Download Stroke - neurology survival guide

Contents
Contents.............................................................................................................................................................................1
Differential Diagnosis ...........................................................................................................................................................1
Stroke ................................................................................................................................................................................1
Acute Ischemic Stroke .......................................................................................................................................................2
tPA ...............................................................................................................................................................................5
Stroke trials ..................................................................................................................................................................6
Vascular Territories ...........................................................................................................................................................7
Intraparenchymal Hemorrhage ......................................................................................................................................... 11
Subarachnoid Hemorrhage (SAH) ..................................................................................................................................... 12
Herniation/high ICP............................................................................................................................................................ 14
Epilepsy/Seizure ................................................................................................................................................................ 14
Status epilepticus ........................................................................................................................................................... 19
Antiepileptic drugs .......................................................................................................................................................... 20
AED Pharmacokinetics .................................................................................................................................................. 20
Headache ......................................................................................................................................................................... 24
DHE protocol .................................................................................................................................................................. 26
ALTERED MENTAL STATES: ................................................................................................................................................. 26
HYPOXIC-ISCHEMIC ENCEPHALOPATHY: ............................................................................................................................ 28
Hypothermia Protocol: ..................................................................................................................................................... 28
Levy Criteria................................................................................................................................................................... 29
Meningitis ......................................................................................................................................................................... 34
Chronic meningitis .......................................................................................................................................................... 37
CSF ............................................................................................................................................................................... 38
Multiple Sclerosis ............................................................................................................................................................... 39
Neuromuscular disorders .................................................................................................................................................... 42
Peripheral Neuroanatomy ................................................................................................................................................. 42
EMG Chart................................................................................................................................................................... 42
Mayo NCS Normal Values .............................................................................................................................................. 43
Dermatomes................................................................................................................................................................ 44
Peripheral Nerves ......................................................................................................................................................... 45
MYASTHENIA GRAVIS ...................................................................................................................................................... 46
Guillian-Barre Syndrome .................................................................................................................................................. 47
Muscle diseases ................................................................................................................................................................. 49
Glycogen Storage Diseases .............................................................................................................................................. 49
Forearm exercise test ................................................................................................................................................... 50
Peripheral Nerve Diseases ................................................................................................................................................ 50
Dizziness .......................................................................................................................................................................... 50
PARKINSONISM ................................................................................................................................................................. 51
UPDRS Motor Subscale .................................................................................................................................................... 53
Serotonin Syndrome .......................................................................................................................................................... 55
Neuroleptic Malignant Syndrome ......................................................................................................................................... 56
Depression........................................................................................................................................................................ 56
Antidepressants .............................................................................................................................................................. 56
Imaging Tips ..................................................................................................................................................................... 57
ICU tips ............................................................................................................................................................................ 57
Opiod Dosing .................................................................................................................................................................... 58
Falls ................................................................................................................................................................................. 58
Lumbar Puncture ............................................................................................................................................................... 59
Differential Diagnosis
VITAMIN C, D, and E
V= Vascular
I= Inflammtory/Infectious
T= Trauma/Toxic
A= Autoimmune/Allergy
M= Metabolic
I= Iatrogenic
N= Neoplastic/Paraneoplastic
C= Congenital
D= Degenerative
E= Episodic, epilepsy
Stroke
Initial questions
1) Hemorrhagic or Ischemic? Risk of hemorrhagic stroke doubled with: coma on arrival, vomiting, severe HA, BP > 220/170,
warfarin, glucose > 170 in non-diabetic pt. Obtain STAT head CT (usually already done).
2) Last normal time? If ischemic, within 3 hour window? If less than 3 hours ago, go to section on IV t-PA. 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. rightsided 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
9)
10)
11)
12)
13)
14)
15)
16)
checking ESR, RPR, TSH, type and screen, LFTs, and CXR as indicated. Consider transcranial dopplers to evaluate for vasospasm
if prior SAH is suspected.
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.
Keep on sliding scale with FSBG checks q 6 (regardless of whether pt has DM). Keep BG<140.
Start antiplatelet therapy if ischemic stroke and not on t-PA
Start on statin on the next day (check LFT's)
If febrile, pan culture, then start on round-the-clock Tylenol for 48 hours. Fever is associated with poor outcome.
GI and DVT prophylaxis- Heparin SQ 5000 U q 12h and TEDS; Zantac 50 mg IV q 8 if in NSICU
NEVER use IV heparin in acute stroke (see exceptions below)
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
< 10
> 20
Favorable outcome @ 1 yr
60-70%
17%
NIHSS at 3 months
All patients
Age>75 + NIHSS>20
Group
tPA
Placebo
tPA
Placebo
Modified Rankin at
3 months
All patients
Initial NIHSS>20
Age>75 + NIHSS>20
tPA
Placebo
tPA
Placebo
tPA
Placebo
NIHSS 0-1
31%
20%
0%
0%
MR 0-1
(Good
outcome)
39%
26%
10%
4%
0%
5%
NIHSS 2-8
30%
32%
26%
14%
MR 2-3
(Moderate
disability)
21%
25%
21%
20%
30%
9%
NIHSS >9
22%
27%
26%
41%
MR 4-5
(Dependent)
Death
17%
21%
48%
45%
Death
23%
27%
21%
38%
22%
41%
17%
21%
48%
38%
48%
45%
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
3
7
14
21
28
% with any HT
6.2
16.9
40
43.1
43.1
Percent chance of hemorrhagic transformation vs. days
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0
5
10
15
20
25
30
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
% ICH
2
3
11-15
5
16-20
4
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
Endarterectomy + Med
9%
Rx
Medical Rx alone
26%
NNT=8; p<0.001
Stroke and death
at 30 days
5.8%
Major or fatal ipsilateral
stroke at 2 years
2.5%
3.3%
13.1%
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
>20
17
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
GCS 5-12
ICH volume > 30
IVH extension
Infratentorial origin
Age >= 80
ICH score
30 d. Mortality
(%)
2
1
1
1
1
1
0
0
1
13
2
26
3
72
4
97
5-6
100
Subarachnoid Hemorrhage (SAH)
Sources: Lange Neurology, Shutter lecture
Determine etiology: Trauma, aneurysm rupture (MCA 29%, ICA 16%, ACOMM 15%, Basilar 14%; multiple in 20%), AVM/vascular
malformation, vertebral or carotid dissections, mycotic aneurismal rupture, ICH, coagulopathy
Risk factors:
ASA, coumadin, ephedra, amphetamines, sympathomimetics
Ruptured berry aneurysm: age 40-59 (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)
23)
24)
25)
If deteriorates -> repeat head CT
Monitor for complications (see below)
Baseline TCDs (transcranial dopplers)
PM&R, PT/OT, Speech
Prognosis
Mortality (with aneurysm): most deaths occur within first few days. 20% of deaths occur before hospital, 25% from initial bleed, and
20% of deaths occur from rebleeding (if aneurysm not surgically corrected)
Mortality ruptured aneurysm @ 30d = 45% (Shutter)
Level of consciousness at presentation predicts outcome
50% of survivors have brain injury
Recovery from ruptured AVM is 90%
Complications
1) Recurrence (20% in 10-14 d with aneurysm)
a) 50% mortality with rebleed
b) Suspect if change in status (new HA, new N/V, increased BP or ICP) in unsecured pt
2) Intraparenchymal extension
3) Arterial vasospasm (42%) -> ischemic stroke
a) Start day 3, peaks day 10-14
b) 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
1
Normal
2
<1mm thick blood
3
>1mm
4
IC or IV clot with diffuse or no SAH
Risk of vasospasm
0-10%
30%
70%
30%
Hunt-Hess
1) Alert, asymptomatic or minimal H/A & slight nuchal rigidity
2) Alert, mod-severe H/A, nuchal rigidity, no neuro deficit other than CN palsy
3) Drowsiness, confusion or mild focal deficit
4) Stupor, moderate-severe hemiparesis
5) Comatose, extensor posturing, moribund
Aneurysm
Epidemiology
Approximately 1 – 5% of adults have intracranial aneurysms
20% between 15 – 45
Rare in children, uncommon < 20yo.
