Most important risk factors: Smoking, hypertension, family history of SAH

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 CTAngiogram as first line. The CTA part should detect AVM and Aneurysms.

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) Goal: prevent high arterial or ICP to prevent rerupture

2) Admit to ICU

3) Q1h neuro checks

4) Elevate head of bed 15-20 deg

5) Strict I/O, NPO until treatment planned, but then start tube feeding or TPN early

6) Prevent increase ICP (bed rest, mild sedation, antiemetics; Antacids; Stool softeners, Keep room dark and quiet, Analgesia)

7) Avoid hypovolemia

8) Aggressive glu control

9) Caution with hypotonic IVF to prevent cerebral edema; use isotonic with no dextrose

10) 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.

11) Emergently reverse coagulopathy (FFP, vitamin K)

12) Avoid ASA (inhibits plt function)

13) DVT prophylaxis 24 hr after unless known hemorrhagic lesions or post-op

14) Low Na -> cerebral salt wasting -> NaCl or hypertonic saline

15) Nimodipine 60mg po q4 x 21 days -> reduce vasospasm

16) 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

17) Check PHT level

18) Steroids provide no benefit

19) If aneurysm -> surgical clipping within 2 days

20) Not surgical candidate if stuporous or comatose

21) If AVM -> removal, ligation or embolization electively (lower rebleeding risk)

22) If deteriorates -> repeat head CT

23) Monitor for complications (see below)

24) Baseline TCDs (transcranial dopplers)

25) 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) Confirm 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 “H” 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	Normal	0-10%
2	<1mm thick blood	30%
3	>1mm	70%
4	IC or IV clot with diffuse or no SAH	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

<7mm -> monitor

>10mm -> refer to neurosurgery

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 with widened pulse pressure, bradycardia and irregular respirations, Uncal: ipsilateral 3^rd 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) 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

3) Do not use mannitol or hyperventilation prophylactically because that can increase morbidity or mortality in stroke patients.

4) Mannitol bolus preferentially shrinks non infarcted brain in ischemic stroke (Neurology 2001; 57:2120-2)

5) 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%

Epilepsy/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, 5^th ed. 2000

Definitions

Seizure = a paroxysmal time-limited event that results from abnormal synchronized neuronal activity in the brain.

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

Symptomatic = due to secondary cause

Idiopathic = genetic epilepsy syndromes

Cryptogenic = unclear etiology (no lesion; may be congenital)

Status epilepticus = seizure lasting longer than 5 minutes or multiple seizures without return to baseline

Simple = no loss of awareness or confusion during seizure

Complex = has loss of awareness or confusion during seizure

Generalized = affecting whole brain

Primary generalized = onset is in thalamus or due to abnormal inhibitory/excitatory interaction between the thalamus and the cortex (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 or atonic seizures: generally very brief; also known as drop attacks because tonic or atonic can cause falls and it is so brief it’s difficult to see what caused the pt to drop.

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 > 5-10 min 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 for seizure (relative risk in parenthesis). Birth complications, previous head trauma with LOC (esp. penetrating trauma, RR 1.5-580 depending on severity), history of meningitis (4) or encephalitis (16), family history of seizures (2.5), personal history of febrile seizures, alcoholism (3.0), prior stroke (20). 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/Non-compliance 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 or cause seizures (i.e. don’t give to EMU patients). Bupropion, ciprofloxacin, promethazine, imipenem, baclofen

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

9) LP

10) Prolactin levels can be measured in 20, 60, 120 minutes to check for pseudoseizures but this is not recommended routinely.

Indications for blood level: poor seizure control, AED toxicity, check compliance, initiation of AED, dose change or addition of new meds, pregnancy, renal or hepatic disease

Indications for CBC/LFT check: initially starting therapy, once during first few months, any AED change, if symptoms occur, maybe annually

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%, but remember that “auras” are simple partial seizures and the presence of even simple partial seizures before a complex partial or tonic clonic seizure mandates treatment since the patient has now had several seizures and recurrence risk is high.

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. Prior failure of medication discontinuation means worse prognosis for safe 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 “benign” triggers in that medication should be adjusted for these triggers.

Adjust AEDs if no clear trigger even if in therapeutic range (treat the patient and not the medication level)

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.

Try to adjust the medication before pregnancy if possible.

Vitamin K during last month

Folic acid 104mg/day

Avoid valproate

Follow levels because pregnancy changes metabolism

Risk of fetal malformations (Vajda FJE et al, Eur J Neurology 2006)

From Ficker Grand Rounds 7/08

SANAD Results (Marson et al. Lancet 2007)

For outcome of probability to remain on drug
Partial epilepsy	Generalized or unclassified epilepsy
LTG > CBZ > TPM=GBP	VLP > LTG > TPM

AED withdrawal

Favorable predictors (MRC Trial, Lancet 1991)

Seizure free > 3 years

Monotherapy

Background EEG normal

No psychomotor retardation

No JME

Longer seizure free interval better

Surgical Outcome

Epilepsy Type	Outcome (seizure freedom)
Temporal lobe lesion	~ 80%
Mesial temporal sclerosis	~ 70%
“Normal” temporal lobe	~ 60%
Lesional extratemporal	~ 60%
Nonlesional extratemporal	< 50%

Prognosis of New onset seizure

Patient Risk of recurrence after 1 event without treatment

Normal EEG + idiopathic sz 24%

Symptomatic sz or abnl EEG 48%

Symptomatic sz + abnl EEG 65%

Chance of seizure freedom in new onset epilepsy with medication treatment

From Kwan NEJM 2000;342:314-9

Treatment	Seizure freedom (% of original population)
1^st AED	47%
2^nd AED	13%
3^rd AED	1%
Duotherapy	3%

Predicting risk of future seizure

Kim et al. Lancet Neurology. 2006

Prognostic index

1 seizure		0
2-3 seizures		1
4+ seizures		2
Neurological disorder or deficit, learning disability or developmental delay		1
Abnormal EEG (specific focal or generalized epileptiform or slow wave abnormality, excluding non-specific abnormality)		1

	Probability of seizure at (without meds -> with meds)
Risk level	1yr	3yr	5yr
Low (score 0)	0.19 -> 0.26	0.28 -> 0.35	0.30 -> 0.39
Medium (score 1)	0.35 -> 0.24	0.50 -> 0.35	0.56 -> 0.39
High (score 2+)	0.59 -> 0.36	0.67 -> 0.46	0.73 -> 0.50

Risk of subsequent seizure after 1-3 seizures (Hauser et al. NEJM. 1998)

Risk of recurrence highest in first 3-6 months

Status epilepticus

Epidemiology

8% pt in coma without sz hx nor overt nor subtle signs of sz were in nonconvulsive 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

· Nonconvulsive status is common after convulsive status, so stat EEG is indicated if patient is not awake after resolution of convulsive status; consider 24 hours of prolonged-intermittent EEG after resolution of convulsive or nonconvulsive status in patients who are not awake.