Risk factors
Congenital: polycystic kidney disease, aortic coarctation, Ehlers-Danlos Syndrome, fibromuscular dysplasia, sickle cell, AVM.
Modifiable: HTN, arteriosclerosis, hyperlipidemia, smoking, heavy ETOH use, & oral contraceptives
Secondary: trauma, infection, drug use
Size
<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 3rd nerve effects, contralateral
cerebral peduncle, Tonsilar: Dysregulation then collapse of respiratory & cardiovascular systems, Subfalcine: Personality change,
contralateral leg weakness, ACA infarct
DDx of high ICP: Agitation, hypercarbia, hypoxia, TBI (occurs in 40% of severe TBI), SAH, IVH, SDH/EDH, mass lesions,
hydrocephalus, stroke, seizures (transient), CNS infections, hepatic encephalopathy, eclampsia, H20 or lead intoxication, HACE,
hematoma (occurs in 50-70%)
Treatment
From Stroke recs Chest 2003, Guidelines for Management of Severe TBI. AANS/BTF 2000 rev, Crit Care Med 2005;33:6, Shutter
lecture
1) Initial treatment
a) Goals: keep ICP<20-25, keep CPP>60
b) Low threshold for head CT!
c) ICP monitoring is controversial in stroke (AANS guidelines say monitor for GCS<=8; consider for hydrocephalus or
significant mass effect if sedated)
d) Mild fluid restriction
e) Head of bed 30 degrees
f) Intubate: treat hypoxia, hypercarbia
g) CSF drainage (if has ICP monitor)
h) Tight glucose control
i)
Control agitation with diazepam, midazolam, propofol
j) Control pain with morphine, fentanyl
k) Control fever with scheduled antipyretic because it decreases cerebral metabolism
l)
Avoid hypotonic fluids or free water
m) BP control. Avoid systemic hypotension (SBP < 90 mm Hg). If HTN encephalopathy, lower MAP carefully based to keep
CPP>60. Avoid vasodilating BP medications (NTG, nitroprusside, hydralazine). Labetolol is drug of choice, then nicardipine.
2) Further treatment if ICP > 20mmHg, CPP < 60mmHg, signs of herniation present, or progressive deteriorating not explained
by extracranial reasons, then:
a) Hyperventilate (goal PCO2 35 mmHg)
b) Hypertonic saline protocol (can bolus with hypertonic saline 7.5% 2ml/kg)
i)
Can use mannitol 0.25-1.0 gm/kg over 20 min IV Q6 instead of hypertonic saline (Aim for euvolemia, avoid
hypervolemia. Keep S osm < 320. Rebound high ICP 6 hours later.)
c) Hyperventilate to PCO2 28-35 mmHg (do not hyperventilate below 25 pCO2)
d) 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, 5th 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/Noncompliance in epilepsy patient, Electrolytes (Na, Ca, glu), Renal failure, liver failure, Sepsis, Anoxia/hypoxia, Drug withdrawal
(barbiturates, benzodiazepines, ethanol, opiates, baclofen), Drug intoxication (including EtOH, amphetamines, cocaine,
phencyclidine, cipro, imipenem, lidocaine, penicillin, theophylline, tricyclics), acute or remote stroke, CNS infection, Head trauma,
Fever/infection, Tumor, Vascular malformation, Congenital, Mesial temporal sclerosis
Mnemonic for seizure etiology – AEIOU TIPS:
A-Alcohol, Anoxia
E-Endo, Electrolyes, Epilepsy, Encephalitis
I-Infection
O-Overdose
U-Uremia
T-Tumor, Trauma
I-Insulin
P-Psych
S-Stroke, SAH, SDH
Triggers of seizures: sleep deprivation, missed meds, stress, illness, menstruation, starting a new medication that interacts with
pt’s AED or lowers sz threshold
Drugs which lower seizure threshold 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
LTG > CBZ > TPM=GBP
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
Generalized or unclassified epilepsy
VLP > LTG > TPM
Epilepsy Type
Temporal lobe lesion
Outcome (seizure freedom)
~ 80%
Mesial temporal sclerosis
“Normal” temporal lobe
~ 70%
~ 60%
Lesional extratemporal
Nonlesional extratemporal
~ 60%
< 50%
Prognosis of New onset seizure
Patient
Normal EEG + idiopathic sz
Symptomatic sz or abnl EEG
Symptomatic sz + abnl EEG
Risk of recurrence after 1 event without treatment
24%
48%
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)
1st AED
47%
2nd AED
13%
3rd AED
1%
Duotherapy
3%
Predicting risk of future seizure
Kim et al. Lancet Neurology. 2006
Prognostic index
1 seizure
2-3 seizures
4+ seizures
Neurological disorder or deficit, learning disability
or developmental delay
Abnormal EEG (specific focal or generalized
epileptiform or slow wave abnormality, excluding
non-specific abnormality)
Risk level
Low (score 0)
Medium (score 1)
High (score 2+)
0
1
2
1
1
Probability of seizure at (without meds -> with meds)
1yr
3yr
5yr
0.19 -> 0.26
0.28 -> 0.35
0.30 -> 0.39
0.35 -> 0.24
0.50 -> 0.35
0.56 -> 0.39
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/hri. 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
%
Mortality
60
47
37
metabolic
infection
stroke
trauma
30
30
27
15
AED
withdrawal
5
ETOH
5
Antiepileptic drugs
Sources: Ficker lecture Epilepsy Rx; UpToDate 2/06; PDR. Clinical handbook of Epilepsy. 1 st edition. 2005. Clinician’s Guide to
Antiepileptic Drug Use, Privitera et al, 2006.
Initial therapy
Seizure Type
Partial sz:
Partial sz adjunct:
Absence
Primary Generalized TC
Young pt/partial sz
Older pt/partial sz
Young pt/generalized
Lennox-Gastaut
Myoclonic seizures
Drug options
PHT, CBZ, VPA, LTG, TPM, OXC, GBP
ZNS, LEV, TGB
VPA, ESM, LTG, TPM
VPA, LTG, TPM, ZNS, LEV, FBM
PHT, CBZ, LTG, OXC, TPM
GBP, LTG, LEV
VPA if male; LTG, TPM if female
LTG; or FB (if severe)
VPA, LEV, KLO
Contraindicated
CBZ, OXC, GBP, TGB, PB
PB
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
3h
<100%
25
5-18 h
5-12
Topiramate
2h
<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
100
Q1-2wk ->
6
300
200
100-150mg/d
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)
8)
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.