· Consider periodic or continuous EEG monitoring in any ICU patients who are confused or unresponsivve

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 10 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) while waiting for fosphenytoin from pharmacy

Lorazepam 0.1mg/kg @ 2mg/min Q2min up to 10mg max

Midazolam 0.1-0.2mg/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 dose 20mgPE/kg @ 150mg phenytoin equivalents/min IV (if not PME/JME) -> Repeat 5-10mg/kg if needed

i. Fosphenytoin should always be used over phenytoin for patients in SE because it is safer

ii. Fosphenytoin is available in NSICU.

iii. 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 20-25 mg/kg (repeat 10-15 mg/kg if necessary) -> 3 mg/kg/hr

i. In 1 RCT, PHT (18 mg/kg) vs. VPA (30 mg/kg) in convulsive status successful 42% vs. 66%

Phenobarbital (PB) 20mg/kg IV @ 50-100mg/min -> Repeat 5-10mg/kg PB if needed

4) Drug-induced coma, midazolam is preferred (after 1 hour)

a. Dr. Woo’s strategy: use propofol to obtain burst suppression x 24hours, then withdraw, if still seizing, use pentobarbital

b. Midazolam 0.1-0.2mg/kg slow bolus, then start maintenance at 0.05-0.5 mg/kg/min

i. 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

c. Propofol 1-2mg/kg bolus over 5 minutes, then 2-10mg/kg/hr-

i. Beware of cardiac toxicity/propofol infusion syndrome, especially using >24hrs; pentobarbital is preferred if anticipating treatment longer than 24 hours

ii. Chance of seizures controlled (Barbiturate 82% vs Propofol 63%)

iii. Time to control longer for barbiturates (123 min) than propofol (2.6 min)

iv. No difference in mortality barb vs propofol

d. Pentobarbital 3-5 mg/kg at 25mg/min, then start gtt 0.5-2mg/kg/h. If not in burst suppression, use 1mg/kg boluses q15-30min to obtain burst suppression, then adjust gtt only if needed to maintain it.

i. Notify ICU team immediately (central line will be needed + has many systemic effects)

ii. Hypotension requiring pressor support in most cases

iii. PTB associated with a lower frequency of breakthrough seizures, and higher rate of hypotension than propofol or midazolam (Claassen Epilepsia 2002;146-153)

e. Ketamine 1-4.5mg/kg load w/supplements of 0.5-2.5 mg/kg every 30-45 min or 10-50 mcg/kg/min

f. Continue anesthesia for 12-24hr then withdraw

g. Goal: burst suppression (call tech for continuous EEG)

To paralyze the patient use

Rapacuronium 1.5mg/kg or

Vecuronium 0.1mg/kg

To reverse: Neostigmine 50-70 microgm/kg

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

· Any ICU patient with altered mental status

Absence status

Often terminates with GTC

Rx: PO benzos vs. PO/IV VPA

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	metabolic	infection	stroke	trauma	AED withdrawal	ETOH
% Mortality	60	47	37	30	30	27	15	5	5

Antiepileptic drugs

Sources: Ficker lecture Epilepsy Rx; UpToDate 2/06; PDR. Clinical handbook of Epilepsy. 1^st edition. 2005. Clinician’s Guide to Antiepileptic Drug Use, Privitera et al, 2006.

Initial therapy

Seizure Type	Drug options	Contraindicated
Partial sz:	PHT, CBZ, VPA, LTG, TPM, OXC, GBP
Partial sz adjunct:	ZNS, LEV, TGB
Absence	VPA, ESM, LTG, TPM	CBZ, OXC, GBP, TGB, PB
Primary Generalized TC	VPA, LTG, TPM, ZNS, LEV, FBM
Young pt/partial sz	PHT, CBZ, LTG, OXC, TPM
Older pt/partial sz	GBP, LTG, LEV
Young pt/generalized	VPA if male; LTG, TPM if female
Lennox-Gastaut	LTG; or FB (if severe)	PB
Myoclonic seizures	VPA, LEV, KLO	CBZ, OXC, LTG may make myoclonus worse

Choice of AED in pt with liver failure. LEV, GBP, PGB; don’t use older drugs, which are metabolized by liver and alter liver metabolism.

AED Pharmacokinetics

Source: Morriss lecture 7/08

Drug	Time to Peak Levels	Oral Bioavailability	Protein Binding (%)	Elimination half-life	Target Serum Level (mg/L)
Carbamazepine	4-24 h	75-85%	75	5-26 h (variable)	4-12
Clonezapam	1-4 h	>80%	85	20-80 h	------
Ethosuximide	<4 h	<100%	0	30-60 h	40-100
Felbamate	1-4 h	90%	20-25	13-30 h	200-460
Gabapentin	2-4 h	60%	0	5-9 h	------
Lamotrigine	1-3 h	<100%	55	30/15/60 h	2-20
Levetiracetam	0.6-1.3 h	<100%	0	6-8 h	-----
Oxcarbazepine	4-5 h	<100%	38 (MHD)	8-10 (MHD) h	10-35
Phenobarbital	1-3 h (variable)	80-100%	45-60	75-120 h	15-40
Phenytoin	8-12 h	95%	70-95	7-42 (mean 20) h	10-20
Primidone	3 h	<100%	25	5-18 h	5-12
Topiramate	2 h	<100%	15	18-23 h	9-12
Valproate	1-8 h (dependent on formulation	<100%	85-95	4-12 h	40-120

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 (steady state) 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 after 3-5 years, megaloblastic anemia, confusion, hallucination, and drowsiness, inhibition of ADH and insulin secretion, Stevens-Johnson syndrome (esp first 8 weeks), neuropathy; hepatotoxicity & bone marrow suppression (check cbc, LFTs)

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) level, total: 10-20 mcg/ml

8) Normal level, free: 1-2 mcg/ml

9) Instructions: take on empty stomach

10) Pregnancy category: D

11) 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, Tegretol XR, 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, CBZ-10-11 epoxide is the active form

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 (5% in elderly), Stevens-Johnson/TEN (esp. within 8 weeks), osteoporosis after 3-5 years

7) Monitor CBC, LFT initially, 3 mo, then q6 months

8) Drug interactions: cimetidine, diltiazem, erythromycin & clarithromycin, INH, propoxyphene decrease metabolism

9) Carbamazepine increases metabolism of other AEDs, warfarin, OCP, etc.

10) 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 3-4 days after initial dose or change)

3) Normal level: 50-150 mcg/ml

4) PK: Liver metabolism P450, INHIBITOR; 90% protein bound, safe with clozapine

5) SE: weight gain, N/V, hair loss, bruising, tremor, jaundice, VLP-associated hyperammonemia (lethargy, seizures, coma, death; however most cases of elevated ammonia in patients receiving VPA are asymptomatic), fatal hepatitis (1/22,000 in adult c other AED; 1/700 in children with children c other AED), sedation, ataxia, dizziness, rash, may cause thrombocytopenia and inhibition of platelet aggregation, hyponatremia, osteoporosis after 3-5 years

6) MOA: blocks Na-channels; increases GABA

7) Monitor CBC, LFTs

8) Interactions: inhibits the metabolism of Phenobarbital, and lamotrigine, etc.

9) Pregnancy category: D (at 1250mg/day -> 30% chance of birth defects; at 750mg/d -> 10% chance)

10) Depakene (acid form) is less well tolerated and requires tid-qid dosing

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, incl SJS; rare hepatotoxicity, marrow suppression (check cbc, LFTs)

4) Dose – 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) PK: Not protein bound, excreted unchanged in urine

5) Instructions: Take >2 hours after antacids

6) Therapeutic uses: -partial sz, generalized tonic-clonic sz

7) Good in elderly and pt with liver disease

8) 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, absence

2) Dose- bid dosing, depends on other AEDs used; total daily dose listed in chart below so divide listed dose bid

a) When transitioning to lamotrigine from another AED: overlap until lamotrigine dose is 100mg bid, then titrate other AED

b) LTG TOTAL DAILY DOSE

Week	With PHT/CBZ	With VPA	Monotherapy
1-2	50mg	25mg QOD	25mg
3-4	100	25 QD	50
5	200	inc 25-50/d Q1-2wk -> 100-150mg/d	100
6	300		200
	inc 100 Qwk -> 300-500mg/d

3) SE: Less sedating that other AEDs, 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

4) PK: Liver metabolism

5) Goal level: 3-10 or 15-18 in refractory cases

6) Drug interactions

a) increased metabolism by carbamazepine, phenytoin

b) decreased metabolism by valproic acid

c) interaction with BC pill: OC increases clearance of LTG

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, depression (be cautions if starting in patients with preexisting depression/mood problems)

6) Pregnancy category: C

7) Good in elderly and pt with liver disease

8) MOA: affects synaptic vesicles

Toprimate [TPM] (Topamax)

1) Therapeutic uses: Partial/generalized seizures (GTC)

2) Initial dose: 25 mg/day increasing weekly by 25 mg to target for newly diagnosed of 100 mg/day; split daily dose BID

3) Doses above 400mg/d rarely more effective than lower doses

4) PK: Clearance doubled by inducers (PHT, CBZ) -> need to double TPM dose

5) MOA: blocks Na channels; increases GABA; inhibits NMDA; modulates Ca++ channels

6) 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.

7) 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. At doses >200mg/d may reduce efficacy of OCP.

8) Pregnancy category: C

Zonisamide [ZNS] (Zonegran)

1) Therapeutic use: Partial seizures. Adjunct therapy.

2) Dose: 100mg/d (or 2-4mg/kg/d in children) -> inc. Q2wk -> 400-600mg/d; divided qd or bid

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: absence sz

2) Dose: Start 250 mg/d and increase by 250mg q 4 to 7d as needed. Divide bid. (Check level after 1-3 weeks)

3) Max dose: 1500mg/d

4) Level: 40-100mcg/ml

5) SE: N/V, sleep disturbance, drowsiness, hyperactivity, liver failure, Stevens-Johnson

6) MOA: Inhibit T-type Ca channel

7) PK: liver P-450 metabolism; however, it does not induce P-450 synthesis

8) 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 – CYP 3A isoform subfamily of cytochrome P-450, highly protein bound

5) MOA: GABA reuptake inhibitor

Oxcarbazine [OXC] (Trileptal)

1) Therapeutic use: Partial seizures. 25% crossrxn with (CBZ)

2) Dose: 300mg once daily or BID and increased by 150-300mg q week to a dose of 1200mg/d; may titrate as tolerated up to 2400-3600 mg/day.

3) PK: liver metabolism, metabolized to 10-monohydroxy oxcarbazepine (MHD) with half-life of 9 hours, 40% protein bound

4) SE: hyponatremia, N/V, cross-hypersensitivity with CBZ (25%), rash, etc.

5) Can induce reduce concentration of other Rx, such as OCP

6) 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 low dose 25-50mg/d to avoid somnolence and slowly titrate to 300mg/d if necessary; divided TID

3) Metabolism – renal

4) Adverse effects – weight gain (7%), dizziness, edema, easy bruising, drowsiness

5) Pregnancy category: C

Felbamate [FB] (Felbatol)

1) Therapeutic use: Usually reserved for severe refractory Lennox-Gastaut (reduces atonic seizures and improves global assessment scores in children with Lennox-Gastaut syndrome). Can be used for refractory partial and generalized seizure. 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. INHIBITOR. Liver metabolized (50%) and renally excreted (90%).

4) Adverse Effects: Caution – Relatively frequent aplastic anemia (1/3000; mean onset ~180 days, usu. within 1yr), liver damage (1/6000; mean onset ~215 days). Patient should sign consent. Can be fatal!

5) Check CBC, LFTs Q1week x 1 mo, then q1mo x 1 year, then q3mo thereafter

6) Not sedating; minimal cognitive effects

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.

d) Treatment. Corticosteroids.

8) THALAMIC PAIN

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

9) 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 3^rd vent, CNS infection, idiopathic.

Migraine prophylaxis

Drug	Useful with	Efficacy	Dose	SE	Contraindications
Propranolol Nadolol	HTN, heart disease	60-80%	(propranolol) 40-80mg qd -> 160mg bid (nadolol) 20-40mg qd -> 80mg bid	Fatigue, insomnia, depression	Asthma, low BP, low HR, DM, PVD, ED, sinus dysfcn, depression, insomnia, fatigue
Amitriptyline Nortriptyline	Depression, anxiety, insomnia		10-25mg qhs -> 100-200mg qhs or level > 200-250ng/ml	Nortrypt has fewer SEs; Dry mouth, sedation, constipation, increased appetite
Verapamil Diltiazem	HTN		120mg qd-bid -> 240-360 bid	Well-tolerated; possible constipation, leg edema, palpitations	Beta-blockers
VLP	Seizures, bipolar disorder	Dec. HA frequency by 50%	125-250mg qhs or ER 500mg qhs -> 1000mg bid or level 50-150mcg/ml	Increased appetite/weight gain, hair loss, nausea, tremor, sedation, liver toxicity	Pregnancy
GBP	Neuropathic pain	2.7 HA/mo vs. 3.5 46% had 50% dec. HA frequency	2400mg/d
Cyproheptadine (anti-histamine)	Allergies		2-4mg qhs -> 8mg tid	Sedation, increased appetite
TPM ($$$)	Obesity	50% had 50% dec. HA freq	25mg qhs -> 100mg bid	Paresthesias (50%), wt loss (10%), dizziness, confusion
CoQ ($$$)		47% had 50% dec HA at 3 mo. (based on 1 study)	100mg tid
Riboflavin		54% had 50% dec. HA at 2 mo. (based on 1 study)	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) Place hep lock

2) Order DHE-45 and metoclopramide (Reglan) to the floor stat.

3) Give 10mg metoclopramide IV followed immediately by 0.5mg DHE IV given over 2 minutes

4) If nausea appears or headache disappears within 1 hour, order DHE 0.5mg IV Q8 + metoclopramide 10mg IV Q8

5) 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.

6) After 5 doses given, d/c metoclopramide

7) Prophylaxis begun after step 4 or 5

8) After pt is headache free, substitute DHE 1mg IM or SC Q8 for IV form

9) Lomotil is usually necessary for diarrhea or codeine withdrawal; the average dose is 2-3 tablets Q6h prn.

10) 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.