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 3rd vent, CNS infection, idiopathic.
Migraine prophylaxis
Drug
Propranolol
Nadolol
Useful with
HTN, heart
disease
Amitriptyline
Nortriptyline
Depression,
anxiety,
insomnia
Verapamil
Diltiazem
HTN
VLP
Seizures, bipolar
disorder
Dec. HA frequency
by 50%
125-250mg qhs or
ER 500mg qhs ->
1000mg bid or level
50-150mcg/ml
GBP
Neuropathic pain
2.7 HA/mo vs. 3.5
46% had 50% dec.
HA frequency
2400mg/d
Cyproheptadine
(anti-histamine)
TPM ($$$)
Allergies
CoQ ($$$)
Riboflavin
Obesity
Efficacy
60-80%
Dose
(propranolol) 4080mg qd -> 160mg
bid
(nadolol) 20-40mg
qd -> 80mg bid
10-25mg qhs ->
100-200mg qhs or
level > 200250ng/ml
120mg qd-bid ->
240-360 bid
50% had 50% dec.
HA freq
47% had 50% dec
HA at 3 mo. (based
on 1 study)
54% had 50% dec.
HA at 2 mo. (based
on 1 study)
2-4mg qhs -> 8mg
tid
25mg qhs ->
100mg bid
SE
Fatigue, insomnia,
depression
Nortrypt has fewer
SEs; Dry mouth,
sedation,
constipation,
increased appetite
Well-tolerated;
possible
constipation, leg
edema, palpitations
Increased
appetite/weight
gain, hair loss,
nausea, tremor,
sedation, liver
toxicity
Contraindications
Asthma, low BP, low
HR, DM, PVD, ED,
sinus dysfcn,
depression, insomnia,
fatigue
Beta-blockers
Pregnancy
Sedation, increased
appetite
Paresthesias (50%),
wt loss (10%),
dizziness, confusion
100mg tid
400mg/d
Treatment of acute headache or status migranosus in ER
Start IVF and try these, roughly in suggested order
1) IVF
2) Sumatriptan 6mg SC (Nonsedating, contraindicated with vascular disease)
3) Prochlorperazine 10mg IV + diphenhydramine 25mg IV (risk of EPS effects, hence the Benadryl, and sedation)
a) Alternatively, with diphenhydramine to prevent EPS:
i)
Metoclopramide 10mg IV (risk of extrapyramidal side effects)
ii) Promethazine 25-50mg IV (risk of EPS or sedation)
iii) Ondanstron 4-8mg IV (nonsedating anti-nauseant) – doesn’t need diphenhydramine
4) Ketorolac (Toradol) 30mg IV or 60mg IM (nonsedating)
5) Dexamethasone 4-10mg IV (nonsedating) OR Medrol dose pack
6) Valproate 500-1000mg IV (nonsedating)
7) Magnesium 2gm IV (nonsedating)
8) Stadol
9) Droperidol 2.5-5.0mg IV Q30min x 3 doses (Risk of QT prolongation, EPS in 1/20 and sedation, needs cardiac monitoring)
10) DHE protocol (see below)
11) Narcotics (rarely should use because causes rebound and makes other acute therapies ineffective)
Triptans
1) MOA: (5-HT1B/1D agonists)
2) Contraindications: Ischemic heart disease/angina, Coronary vasospasm (including Prinzmetal’s angina), Multiple risk factors for
coronary artery disease, unless workup is fully negative, Hemiplegic or basilar migraine, Uncontrolled hypertension, Pregnancy
3)
4)
category C, Concomitant use of MAO inhibitors (or use within 2 weeks); specifically rizatriptan, sumatriptan, and zolmitriptan,
Use within 24 hours of an ergot
SE: Tingling, Warmth, Flushing, Chest discomfort, Sensations of pressure, Dizziness, somnolence. The SC form of sumatriptan
has more Ses
Dosing: take at onset of headache, may repeat in 2 hours if necessary
Suma 25-50mg PO, max 200mg daily
Suma 5-20mg intranasal, max 40mg daily
Suma 6mg SC, max 12mg daily
*Ele 40-80mg – no major SEs
Nara 2.5mg – no major SEs, slow acting
*Riza 10mg (dec. dose if on propranolol) – SE: dizziness, fatigue, nausea
Zolmi 2.5mg – SE: nausea, dizziness, fatigue, tingling
*Best choice
Preventing Rebound
Prefer non-combination analgesics up to 2 days/week
APAP (without caffeine) up to 1000mg q4h (max 4000mg/d)
ASA (without caffeine) up to 1000mg q4h
Ibuprofen 200-800mg q4-6h
Naproxen 220-660mg q6-8h
Use non-medication measures (lie down, eat something, relax, quiet room, sleep, ice/heat, massage, neck stretches, exercise)
Other meds up to 2 days/month
DHE protocol
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
Place hep lock
Order DHE-45 and metoclopramide (Reglan) to the floor stat.
Give 10mg metoclopramide IV followed immediately by 0.5mg DHE IV given over 2 minutes
If nausea appears or headache disappears within 1 hour, order DHE 0.5mg IV Q8 + metoclopramide 10mg IV Q8
If no nausea and headache persists, give additional DHE 0.5mg IV with no metoclopramide 1 hour after first DHE dose, then
order DHE 1mg IV Q8 + metoclopramide 10mg IV Q8. Keep to schedule of 6am – 2pm – 10pm.
After 5 doses given, d/c metoclopramide
Prophylaxis begun after step 4 or 5
After pt is headache free, substitute DHE 1mg IM or SC Q8 for IV form
Lomotil is usually necessary for diarrhea or codeine withdrawal; the average dose is 2-3 tablets Q6h prn.
Chlorpromazine 10mg IV q30 min, up to 3 doses (total 30mg) is useful for pain control or sleep. This sequence may be repeated
up to 4 times in 24 hours.
Morphine 4mg IV once only may be ordered for the first 24 hours in the event that IV chlorpromazine fails.
Naproxen 500mg PO q6h prn may be used for headache control 48 hrs after all analgesics have been d/c’d.
At discharge, order 20 DHE ampules, 3ml syringes both #25 x 5/8 and #23 x 1” needles, prophylactic medications and naproxen
for prn use.
ALTERED MENTAL STATES:
Definitions
1. Coma = total or near-total unresponsiveness. Not arousable to any stimuli.
2. Stupor = state of severely impaired arousal. Some responsiveness to vigorous stimuli.
3. Obtundation = some responsiveness to touch or voice
4. Lethargy/Somnolence = state in which pt has diminished arousal but is able to maintain arousal spontaneously or with repeated
light stimulation.
5. Acute Confusional State = inadequate arousal to perform a coherent thought or action (inattention, disorientation)
6. Delirium = state of confusion w/periods of agitation, irritability, hallucinations. Typically alternates with periods of decreased
arousal.