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

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

13) 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; see below for tables from original article): 210 pts with serial neuro exams after cardiac arrest.

a. Total of 13% regained independence within 1^st 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. UniversityHospital 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 33^O 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 33^O C (bladder, rectal, or tympanic), keep patient at 33^O 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 36^O 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%

Levy Criteria

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

CN 7 + 8 palsy -> Rhomboencephalitis -> Listeria

Labs

LP (see “CSF” section for tests to order)

Etiology: Bacterial

1) Definition: Non-elderly=age<60; elderly=age>60

2) N. meningitidis

a) 20% of meningitis in non-elderly; 3-4% in elderly

b) Risk factors: childhood-mid 20s

c) High mortality 5-10%

d) Waterhouse-Friderichsen syndrome a massive, usually bilateral, hemorrhage into the adrenal glands

e) Culture + in 80%

f) Meningococcal rash

g) Chemoprophylaxis

3) S. pneumoniae

a) 60% of meningitis in non-elderly; 70% in elderly

b) Risk factors: pneumococcal bacteremia, cribriform plate fracture, complement deficiency, hypogammaglobulinemia, splenectomy, diabetes, sickle cell, alcoholism, thalassemia, skull fractures, CSF rhinorrhea

c) Precedent illnesses: pneumonia, acute otitis media, sinusitis

4) L. monocytogenes

a) 6% of meningitis in non-elderly; 20% in elderly

b) Risk factors: defects in cell mediated immunity; Immunosuppressed, elderly and young

c) Site of entry: GI tract (cheese, ice cream, lunch meats)

d) Rhombencephalitis (VIIth and VIIIth palsies)

e) High mortality

5) S. epidermidis

a) Risk factors: surgery/foreign body

6) S. aureus

a) Risk factors: endocarditis, surgery/foreign body

7) Group B strep

a) 4% of meningitis in non-elderly; 3-4% in elderly

b) Risk factors: newborn

8) GNR

a) Risk factors: advanced medical illness, neurosurgery

9) H. influenzae

a) 10% of meningitis in non-elderly; 3-4% in elderly

b) Risk factors: diminished humoral immunity (Old age, Young age, splenectomy, acquired immunodeficiency)

10) Legionella

a) Acute febrile illness, often epidemic

b) Pneumonia, encephalopathy, HA, confusion

11) Mycoplasma

a) Sometimes aseptic meningitis

b) 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	Sev. Hundred->60,000, usually a few thousand, PMNS	Usually 100-500, occ > 1000	5-40 in most cases
Tuberculous	Usually elevate, but can be low with spinal block	25-100, rarely >500, lymphs (except early)	Usually 100-200, can be higher with block	Usually low, < 45 in 75%
Cryptococcal	Usually elevated	0-800, avg 50, lymphs	20-500, usually 100	Reduced, avg 30
Viral	Normal to mod elevated	5-few hundred, may be up to 1000, lymphs except within 48h	nl or sl elevated, <100	nl (except mumps, HSV or CMV, which is low in 25%)
Acute syphillis	Usually elevated	Avg 500, usu. Lymphs	Avg 100	Nl
Cystercircosis	Often inc. but can be low with block	Increased, with 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	0-sev hundred, mono + malignant	Elevated, often very high	Nl to low in 75%
Legionella		Minor pleocytosis (20%)	Usually nl
Mycoplasma	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)

If Neiserria, chemoprophylaxis close contacts and patient (to clear nasopharynx) with ciprofloxacin x 1

Length of antibiotics in bacterial meningitis

10-14 days for S. pneumoniae

5-7 days for meningococcus

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*]
Impaired cellular immunity (HIV, Malignancy, Chemotherapy, Chronic steroids and immunosuppression)	AMP + TAZ [+ VANC*]
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 10 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 “CSF pellet”, 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/Reye’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 Neel’s lecture 2006

Diagnosis

CNS white matter lesions disseminated in space and time with no other etiological explanation!!!

Typical MS lesions on MRI:

§ Ovoid lesions with well-defined margins, usually asymmetric distribution

§ Typical Ms locations: periventricular (perpendicular: “Dawson’s fingers), subcortical/juxtacortical, corpus callosum, middle cerebellar peduncle, pons/medulla, C-spine

Atypical clinical features that should prompt extensive work-up for other etiologies:

§ Age of onset <15y or >50y

§ Hx of prior ischemic events or prominent vascular risk factors

§ Systemic features (rash, lymphadenopathy, fever, malaise, arthralgias, wt. loss, anemia, leucopenia)

§ Pregnancy, ovarian failure/amenorrhea/infertility

§ Hyponatremia, alcoholism, malnutrition, drug abuse, HIV+

§ Hx of malignancy, chemotherapy, radiotherapy

§ Prominent autonomic features, peripheral nervous system involvement

§ Prominent H/A, confusion +/- psychiatric disturbances, myoclonus, sz

§ Hearing loss

Atypical paraclinical features that should prompt extensive work-up for other etiologies:

§ Marked CSF pleiocytosis (>50 cells/ml), high CSF protein, low CSF glucose, Lack of OCB/IgG index

§ MRI atypical features: diffuse/confluent WM involvement, prominent GM (basal ganglia) involvement, meningeal or atypical enhancement (milliary, streaks), persistent enhancement after steroids, paucity of MRI findings

Phase of illness: relapsing remitting, secondary progressive, primary progressive

2005 Revised McDonald MS diagnostic criteria

McDonald et al. Ann Neurol 2001; 50(1): 121-7.

Polman et al. Ann Neurol 2005; 58: 840-846

Barkhof et al. Brain 1997 Nov;120 ( Pt 11):2059-69

Tintore et al. AJNR Am J Neuroradiol. 2000 Apr;21(4):702-6

“Positive MRI” for dissemination in space: Need 3 of 4

1) One gadolinium-enhancing lesion (brain or cord) OR nine or more T2-hyperintense lesions (including cord lesions)

2) At least one infratentorial lesion (brainstem or cord)

3) At least one juxtacortical lesion

4) At least three periventricular lesions

“Positive CSF”:

Oligoclonal IgG bands in the CSF (absent in serum) OR elevated IgG index

“Positive visual evoked potential (VEP)”:

Delayed but well-preserved wave form

MRI evidence of dissemination in time:

1) A new GdE lesion ≥3 mo after onset of initial clinical event at a site different from initial event OR

2) A new T2 lesion at any time compared to a reference scan done at least 30 days after initial clinical event

Revised McDonald criteria for diagnosing MS

Clinical attacks	Objective lesions	Additional requirements to make Dx
≥2	≥2	None (but alternative diagnoses have to be considered and ruled out)
≥2	1	Dissemination in space by MRI OR (2 or more lesions c/w MS + positive CSF) OR await further clinical attack implicating different site
1	≥2	Dissemination in space by MRI OR second clinical attack
1	1	Dissemination in space by MRI OR (2 or more lesions c/w MS + positive CSF) AND Dissemination in time by MRI OR second clinical attack
0 progression from onset	≥1	Disease progression for 1 year AND 2 out of 3 of the following: § Positive brain MRI (≥9 T2 lesions OR ≥4 T2 lesions + positive VEP § Positive spinal cord MRI (≥2 focal T2 lesions) § Positive CSF

An attack must last at least 24 hours

Separation in time = at least 30 days from onset to onset

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 q day 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. Additionally, IV Methylrednisolone therapy decreased rate of conversion to clinically-definite MS

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 of debilitating symptoms: especially involving spinal cord, when patient requires urgent work-up and treatment

2) When going to perform LP as a part of diagnostic work-up to r/o MS, please call Dr. Bielekova’s lab: 558-3857 or page Dr. Bielekova 230-0473 PRIOR to performing LP in order to allow patient to participate in Waddell Center for MS research protocol

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 and the diagnostic work-up (including LP) can be performed at outpatient basis by urgent referral to the Waddell Center for MS

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. Treat early, when the symptoms are developing, not when they are already improving.

ii) Methylprednisolone 1000mg IV Qday x 3-5 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, aseptic necrosis of joints

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 low inflammatory MS

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 expand regulatory T cells that mediate bystander suppression of encephalitogenic T cells. Because GA-specific T cells also produce BDNF, theoretically GA may have some neuro-restorative potential

b) Interferon-beta (potency/dose: Avonex < Rebif < Betaseron)

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%; 5-yr 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 NSAID 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 NSAID); 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 (try to avoid bc of severe cardiotoxicity and risk of AML)

i) Indicated in RR or progressive MS not responding to other therapy

ii) Side effects: cardiotoxic (use limited to <2-3 years (depending on the dosing schedule), check EF before starting, don’t start if EF<50%), acute myelogenous leukemia estimated 1 in 300-500 patients

iii) Dose: 12mg/m2 q3 months over 5-15 min

iv) Monitor CBC, LFTs prior to each dose, EchoKG q 6 months

v) Contraindicated in pregnancy

d) Natalizumab (Tysabri)

i) Humanized monoclonal Ab against VLA-4

ii) MoA: prevents transmigration of T cells, B cells, NK cells and monocytes/macrophages across BBB

iii) Risk of PML estimated 1/1000 patients treated for 2 years → because of this risk, Natalizumab can be administered only as a part of TOUCH program by TOUCH-certified MS specialists: please refer potential patients to the Waddell Center for MS

e) Pulse steroids, Immunosuppresants → please refer patients to the Waddell Center for MS

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, special “cooling” vests

iv) Keep rooms cool

v) Treat fever

vi) Amantadine 100mg QAM + Q noon

vii) Modafinil 50-200mg 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

Neuromuscular disorders

Peripheral Neuroanatomy

EMG Chart

		C3	C4	C5	C6	C7	C8	T1
	Median				PT/FCR	PT/FCR	APB/OP	APB/OP
						FDP1-2	FDP1-2
							FPL	FPL
							PQ	PQ
	Ulnar						FDI/ADM	FDI/ADM
							FDP3-4	FDP3-4
							FCU
	Radial			BR	BR	EDC	EDC
					ECR	ECR
						APL	APL
						ECU	ECU
					T	T	T
						EIP	EIP
	Axillary			D	D
				Tmin	Tmin
	Musculocutaneous			B	B
	Suprascapular			IS/SS	IS/SS
	Dorsal scapular			Rhom
	Subscapular			Tmaj	Tmaj
	Spinal accesory	Trap	Trap

			L2	L3	L4	L5	S1	S2
Sciatic	Tibial	Medial Plantar					AH	AH
						ST	ST
						S	S	S
						BFLH	BFLH
						LG	LG
							MG	MG
						PT
		Lateral Plantar					ADQ	ADQ
							IO	IO
	Peroneal	Deep Branch			AT	AT
						EDB	EDB
					EHL	EHL
		Sciatic portion					BFSH	BFSH
		Superficial Branch				PL	PL
		Obturator	AL	AL	AL
		Inferior Gluteal				GMax	GMax
		Superior Gluteal				GMin	Gmin
						TFL
		Femoral	IP	IP	IP
			RF	RF	RF
			VL/WM	VL/WM	VL/WM

Mayo NCS Normal Values

Nerve	Distance (cm)	Latency (ms)	Amplitude	Velocity (m/s)	F-wave (ms)	Comments
Median Motor	7	At wrist 2.5-4.4	At elbow 4.0-18 mV	49-70	22-31	Amp difference wrist-elbow<20% Median <= ulnar latency by 1.8ms Medial/ulnar F-wave difference <3ms Difference b/t arms: amp<10mV, velocity<5ms
Ulnar Motor	6.5	At wrist 2.1-3.3	At elbow 6.6-15 mV	53-72	21-32	Amp difference wrist-elbow<20% Difference b/t arms: amp<7mV, velocity<5ms
Median Palmar	8	1.5-2.2	50-180 mcV			Median <= ulnar latency at Same distance by 0.2ms Latency difference b/t hands at same distance should be <=0.5ms
Ulnar Palmar	8	1.5-2.2	15 mcV			Latency difference b/t Ree hands at same distance should be <=0.2ms
Median Sensory	13	2.5-3.5	25-86 mcV	57-71		Amplitude can be 15 over age 60
Ulnar Sensory	11	2.1-3.0	10-58 mcV	56-76
Radial sensory	10	At wrist 1.9-2.8	At wrist	20-60 mcV
Peroneal Motor	8.5	Ankle 2.4-7.0	Knee 2.0-12 mV	41-59	38-57	Amp difference ankle-knee<22% Tibial/peroneal F difference <7ms Diff b/t legs: amp<5mV, vel<5ms
Tibial Motor	8	Ankle 3-6.0	Knee 4.0-25 mV	40-58	41-57	Amp diff ankle-nee<50%
Sural sensory	14	3.2-4.0	6-25 mcV			Latency up to 4.4 if >40 y/o
Superficial Peroneal sensory	14	Ankle 2.9-4.0	6			Response may be absent w/ large calf & age>55
Medial Plantar Sensory	12-14	2.4-4.0	7-44 mcV

Dermatomes

Peripheral Nerves

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:

i) ·Group 1: ocular, 15-20%

ii) ·Group 2A: mild generalized, 30%

iii) ·Group 2B: moderately severe generalized, 20%

iv) ·Group 3: acute fulmiating, 11%

v) ·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) 3. Diagnosis:

i) Clinical evaluation

(1) 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.

(a) Patient should ideally be off any AChE inhibitors for at least 24hrs

(b) Assess objective sign of weakness prior to administration and after. Any improvement will likely last less than 30min.

(c) 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.

(d) Monitor pulse and BP. Have atropine at bedside in case of severe bradycardia.

(e) Side effects include fasciculations, bradycardia, nausea, vomiting, lacrimation, salivation.

(f) Test is only positive if objective improvement occurs, not just subjective improvement from patient’s perspective.

ii) Labs

(1) AChR antibodies (3 types-blocking, binding, modulating) positive in 80-90% of patients with generalized MG. Present in 70% in patients with ocular form.

(2) Antibody levels do not necessarily correlate with disease severity in the individual patient.

(3) 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.

(4) Anti-striatal muscle Ab (antititin Ab) positive in 30% of patients with MG often find abnormal ANA, TSH associated with MG.

iii) Electrophysiology

(1) 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

(2) Single fiber EMG: increased jitter and blocking of transmission.

4) 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.