Localization: Results from damage to components of reticular activating system (midbrain and rostral pons to thalamus to cerebral
cortex)
Etiology:
1) Common causes: medications, infection/sepsis, renal failure, hepatic encephalopathy, uremia, respiratory failure, acidosis,
alkalosis, HTN encephalopathy/PRES, drug intoxication (EtOH, cocaine, sedatives, methanol, ethylene glycol), drug withdrawal,
hypoxic-ischemic, nutritional deficiency (Wernicke’s, B12, niacin), sundowning, dehydration, ICU psychosis, hypotension
2) Neurologic causes: seizure, postictal state, ischemic stroke, head injury/trauma, concussion, nontraumatic ICH, SAH, SDH,
epidural hematoma, CNS infection, brain tumor, demyelination (MS/ADEM), paraneoplastic syndrome, basilar migraine, transient
global amnesia, abscess, right parietal lesion, tertiary syphilis, Lyme, leptomeningeal carcinomatosis, Creutzfeldt-Jakob disease,
pituitary apoplexy, locked-in syndrome
3)
Uncommon causes: Myxedema, thyrotoxicosis, Addison’s disease, Cushing’s disease, hypo/hyperparathyroidism, HIV, lupus
cerebritis/vasculitis, TTP, catatonia, severe depression, psychogenic coma, porphyria, Reye syndrome, Wilson’s disease,
hypothermia, occupational exposure (carbon monoxide, cyanide, organic solvents, heavy metals [Pb, Ar, Mg]), hypervisocisity
syndrome (polycythemia vera, multiple myeloma, Waldenstrom’s)
History: Time course? Medications? History of trauma? Headache, Hemiparesis, Ataxia, Vomiting? (suggests neuro cause) EtOH or
recreational drug use? History of psych illness? History of seizure? Recent surgery? Occupational, environmental exposures?
Exam: Vitals, jaundice, spider angiomas, signs of anemia (pallor), signs of hypothyroid (dry skin, brittle hair, edema), needle tracks,
hot dry skin (anticholinergic), asterixis, rashes, nuchal rigidity, Brudzinski’s sign, Battle’s sign, raccoon eyes, oto-/rhinorrhea,
murmur (endocarditis), coma exam (see below), check language function since sometimes “mental status changes” is really
aphasia
Medications causing acute confusional states (partial list): acyclovir, amantadine, amphetamines, anticholinergics,
anticonvulsants, antidepressants, antihistamines, antipsychotics, baclofen, benzodiazepines, cephalosporins such as cefepime (rare),
chloroquine, clonidine, cocaine, corticosteroids, cyclosporine, digoxin, ergot, ethanol, ganciclovir, isoniazid, levodopa, lidocaine,
methylphenidate, opiods, selegiline, thyroid hormones, lithium, TCAs
Plan:
1) Minimize sedating medications (use low dose quetiapine if absolutely necessary)
2) Consider empiric naloxone, thiamine, CIWA protocol
3) Rule out or treat infection (fever, vitals/SIRS criteria, WBC, CXR, UA, blood cx)
4) Treat medical causes
5) Check Na, Ca, HCO3, Mg, glucose, BUN, anion gap, liver profile, CBC, ammonia, urine or serum tox, coags (if liver disease),
ABG, TSH, B12, B1, RPR/FTA
6) Low threshold for EEG since many ICU patients are in nonconvulsive status epilepticus
7) LP if any signs of meningitis (fever, nuchal rigidity, immunocompromised) – send for HSV, VDRL. CSF glutamine is specific for
hepatic encephalopathy (but not sensitive)
8) Head CT or MRI if there are focal findings or if concern for SAH
9) If above workup is negative, consider ESR, CRP, ACTH stim test, HIV, PTH, serum Cu, ceruloplasmin, imaging for cancer
screening
10) Call poison control if concern for intoxication
11) AED levels if on AEDs
COMA EXAMS:
1. Goal of exam is to distinguish coma caused by damage to brain tissue or from secondary mechanism affecting the brain
(metabolic, toxic)
2. Purely unilateral cerebral lesions usually do not produce coma (must have increased pressure/shift of a single lesion to produce
true coma)
3. Glasgow Coma Scale: used mostly in traumatic injuries
a. Eye Opening: 4=spontaneous, 3=to speech, 2=to pain, 1=none
b. Verbal: 5=oriented, 4=confused, 3=inappropriate, 2=unintelligible, 1=none
c. Motor: 6=obeys commands, 5=localizes to pain, 4=withdraws to pain, 3=flexion to pain/decorticate, 2=extensor
response to pain/decerebrate, 1=none
d. Score less than 8 is indicative of comatose state
4. Coma Exam:
a. All components of exam may be impaired by hypothermia, drug intoxication, sedative medications, making exam
unreliable
b. Level of consciousness: describe what level of stimulation pt responds to if any.
c. Nuchal rigidity
d. Pupillary exam (CN II): describe size, reactivity, shape, and symmetry
e. Fundoscopic exam: look for papilledema (increased ICP), retinal hemorrhage
(HTN), subhyaloid blood (massive SAH), retinal infarcts (stroke, vasculitis)
f. Gaze deviation:
tonic horizontal deviation towards side of lesion/away from weakness=stroke or other cerebral hemispheric
damage
tonic horizontal deviation away from side of lesion/towards weakness=seizure or brainstem process (“wrong way
eyes”)
g. Roving eye movements: may be conjugate or dysconjugate. Good prognostic sign in post-anoxic injury.
h. Ocular bobbing: fast downward or upward movement w/slow return to mid-position (pontine lesions or metabolic coma)
i. Corneal reflex (CN V, VII)
j. Vestibulo-ocular reflex (CN III, VI, VIII)
do not perform in pts w/neck injury or unstable C-spine
absence of reflex indicates destruction of brainstem or severe metabolic
depression
Calorics: elevate head to 30 degrees. Inject 50-100ml or more of ice
water into auditory canal until nystagmus or tonic deviation of eyes
occurs. In comatose state eyes deviate towards side of cold stimulation, no
nystagmus/fast phase seen. In awake pt see both slow and fast phases. In brain death have no movement of eyes
at all. COWS refers to direction of fast phase.
k. Motor exam: Observe for spontaneous movement or subtle movements that may indicate nonconvulsive sz. Evaluate
tone and response to noxious stimuli.
Decorticate posturing: Indicates damage to mesencephalic region with lesion above the red nucleus, facilitation of
rubrospinal tract, disinhibition of vestibulospinal tract.
Decerebrate posturing: Indicates damage below level of red nucleus, facilitation of vestibulospinal tract
l. DTRs and plantar responses
BRAIN DEATH EXAM:
1. Prerequisites must be met prior to examination:
a. Rule out presence of medical condition that may confound assessment (electrolyte disturbance, acid-base, endocrine)
b. Absence of severe hypothermia (body temp must be >32 degrees C)
c. SBP must be equal to or > 90mmHg
d. Absence of drugs that may interfere with examination
e. Interpretation of neuroimaging to assess for cause of brain death
f. Performance of any confirmatory lab tests deemed necessary to evaluate pt
g. Often need period of observation (6-24hrs) if possibility of drug-induced or hypothermic depression of CNS may be
contributing factor, or if cardiac arrest is cause of brain death.