5) Treatment

a) Acetylcholinesterase inhibitors: Most commonly Mestinon (pyridostigmine)

i) usually used patients with mild, stable weakness or ocular sx only

ii) Start at 30-60mg po q6hrs. Dose titrated gradually. Most adults require 60-120mg q4-6hrs.

iii) Side effects: nausea, vomiting, abdominal cramping, diarrhea, increased oral/bronchial secretions, bradycardia, confusion, psychosis

b) Corticosteroids (Prednisone)

i) 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)

ii) Because of the above point, start low, increase slowly: start with 60mg daily, increase by 5mg/day every 3-4 days until symptoms improve.

iii) Generally gradually taper dose after at least 1 month to alternate-day dosing, with continued tapering after another month.

iv) If hospitalized, start prednisone at high dose (60mg daily) and monitor for temporary worsening.

v) May take weeks to months to see symptomatic improvement.

vi) 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.

i) 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.

ii) 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.

i) 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.

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

iii) PE requires placement of dialysis catheter. Exchanges occur every other day (2-3 L exchanged) for total of 5 treatments

e) Thymectomy

i) Indicated for patients with thymoma.

ii) In patients without tumor, the issue is more controversial. 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. There is significant risk of complications.

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:

(a) ·Anti-GM1 (most commonly seen in AIDP and most closely associated with C. jejuni infection).

(b) ·Anti-GD1a (most commonly seen in AMAN form)

4) Diagnosis:

a) Clinical features and history most helpful in diagnosis

i) CSF shows elevated protein levels with normal cell counts (may have slightly elevated WBC in 10% of patients) and no evidence of pleocytosis.

ii) EMG: May show no abnormalities in early stages.

(a) 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.

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

(d) In Miller-Fisher syndrome reduced amplitude action potentials are most prominent. May have abnormal blink responses.

5) Differential diagnosis. Sarcoid radiculopathy, Carcinomatous radiculopathy, Lymphoma, Spinal cord compression, HIV radiculopathy, Paraneoplastic syndromes, Diabetic amotrophy

6) 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.

i) IVIG given as 2mg/kg total dose with equal infusions over 5 days (400mg/kg/day)

b) Treatment should begin as soon as possible, preferably within 7-10 days for best results. Some attendings (Quinlan) recommend first dose IVIG on night of admission, others (Kissela) prefer to wait until rounds the next morning.

c) Mean time to improvement in studies ranged from 6 to 27 days with both treatment types.

d) Up to 10% of patients receiving IVIG or PE may have relapse of symptoms within several weeks necessitating repeat treatments with IVIG or PE.

e) Patients should be monitored in ICU until they have reached a plateau in the progression of their symptoms.

f) Must have telemetry if on floor to evaluate for autonomic dysfunction

g) Consider checking Camylobacter jejuni Ab (this is a worse prognostic sign)

h) Frequent monitoring of NIF and FVC should be done (Q6h for at least 24h).

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

ii) 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.

iii) For FVC 15-20mg/kg, check NIF & FVC Q2h.

i) Other treatments to keep in mind include early physical therapy, frequent repositioning, DVT prophylaxis, treatment of depression, neuropathic pain control.

j) There is no benefit of corticosteroids in AIDP.

7) 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.

Approach to ataxia.

From Sahay lecture 5/08

DDX.

Vascular: stroke, superficial hemosiderosis

Infectious: viral cerebellitis (varicella), rubella, H flu, CJD, abscess, basilar meningitis, Whipple’s

Trauma

Toxic: Alcohol, Thallium, bismuth, methyl mercury, methybromide, toluene

Autoimmune: SLE, stiff-person (anti-GAD), sarcoid, Celiac disease (anti-gliadin Ab)

Metabolic, acquired: B1, B12 deficiency, vitamin E deficiency, hypothyroidism, hyperammonemia, hypoparathyroid

Iatrogenic: Meds (PHT, CBZ, Brabiturates, Lithium, Cyclosporine, Methotrexate, 5FU, Serotinin syndrome)

Neoplastic: tumor, paraneoplastic (Anti-Hu, -Yo, -Ri)

Congenital, inherited: SCA (types 1,2,3,6,7,8), DRPLA, Fredreich’s, Episodic ataxia, ataxia-telangiectasia, Von-Hippel-Lindua syndrome

Congenital, metabolic: hexosaminodase deficiency, Wilson’s disease, abetalipoproteinemia, aminoaciduria, Refsum disease

Degenerative: MSA, progressive myoclonic epilepsy

Demyelinating: MS, Miller-Fisher variant

Episodic: Migraine, vestibular dysfunction

Other: hydrocephalus, amyloid, Chiari malformation, sensory ataxia

Clues to SCAs:

· Childhood onset (7, 13, DRPLA)

· Young adult onset (1, 2, 3, 21)

· Older adult onset (6)

· Anticipation (1, 7, DRPLA)

· UMN signs (1, 3, 7, 12; some in 6, 8; rare in 2)

· Slow saccades (early-2, 7, 12; late-1, 3; rare- 6)

· Chorea (DRPLA)

· Parkinsonism (2, 3, 21)

· Visual loss (7; possibly 2, 6, 10)

· Dementia (12, DRPLA; early- 2,7)

· Myoclonus (2, 14)

· Seizures (10, 17)

Disease	% of AD cerebellar ataxias	Clinical features (all have dysarthria & ataxia)
SCA 1	5.6 %	Slow, hypermetric saccades; ++Tendon reflexes; Evoked motor potentials, Long conduction times; peripheral neuropathy (42%); UMN signs, anticipation, onset 20-39 Ataxin-1 (6p) CAG repeat>40
SCA 2	15.2 %	Slowing saccades; Myoclonus or action tremor; peripheral neuropathy (80%); decreased reflexes; onset 2-65 40% < 25 yr; pyramidal signs (20%), anticipation, may be sporadic Ataxin-2 (12q) CAG > 34 repeats
SCA 3	20.8 %	Gaze-evoked nystagmus; prominent spasticity or neuropathy; Parkinsonism; fasiculations; absent reflexes; extensor plantar responses; bulging eyes; limited EOM; muscle atrophy; peripheral neuropathy (54%) Ataxin-3 (14q) CAG > 56 repeats
SCA 6	15.2 %	Pure cerebellar syndrome; -ve family history; dementia; frontal lobe signs; peripheral neuropathy; seizures 27% sporadic; onset 30-50 CACNL1A (19p13) CAG > 21 repeats
SCA 7	4.5 %	Retinal degeneration; visual loss; ophthalmoplegia (70%); slow saccades; pyramidal signs; Hearing loss; Onset in 1st decade; no peripheral neuropathy Ataxin-7 (3p21) CAG > 38 repeats

Muscle diseases

Metabolic myopathy

1) Glycogen

2) Lipids

3) Purines

4) Mitochrondrial

Glycogen Storage Diseases

Acid maltase deficiency

Source: Continuum 6/06

Age of onset: Three forms: infantile, juvenile and adult onset (typically age 20s-30s, max 18-65)

Epidemiology: Autosomal recessive, chromosome 17

Clinical features: Proximal>distal weakness, rarely scapuloperoneal; asymmetric (8%); macroglossia (8%); atrophy 20%; no hepatomegaly; respiratory involvement 16-33% (dyspnea, sleep apnea symptoms)

Labs: CK moderately elevated; normal forearm ischemic exercise test; myopathic EMG, abundant myotonic and CRD esp. paraspinals; EKG LAD, short PR, large QRS, inverted T, ST depression, WPW; FVC & NIF reduced; reduced a-glucosidase activity to <10% in muscle fibers, leukocytes or urine

Pathology: Muscle biopsy=increased fiber size variability, fiber splitting, atrophy, nonrimmed vacuoles, PAS+ material digested by diastase, vacuoles stain + with acid phosphatase.

Treatment: Enzyme replacement for Pompe’s disease effective in open label trial

Pathogenesis: Defect in a-glucosidase, which cleaves a-1,4 and a-1,6 linkages in glycogen, maltose and isomaltose

Debrancher enzyme deficiency (Cori-Forbes)

Source: Continuum 6/06

Age of onset: typically age 30s-40s, 1/3 in infancy

Epidemiology: 25% of glycogen storage disease, gene AGL chromosome 1

Clinical features: static myopathy, respiratory involvement, slowly progressive, atrophy & weakness of distal muscles 50%, polyneuropathy; cardiomyopathy

Labs: CK 2-20x normal; forearm test=no rise in lactate, normal ammonia; EKG conduction defects & arrhythmia; TTE=hypertrophic obstructive cardiomyopathy; NCS=normal or moderate sensorimotor polyneuropathy; EMG=minimal change to myopathy with marked abnormality including myotonia; assay of debrancher enzyme activity in muscle fibroblasts or lymphocytes

Pathology: Muscle biopsy=PAS+ and diastase digestable glycogen particles, (-)acid phosphatase stain

Treatment: prevent fasting hypoglycemia with frequent low-carb, high-protein intake; liver transplant does not fix muscle problem

Polyglucosan body disease (Anderson’s disease)

Source: Continuum 6/06

Age of onset: 4 forms based on age of onset-this refers to adult onset form

Epidemiology: Autosomal recessive, chromosome 3, gene for glycogen branching enzyme BGE1

Clinical features: Mixed upper & lower motor neuron loss; sensory involvement; cerebellar ataxia; neurogenic bladder; dementia

Labs: CK sometimes elevated; abnormal EKG; NCS normal or axonal sensorimotor neuropathy; EMG myopathic, active denervation; decreased branching enzyme activity in skin fibroblasts

Pathology: Muscle biopsy=PAS+ diastase resistant filamentatous polysaccharide known as polyglycosan bodies

Treatment: Liver transplant in children, but not always curative

Pathogenesis: Defect in glycogen creation

Myophosphorylase deficiency (McArdle’s disease)

Source: Continuum 6/06

Age of onset: Childhood

Epidemiology: autosomal recessive, chromosome 11, gene muscle phosphorylase PYGM (there are different isozymes)

Clinical features: Exercise intolerance; fatigue; myalgia; cramps; poor endurance; muscle swelling; later fixed proximal weakness 33%; painful contractures with continued exercise; second wind phenomenon after brief rest; myoglobinuria 50% (age 10s-20s)

Labs: Forearm ischemic exercise test=flat lactate curve; CK elevated; NCS-rep stim following maximal exercise may show decrement; EMG usually normal, but myotonic discharges, PSW or fibs in 50%; can see complete electrical silence despite maximal contraction during an attack

Pathology: Muscle biopsy=variable fiber size; necrotic fibers, glycogen accumulations; negative myophosphorylase stain, but must not be within 1 month after myoglobinuria; phosphorylase activity in muscle < 10%

Treatment: ingestion of sucrose before exercise improved exercise tolerance in a small, single-blind study

Phosphofructokinase deficiency (Tauri’s disease)

Source: Continuum 6/06

Epidemiology: autosomal recessive, chromosome 12 (muscle isozyme), PFKM gene, 9:1 males

Clinical features: exercise intolerance; exercise-induced myoglobinuria; rarely fixed weakness; glucose leads to reduced exercise tolerance (cells can’t use glucose and giving it reduces fatty acids); mild hemolysis -> gouty arthritis & jaundice.

Atypical forms: fatal infantile form (cardiomyopathy, contractures, cortical blindness); late onset permanent myopathy (no myoglobinuria, mild exercise intolerance, proximal or scapuloperoneal weakness); hemolytic anemia without myopathy

Labs: CK elevated; ischemic forearm test=no lactate rise, normal ammonia; hemolytic anemia (high retic, high bili, high uric acid);

Pathology: Muscle biopsy=free glycogen with normal structure, PAS+ diastase resistant (infantile form nonspecific, no vacuoles)

Treatment: Aerobic conditioning program might improve exercise tolerance

Pathogenesis: PFK catalyzes the rate limiting step in glycolysis; usually 0% in muscle meaning muscle can’t use glucose

Forearm exercise test

Butterfly needle in antecubital fossa

Draw baseline ammonia & lactate

Open and close hand rapidly and strenuously for 1 minute

Draw ammonia & lactate at 1, 2, 4, 6, and 10 minutes

Normal=lactate and ammonia 3-5x rise above baseline

If both do not rise, then probably didn’t exercise enough

If lactate rises, ammonia doesn’t: myoadenylate deaminase deficiency

If ammonia rises, lactate doesn’t: myophosphorylase, phosphofructokinase, phosphoglycerate mutase, phosphoglycerate kinase, phophorylase b kinase, debrancher, or lactate dehydrogenase deficiencies

Peripheral Nerve Diseases

Charcot-Marie-Tooth disease

From Medlink 7/08

Better known as hereditary motor sensory neuropathy

Type 1: demyelinating

Type 2: axonal

Type 1A is most common, caused by duplication of PMP22 gene on chromosome 17

Autosomal dominant, but can be X-linked

Epi. 1A accounts for 60% of AD neuropathies; estimated prevalence 1/10,000

Clinical features. Variable severity & age of onset. Weakness, slowest in grade school class, numbness in hands and feet. Foot drop. Painful calluses, difficulty finding shoes d/t high arches. Cold feet, leg edema, hair loss. Dysethetic pain less common than in acquired neuropathies. Scholiosis, gait abnormality. Leg or hand cramps. Difficulty manipulating small objects.

Exam. Hammer toes, calf atrophy, high arches, palpable peroneal nerve at fibular head or ulnar nerve at medial epicondyle, stocking glove sensory loss, distal weakness. Decreased DTRs. Poor tandem, positive Romberg.

DDX. Hereditary sensory autonomic neuropathy type 1 (HSAN-1) often has motor involvement, despite the name, which is sometimes demyelinating (check SPTLC1 gene on chrom 9).

Diagnostics. Reliable genetic testing available for type 1. Check EMG to see if it’s demyelinating or axonal and if demyelinating (type 1) then send genetic testing. Uniform decreased conduction velocities on EMG are typical vs. non-uniform in most acquired causes. Check for additional causes of neuropathy. Evaluate pedigree.

Treatment. AFO.

Prognosis. Slow clinical course in 2^nd-4^th decade.