2. Requirements:
a. Coma of known cause
b. Absence of motor responses
c. Absence of pupillary responses, pupils mid-position and 4-6mm.
d. Absence of corneal reflex
e. Absence of caloric response
f. Absence of gag reflex
g. Absence of coughing in response to tracheal suctioning
h. Apnea Test: Absence of respiratory drive at a PaCO2 that is at least 60mmHg or
20mmHg above baseline values.
Must pre-oxygenate w/100% O2, remove ventilator and watch for respiratory effort.
Check ABG after approximately 8 minutes and reconnect ventilator.
If SBP reaches <90, O2 sats drop markedly, and/or cardiac arrhythmias occur immediately draw ABG and connect
ventilator. Test is + if above conditions met.
3. Neurologic states that can mimic brain death: Locked-in syndrome, Guillian-Barre syndrome, hypothermia, sedative/anesthetic
agents, drug intoxication
4. Confirmatory Tests: Can use EEG, transcranial dopplers, nuclear imaging for metabolic function assessment (not often used in our
experience).
HYPOXIC-ISCHEMIC ENCEPHALOPATHY:
1. The longer the duration of the coma, the less likely a patient will awaken and the higher likelihood of having neurologic deficits.
Studies show vast majority (90-92%) of pts that will awaken do so within first 3 days.
2. Prediction criteria based on findings of Levy et al (NEJM, 1985; see below for tables from original article): 210 pts with serial
neuro exams after cardiac arrest.
a. Total of 13% regained independence within 1st year after arrest.
b. 52 pts had absent pupillary reflex on initial exam, and none of these regained independent function after 1 yr.
c. Presence of pupillary reflex, motor response of extention, flexion, or withdrawl, and development of spontaneous eye
movements that were roving/conjugate or better predicted recovery of independent function in 41-63% of pt with these
exam findings. These exam findings held their predictive value up to day 14 after arrest.
3. Overall literature review has found that absent pupillary response, absent corneal reflexes, extensor or absent motor response to
pain at 72hrs, and myoclonic status epilepticus were all strongly predictive of death or poor neurological outcome following
cardiac arrest (motor response has been shown to be most reliable). However, use of clinical exam alone for prognosis is
compromised by frequent presence of reversible states that affect consciousness.
4. EEG: Generalized epis, status, and burst suppression predict poor outcomes but with insufficient prognostic accuracy.
5. SSEP: Bilateral absent cortical responses at 72hrs predicted poor outcome.
6. Serum neuron-specific enolase (NSE): Levels >33 mcg/L on days 1-3 indicate poor prognosis.
7. Imaging may show loss of gray-white differentiation, diffuse cortical necrosis, changes in hippocampus, basal ganglia,
hypothalamus, thalamus, watershed infarcts
8. Prognosis in anoxic injury + myoclonic status: Hui et al. (Eur Neurol. 2005;54(1):10-15) performed a meta analysis of 134
cases in which 89% died, 8% PVS, 1% severe disability, 2% good outcome. In this study by itself, there were 18 cases. 16 of these
died, of which all but 2 died within 8 days.
Hypothermia Protocol:
1. Advisory statement of International Liaison Committee on Resuscitation: Unconscious adult pts w/spontaneous circulation after
out-of-hospital arrest should be cooled to 32 to 34 degrees C for 12 to 24 hrs when initial rhythm was V fib.
2. Evidence. Multiple trials done on comatose patients following out-of-hospital cardiac arrest show improved functional outcome in
patients with induced mild hypothermia (to 32 degrees C).
a. What is done. Patients received active cooling with external measures (blankets/ice packs) as
soon as possible after arrest (up to 4-6 hrs post-arrest). Cooling continued for up
to 24 hrs with passive rewarming.
b. Efficacy: One trial showed favorable neurological outcome (able to live independently and work part-time) in 55% of pts
tx w/hypothermia vs 39% of those not tx (RR1.4, NNT=6). Other trials with good outcome in 49% of pts tx vs 26% of
those not tx (RR1.85, NNT=4)
3. Mechanism. Proposed that hypothermia reduces cerebral metabolic rate for oxygen and suppresses many chemical reactions
associated w/reperfusion injury (free radical production, electrolyte shifts, amino acid release)
4. Potential risks include arrhythmias, infection, coagulopathy
5. Contraindications. Not recommended for use in pregnancy, children, pts with severe cardiogenic shock or life-threatening
arrhythmias, pts with primary coagulopathy. Thrombolytic therapy does not preclude use of hypothermia.
6. Initiate cooling ASAP but restore normothermia slowly/passively as rebound hyerthermia can occur.
7. University Hospital Hypothermic Protocol:
a. Inclusion criteria:
Age 18 or older
If women are 50 years of age or less must have negative pregnancy test
Cardiac arrest with return of normal sinus rhythm. Preferred initial
rhythm of Vfib or pulseless Vtach. Can be considered for PEA, asystole as well.
Persistent coma following arrest as evidenced by no eye opening to pain
after resuscitation (no waiting period required)
SBP of at least 90mmHg (spontaneously or with fluid/pressor support)
No limit on duration of resuscitation effort, but “down time” of less than 1 hour desirable.
b. Exclusion Criteria:
Pregnancy
Presence of another condition that may be cause of comatose state (drug
overdose, head injury, storke, status epilepticus)
Known terminal illness preceeding arrest (as per primary treating
physician determination)
Pre-existing DNI status (if pt not intubated during resuscitation efforts)
Refractory cardiogennic/non-cardiogenic shock despite fluids/pressors
c. Protocol Specifics/Orders: (goal temperature 33O C as to be achieved as soon as possible):
Patients should be enrolled as quickly as possible. For out-of-hospital arrests, ED attending will make decision to
implement protocol. For in-hospital arrests, CCU resident in charge of completed code will make decision.
Page Neurology at 0904 or Dr. Daniel Woo at 249-3112 for immediate initial neurologic assessment prior to
pharmacologic paralysis. Do not delay initiation of hypothermia pending this assessment.
Immediately place ice packs under the armpits, next to the neck, on the torso and the limbs.
Temperature sensing Foley catheter should be placed if available, otherwise rectal or tympanic temperatures
should be used (in that order).
Two cooling blankets should be used, one under and one over the patient.
Page the ICU Resident to manage the ventilator and sedation.
The ventilator humidifier should be turned off and a Heat Moisture Exchanger (HME) should be used.
The room thermostat should be turned off if set to heat.
Administer midazolam 2-6 mg/hour and fentanyl 25-75 mcg/hour
Once sedation is started, give vecuronium 0.1 mg/kg bolus, then start a drip of 1 mg/hour. Titrate the drip 0-5
mg/hr to keep 1/4 twitches.
Patients should be on insulin drip if glucose > 180 mg/dl, daily aspirin, on pressors and or nitrates to maintain
blood pressure, and any anti-arrythmics necessary.
Patients may receive other cardiac interventions including systemic thrombolysis, anticoagulation, and urgent
cardiac cath interventions as needed. Hypothermia should proceed concurrent with these interventions.