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 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 asymmetric, levodopa-responsive Parkinson’s disease but atypical forms 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 a combination of 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 alpha-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 a subcortical frontal-predominant type of dementia)

·Treatment:

-Dopamine Agonists (non-ergots: Ropinerole, Pramipexole; ergots: Pergolide [recently discontinued due to induction of drug-induced valvulopathy], Bromocriptine [almost never used]). 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, and impulse control disorders (excessive shopping, compulsive gambling, hypersexuality). 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): Mostly unable to cross the BBB, they are used only in conjuction with levodopa to prevent its peripheral decarboxylation into dopamine outside the brain, allowing more levodopa to follow its concentration gradient into nigrostriatal pre-synaptic terminals. May increase amount of “on” time and diminish severity of motor fluctuations as it extends the area under the curve for levodopa. 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.

-MAO-B inhibitors (Selegiline, Rasagiline): May have mild symptomatic benefits in early PD. Selegiline was previously thought to have some neuroprotective benefits but now it is generally felt this is not the case. Both of these drugs increase levodopa (though to a lesser extent than COMT inhibitors) and dopamine bioavailability in the brain.

-Anticholinergic drugs (trihexyphenidyl, benztropine): Rarely used now but remain an effective antitremor option in early disease stages. Later, it is avoided due to its cognitive and psychiatric side effects.

·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. Then, if present, attempt at reducing or eliminating anticholinergic drugs, amantadine, and dopamine agonists, in that order if necessary. Replacement of dopamine agonists with levodopa may often be sufficient to control behavioral difficulties. Finally, if the above steps are not successful, low doses of seroquel or, if ineffective, clozapine may be necessary. Risperdone and olanzapine are generally avoided as these “atypical” antipsychotics behave in typical neuroleptic fashion. 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 sporadic 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. Visual hallucinations should never be treated with antypsychotics as paradoxical worsening occurs. Rivastigmine is best used for this purpose.

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 a symmetric akinetic rigid tremorless 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 (supranuclear vertical gaze palsy).

b. Corticobasal degeneration (CBD): age of onset in 60’s or 70’s. Have markedly asymmetric parkinsonian symptoms, apraxia, aphasia, cortical sensory loss, “alien limb” phenomenon, frontal-type dementia.

c. Frontotemporal dementia (FTD): 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. Primary progressive aphasia (PPA) due to left frontal and temporal atrophy, and semantic dementia (or fluent PPA) due to left anterolateral temporal atrophy (or prosopagnosia if similar lesion on the right) are non behavioral FTD variants. “Pick’s disease” was the former nomenclature of these variants, named for the 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.

UPDRS Motor Subscale

18. Speech

0 = Normal.

1 = Slight loss of expression, diction and/or volume.

2 = Monotone, slurred but understandable; moderately impaired.

3 = Marked impairment, difficult to understand.

4 = Unintelligible.

19. Facial Expression

0 = Normal.

1 = Minimal hypomimia, could be normal "Poker Face".

2 = Slight but definitely abnormal diminution of facial expression

3 = Moderate hypomimia; lips parted some of the time.

4 = Masked or fixed facies with severe or complete loss of facial expression; lips parted 1/4 inch or more.

20. Tremor at rest (head, upper and lower extremities)

0 = Absent.

1 = Slight and infrequently present.

2 = Mild in amplitude and persistent. Or moderate in amplitude, but only intermittently present.

3 = Moderate in amplitude and present most of the time.

4 = Marked in amplitude and present most of the time.

21. Action or Postural Tremor of hands

0 = Absent.

1 = Slight; present with action.

2 = Moderate in amplitude, present with action.

3 = Moderate in amplitude with posture holding as well as action.

4 = Marked in amplitude; interferes with feeding.

22. Rigidity

(Judged on passive movement of major joints with patient relaxed in sitting position. Cogwheeling to be ignored.)

0 = Absent.

1 = Slight or detectable only when activated by mirror or other movements.

2 = Mild to moderate.

3 = Marked, but full range of motion easily achieved.

4 = Severe, range of motion achieved with difficulty.

23. Finger Taps

(Patient taps thumb with index finger in rapid succession.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.

3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.

4 = Can barely perform the task.

24. Hand Movements

(Patient opens and closes hands in rapid succesion.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.

3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.

4 = Can barely perform the task.

25. Rapid Alternating Movements of Hands

(Pronation-supination movements of hands, vertically and horizontally, with as large an amplitude as possible, both hands simultaneously.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.

3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.

4 = Can barely perform the task.

26. Leg Agility

(Patient taps heel on the ground in rapid succession picking up entire leg. Amplitude should be at least

3 inches.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.

3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.

4 = Can barely perform the task.

27. Arising from Chair

(Patient attempts to rise from a straightbacked chair, with arms folded across chest.)

0 = Normal.

1 = Slow; or may need more than one attempt.

2 = Pushes self up from arms of seat.

3 = Tends to fall back and may have to try more than one time, but can get up without help.

4 = Unable to arise without help.

28. Posture

0 = Normal erect.

1 = Not quite erect, slightly stooped posture; could be normal for older person.

2 = Moderately stooped posture, definitely abnormal; can be slightly leaning to one side.

3 = Severely stooped posture with kyphosis; can be moderately leaning to one side.

4 = Marked flexion with extreme abnormality of posture.

29. Gait

0 = Normal.

1 = Walks slowly, may shuffle with short steps, but no festination (hastening steps) or propulsion.

2 = Walks with difficulty, but requires little or no assistance; may have some festination, short steps, or propulsion.

3 = Severe disturbance of gait, requiring assistance.

4 = Cannot walk at all, even with assistance.

30. Postural Stability

(Response to sudden, strong posterior displacement produced by pull on shoulders while patient erect with eyes open and feet slightly apart. Patient is prepared.)

0 = Normal.

1 = Retropulsion, but recovers unaided.

2 = Absence of postural response; would fall if not caught by examiner.

3 = Very unstable, tends to lose balance spontaneously.

4 = Unable to stand without assistance.

31. Body Bradykinesia and Hypokinesia

(Combining slowness, hesitancy, decreased armswing, small amplitude, and poverty of movement in general.)

0 = None.

1 = Minimal slowness, giving movement a deliberate character; could be normal for some persons. Possibly reduced

amplitude.

2 = Mild degree of slowness and poverty of movement which is definitely abnormal. Alternatively, some reduced

amplitude.

3 = Moderate slowness, poverty or small amplitude of movement.

4 = Marked slowness, poverty or small amplitude of movement

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 drug…usually 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) I’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	Type of hemoglobin	T1	T2
Hyperacute (0-24hr)	oxyhemoglobin	Isodense	Bright
Acute (1-3 d)	deoxyhemoglobin	Isodense	Dark
Subacute (3-7 days)	intracellular methemoglobin	Bright	Dark
Chronic (<2 wk)	extracellular methemoglobin	Bright	Bright
Chronic (>2 weeks)	hemosiderin	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)	Notes
Morphine	10	30	3-4	PO 15-60
Oxycodone	NA	30	3-4	PO 10-15	Safe in renal insfx.
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

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 1^st 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 1^st)

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 4^th 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, 2^nd ed. 2003.

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