Once the patient reaches 33O C (bladder, rectal, or tympanic), keep patient at 33O C by removing ice packs and
top cooling blanket if necessary.
Begin passive rewarming 24 hours after the beginning of cooling (not 24 hours after target temperature is
reached):
-Turn room thermostat up to normal.
-Turn on heater on ventilator.
-Turn off cooling blanket.
-May use regular blankets.
-Do not use warm air blanket unless temp not 36O C after twelve hours of passive rewarming.
Paralysis, then sedation, may be discontinued during or after rewarming, based on shivering and other critical care issues.
NEJM 2002;346(8):557
Randomized, unblinded trial of 77 patients with out-of-hospital witnessed VF or VT cardiac arrest (head trauma, stroke patients
excluded) in which patients had core body temperature reduced to 33 C within 2 hours of restored circulation and maintained for 12
hours
Discharge to home or rehab
Mortality @ 30d.
Hypothermia
49% (21/43)
p=0.046
51%
p=0.145
Normothermia
26% (9/34)
OR=5.25
68%
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
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
5)
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. HundredUsually 100-500, 5-40 in most
>60,000, usually occ > 1000
cases
a few thousand,
PMNS
Tuberculous
Usually elevate, 25-100, rarely
but can be low
>500, lymphs
with spinal block (except early)
Usually 100-200, Usually low, < 45
can be higher
in 75%
with block
Cryptococcal
Usually elevated
0-800, avg 50,
lymphs
20-500, usually
100
Viral
Normal to mod
elevated
5-few hundred,
nl or sl elevated, nl (except
may be up to
<100
mumps, HSV or
1000, lymphs
CMV, which is
except within 48h
low in 25%)
Acute syphillis
Usually elevated
Avg 500, usu.
Lymphs
Cystercircosis
Sarcoid
Reduced, avg 30
Avg 100
Nl
Often inc. but can Increased, with
be low with block eos in 50%
50-200
Reduced in 20%
Normal to
considerably low
Sl to mod
elevation
Reduced in 50%
0-100,
mononuclear
Carcinomatosis
Legionella
Nl to incr
0-sev hundred,
Elevated, often
mono +
very high
malignant
Minor pleocytosis Usually nl
(20%)
Mycoplasma
Nl to low in 75%
Highly variable
From UpToDate in Kleindorfer lecture 8/06
Glucose < 10 mg/dl
Bacterial, TB or fungal meningitis
Glucose 10-45
Bacterial, syphilitic, or some viral (mumps) meningitis
Protein > 500 mg/dl
Bacterial or TB meningitis
Protein 50-500
Viral, Layme or syphilitic meningitis
WBC > 1000/mcl
Bacterial or sometimes mumps
WBC 100-1000
Bacterial or viral meningitis, or encephalitis (e.g. West Nile)
WBC 5-100
Early bacterial, viral, syphilitic, TB meningitis or encephalitis (e.g. HSV)
PMNs > 50%
Bacterial meningitis
PMNs < 10%
Viral meningitis
From Kleindorfer lecture
1,232 cases in Chicago study of acute purulent meningitis
Test
Sens for bacterial meningitis
WBC > 100
91%
PMN < 50%
90%
Abnl Glu
76%
Abnl prot
86%
Treatment
Start IV antibiotics/dexamethasone immediately (i.e. before LP)
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,
AMP + TAZ [+ VANC*]
Chemotherapy, Chronic steroids and
immunosuppression)
Head trauma, neurosurgery, CSF shunt, nosocomial
VANC + TAZ
Gram-positive cocci
If dexamethasone: RIF + CEF
If neonate: VANC + TAX
Otherwise: VANC + TRI
Gram negative cocci/N meningitides
PCN x 7 days
Gram positive rods
[AMP or PCN] + GENT
Gram negative rods
If neonate: TAX + GENT
Otherwise: [TRI or TAZ] + GENT
S pneumoniae
VANC + CEF x 10-14 d
H influenzae
TRI x 7 d
L monocytogenes
AMP + GENT x 14-21 d
S agalactiae
PCN x 14-21 d
Enterobacteriaceae
CEF + GENT x 21 d
P aeruginosa, acinetobacter
TAZ + GENT x 21 d
Consider meropenem
* Add vancomycin if there is high prevelance of cephalosporin resistant pneumococcus in the community.
AMP = ampicillin 4gm IV Q4 (adult) OR 100 mg/kg IV Q8 (children)
TRI = ceftriaxone 2gm IV Q12 (adult) OR 50-100mg/kg IV Q12 (children)
TAX = cefotaxime 2gm IV Q6 (adult) OR 50mg/kg IV Q6 (children)
CEF = TRI or TAX
VANC = vancomycin 15mg/kg IV Q6 (max 4gm/d)
TAZ = ceftazidime 50-100mg/kg IV Q8 (max 2gm Q8)
PCN = penicillin G 300,000 units/kg/d IV (max 24,000,000 units/d)
RIF = rifampin 600mg/d
GENT = gentamicin 1.5mg/kg IV load -> 1-2mg/kg IV Q8
Consider acyclovir 12 mg/kg IV q 8 hours
Dexamethasone IV 0.15 mg/kg or 10mg Q6 x 4 days (NEJM 347(20):1549-1556)
-Measure GCS (see “Altered Mental status” section)
-Given 15 minutes before or at the time of antibiotics in suspected bacterial meningitis with GCS 8-11
-Discontinue if Gram stain/culture does not show pneumococcus
RTC in adults of intravenous dexamethasone vs. placebo
At 8 weeks significant reductions in mortality (14% vs. 34%) and the combined end point of death or neurologic disability (26% vs.
52%) seen only in patients with S. pneumoniae meningitis only in those with an intermediate neurologic deficit on admission
Chronic meningitis
Sources: Neel lecture ‘06, Continuum 12(2) April 2006
Etiology: Chronic meningitis
1) Infectious
a) MYCOBACTERIAL: Mycobacterium tuberculosis
b) FUNGAL: Coccidiodes immitis (CSF eos), Cryptococcus neoformans (50% of fungal meningitis), Histoplasma capsulatum,
Blastomyces dermatitidis, Candida, Apergillus
c) PARASITES: Amoebas (Acanthamoeba, Naeglaria), Taenia
d) ATYPICAL BACTERIA AND SPIROCHETES: Brucella, Leptospira, Nocardia, Actinomyces, Borrelia burgdorferi , Treponema
Pallidum
e) RICKETTSIA: Ehrlichia chaffeensis, Coxiella burnetti
2) Non-infectious: Chronic subarachnoid, Sarcoid, Leptomeningeal metastasis, neoplastic (Breast, lung, leukemia, melanoma),
Chemical meningitis, IVIG, craniotomy, Dermoid cyst, Vasculitis, Giant cell arteritis, Wegener’s, Amphetamines and cocaine
abuse, Connective Tissue diseases, Lupus, Rheumatoid
3) No etiology in 15-25%
Common causes
1) TB (PPD sn 50%, high-volume CSF culture & PCR x 3 sn 50-80%, otherwise 20-40% on routine LP, CXR->Ghon complexes, h/o
active TB)
2) Crytococcus neoformans (cryptococcal Ag, fungal cx sn 75%)
3) Coccidiodes immitis (CSF > 10% eos, fungal cx sn 50%)
4) Histoplasma (CSF fungal cx sn 50%, high serum histoplasma Ab titer)
5) Neurosyphilis (CSF-VDRL, FTA Ab, RPR)
6) Lyme disease (CSF anti-B. burgdorferi Ab)
7) HIV (low-grade lymph pleocytosis, normal-slightly high protein, normal imaging, serum HIV-PCR)
8) VZV (immunosuppresed, MRI-multiple focal area white matter demyelination/infarctions, CSF VZV-PCR)
9) Enteroviruses (rarely chronic, hypogammaglobulinemia, CSF enterovirus PCR)
10) Rickettsia (travel/residence in endemic area, serum indirect immunoflourescent Ab test showing high titer or 4-fold increase)
11) Cysticercosis (residence/travel Latin America, MRI-parenchymal/meningeal cysts, CSF & serum cysticercosis Ab)
12) Neurosarcoidosis
History in chronic meningitis
Travel
1) Southwest US = coccidiodes
2) Midwest = Histoplasma, Blastomyces, Ehrlichia
3) Northeast, Northwest = Borrelia, Babesia
4) Mexico, Latin America = Taenia, Tyrpanosoma cruzii
Animal exposure
1) Goats, unpasteurized milk = Brucella, Listeria
2) Cats = Bartonella
3) Rabbits = Francisella
TB meningitis
Symptoms: Low Temp, HA, then slow development of focal neurologic deficits (CN, seizures)
Risk factors: previous pulmonary infection, AIDS and immunosuppression
Diagnosis
Tuberculin positive in only 50%
CXR seldom shows active pulm infection
CSF PCR - Specificity 56%, sensitivity 98% (!!)
CSF Mycobacterial culture needs large volume (20-40 ml), high speed centrifuge for “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/l), 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
Clinical
Objective
attacks
lesions
≥2
≥2
≥2
1
1
1
≥2
1
0
progression
from onset
≥1
for diagnosing MS
Additional requirements to make Dx
None (but alternative diagnoses have to be considered and ruled out)
Dissemination in space by MRI OR (2 or more lesions c/w MS + positive CSF) OR
await further clinical attack implicating different site
Dissemination in space by MRI OR second clinical attack
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
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 GAspecific 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%; 5yr MRI burden remained the same whereas it increased 30% for placebo (Neurology 1993 Apr;43(4):655-61.;
Neurology 1995 Jul;45(7):1277-85.)
(2) Avonex: Reduces freq of relapses 0.61 vs 0.9/yr; a decrease in MRI lesion volume (mean 74 versus 122), and less
disability of decreasing 1 point on EDSS (22% versus 35%). (Ann Neurol 1996 Mar;39(3):285-94.)
(3) Rebif: Reduction in relapse rate over 2 years 27% vs 33%; reduced MRI burden 3.8% vs 10.9% (Lancet 1998 Nov
7;352(9139):1498-504.)
vi) Instructions: Take APAP or 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
Median
Ulnar
C4
C5
C6
C7
C8
T1
PT/FCR
PT/FCR
FDP1-2
APB/OP
FDP1-2
FPL
PQ
FDI/ADM
FDP3-4
APB/OP
FPL
PQ
FDI/ADM
FDP3-4
Radial
BR
BR
ECR
T
Axillary
Musculocutaneous
Suprascapular
Dorsal scapular
Subscapular
Spinal accesory
Trap
D
Tmin
B
IS/SS
Rhom
Tmaj
D
Tmin
B
IS/SS
L3
L4
EDC
ECR
APL
ECU
T
EIP
FCU
EDC
APL
ECU
T
EIP
Tmaj
Trap
L2
L5
Medial Plantar
Tibial
S1
S2
AH
AH
ST
ST
S
S
BFLH
BFLH
LG
LG
S
MG
MG
ADQ
ADQ
IO
IO
PT
Sciatic
Lateral Plantar
AT
Deep Branch
AT
EDB
Peroneal
EHL
EDB
EHL
BFSH
Sciatic portion
Superficial Branch
Obturator
Inferior Gluteal
Superior Gluteal
AL
Femoral
IP
RF
VL/WM
AL
PL
PL
GMax
GMin
TFL
GMax
Gmin
BFSH
AL
IP
RF
VL/WM
IP
RF
VL/WM
Mayo NCS Normal Values
Nerve
Distance
(cm)
7
Latency
(ms)
At wrist
2.5-4.4
Amplitude
Ulnar
Motor
6.5
At wrist
2.1-3.3
Median
Palmar
8
1.5-2.2
At elbow
6.6-15
mV
50-180
mcV
Ulnar
Palmar
Median
Sensory
Ulnar
Sensory
Radial
8
1.5-2.2
15 mcV
13
2.5-3.5
11
2.1-3.0
10
At wrist
25-86
mcV
10-58
mcV
At wrist
Median
Motor
At elbow
4.0-18
mV
Velocity
(m/s)
49-70
F-wave
(ms)
22-31
53-72
21-32
57-71
56-76
20-60
Comments
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
Amp difference wrist-elbow<20%
Difference b/t arms: amp<7mV,
velocity<5ms
Median <= ulnar latency at
Same distance by 0.2ms
Latency difference b/t hands at same
distance should be <=0.5ms
Latency difference b/t Ree hands at
same distance should be <=0.2ms
Amplitude can be 15 over age 60
sensory
Peroneal
Motor
8.5
1.9-2.8
Ankle
2.4-7.0
Knee
2.0-12
mV
Knee
4.0-25
mV
6-25 mcV
Tibial
Motor
8
Ankle
3-6.0
Sural
sensory
Superficial
Peroneal
sensory
Medial
Plantar
Sensory
14
3.2-4.0
14
Ankle
2.9-4.0
6
12-14
2.4-4.0
7-44 mcV
Dermatomes
mcV
41-59
38-57
40-58
41-57
Amp difference ankle-knee<22%
Tibial/peroneal F difference <7ms
Diff b/t legs: amp<5mV, vel<5ms
Amp diff ankle-nee<50%
Latency up to 4.4 if >40 y/o
Response may be absent w/ large calf &
age>55
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.
c)
d)
e)
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.
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.
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
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)
2)
3)
4)
5)
6)
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)
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
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)
(c) Anti-GQ1b (most commonly seen with Miller-Fisher syndrome)
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.
(c) In AMAN the nerve conduction studies show same motor findings as in AMSAN but sensory studies are normal.
(d) In Miller-Fisher syndrome reduced amplitude action potentials are most prominent. May have abnormal blink
responses.
Differential diagnosis. Sarcoid radiculopathy, Carcinomatous radiculopathy, Lymphoma, Spinal cord compression, HIV
radiculopathy, Paraneoplastic syndromes, Diabetic amotrophy
Treatment:
a)
7)
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.
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
SCA 1
% of AD
cerebellar
ataxias
5.6 %
SCA 2
15.2 %
SCA 3
20.8 %
Clinical features (all have dysarthria & ataxia)
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
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
Gaze-evoked nystagmus; prominent spasticity or neuropathy; Parkinsonism;
SCA 6
15.2 %
SCA 7
4.5 %
fasiculations; absent reflexes; extensor plantar responses; bulging eyes; limited
EOM; muscle atrophy; peripheral neuropathy (54%)
Ataxin-3 (14q) CAG > 56 repeats
Pure cerebellar syndrome; -ve family history; dementia; frontal lobe signs;
peripheral neuropathy; seizures
27% sporadic; onset 30-50
CACNL1A (19p13) CAG > 21 repeats
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 2nd-4th 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.
0=
1=
2=
3=
4=
Speech
Normal.
Slight loss of expression, diction and/or volume.
Monotone, slurred but understandable; moderately impaired.
Marked impairment, difficult to understand.
Unintelligible.
19.
0=
1=
2=
3=
4=
Facial Expression
Normal.
Minimal hypomimia, could be normal "Poker Face".
Slight but definitely abnormal diminution of facial expression
Moderate hypomimia; lips parted some of the time.
Masked or fixed facies with severe or complete loss of facial expression; lips parted 1/4 inch or more.
20.
0=
1=
2=
3=
4=
Tremor at rest (head, upper and lower extremities)
Absent.
Slight and infrequently present.
Mild in amplitude and persistent. Or moderate in amplitude, but only intermittently present.
Moderate in amplitude and present most of the time.
Marked in amplitude and present most of the time.
21.
0=
1=
2=
3=
4=
Action or Postural Tremor of hands
Absent.
Slight; present with action.
Moderate in amplitude, present with action.
Moderate in amplitude with posture holding as well as action.
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.
0=
1=
2=
3=
4=
Posture
Normal erect.
Not quite erect, slightly stooped posture; could be normal for older person.
Moderately stooped posture, definitely abnormal; can be slightly leaning to one side.
Severely stooped posture with kyphosis; can be moderately leaning to one side.
Marked flexion with extreme abnormality of posture.
29.
0=
1=
2=
3=
4=
Gait
Normal.
Walks slowly, may shuffle with short steps, but no festination (hastening steps) or propulsion.
Walks with difficulty, but requires little or no assistance; may have some festination, short steps, or propulsion.
Severe disturbance of gait, requiring assistance.
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)
2)
3)
4)
5)
6)
7)
8)
9)
Remove precipitating drug…usually resolves within 24 hours
Supportive care: IVF, correct vital signs
Control agitation: benzodiazepines (lorazepam 1-2mg, then titrate to eliminate agitation), no restraints
Control autonomic instability
a) norepi or phenylephrine for hypotension
b) esmolol or nitroprusside for hypertension
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
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)
Propranolol (5HT1A antagonist) not recommended because of hypotension + bradycardia
Bromocriptine not recommended because may worsen NMS or serotonin syndrome
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
Hyperacute (0-24hr)
Acute (1-3 d)
Subacute (3-7 days)
Chronic (<2 wk)
Chronic (>2 weeks)
Type of hemoglobin
oxyhemoglobin
deoxyhemoglobin
intracellular methemoglobin
extracellular methemoglobin
hemosiderin
T1
Isodense
Isodense
Bright
Bright
Dark
T2
Bright
Dark
Dark
Bright
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
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
Safe in renal
insfx.
Falls
Etiology
1) Central processing: dementia
2) Neuromotor: Parkinson's disease, stroke, myelopathy, cerebellar degeneration, peripheral neuropathy
3) Vision: cataracts, glaucoma, age-related macular degeneration
4) Vestibular: PPV
5) Proprioception: peripheral neuropathy, vitamin B12 deficiency
6) Musculoskeletal: arthritis, foot disorder, muscle weakness
7) Systemic: postural hypotension, metabolic disease (thyroid), cardiopulmonary disease, other acute illness
8) Medications
a) Reduce alertness or retard central processing: analgesics (narcotics), psychotropics (TCA, benzo, phenothiazine)
b) Impair cerebral perfusion: antihypertensives, antiarrhythmics
c) Direct vestibular toxicity: AMG, high dose loop diuretics
d) Extrapyramidal syndromes: phenothiazes
Plan
-evaluate pt to get details of fall
-assess for any trauma (esp any abrasions, cuts, localized pain, ROM at hip) and do quick neuro check
-check serum osm & calculate serum osm, if gap present then hidden substrate
-XRAY limbs/pelvis or head CT if indicated by exam
-consider if new organic cause (MI, Sz, agitation from pain, MS changes, over sedation)
-make sure to leave a cross-cover note
Lumbar Puncture
Indications:
Suspected CNS infection (meningitis, encephalitis)
Suspected SAH (HCT 1st to exclude increased ICP.
Pseudotumor cerebri (therapeutic) or NPH (diagnostic)
Guillian-Barre syndrome (very high protein level > 200mg/100ml)
Multiple sclerosis (elevated IgG index and OCBs present on electrophoresis)
Spinal analgesia
SLE
Acute demyelinating disorders (encephalomyelitis, transverse myelitis)
Dementia
Meningeal carcinomatosis
Staging of lymphoma
Diagnosis of tertiary syphilis
Unexplained neurologic disorders if CT is negative
Contraindications:
Local skin infections (absolute CI)
Raised ICP (ok for pseudotumor or suspected NPH)
Suspected venous sinus occlusion
Supratentorial mass lesions (HCT 1st)
Severe bleeding dithesis, coagulopathy, or anticoagulated patient (relative CI)
Platelet count les than 50,000/mm3
Precautions:
Pt w/ coma, focal neurological findings, or papilledema should have a CT w/ IV contrast prior to the procedure
Imaging rarely indicated in pts w/ suspected acute meningitis, esp if pt is immunocompetent w/ no h/o CNS lesions, a normal neuro
exam, & no clinical evidence of ICP (no papilledema & nl SBP)
Instituting antibiotic therapy one to two hrs before LP will not decrease diagnostic sensitivity if the culture of the CSF is done in
conjuction w/ testing of CSF fluid for bacterial antigens and w/ blood cultures
Risks/Complications:
1. Post-LP headache: HA occurs in 10-25% of pts and is usually self-limited. The HA usually lasts for a few days, but may last longer
than a week and can be debilitating. Spinal HA usually occurs w/I 48 h following dural puncture, but it may occur up to 12d later. It
is exacerbate by sitting upright and is relieved by lying down. The incidence is reduced by using a 20- gauge or smaller needle; by
keeping the bevel of the needle oriented parallel to the long axis of the ts spine, thereby spreading rather than cutting the fibers of
the ligamenta flava; by telling the pt to remain at bed rest following the procedure. Oral and IV caffeine benzoate can be used to
treat refractory HA. IV doses of 500mg are given over a few minutes. A repeat dose can be given in an hour for an 85% chance of
alleviating symptoms. Epidural blood patch can be performed for those refractory to caffeine. This is done by injecting 15 ml of
autologous blood into the dural space.
2. Epidermoid tumors have been associated with LP performed in the neonatal period, when needles are used w/o stylus.
3. Seizures reported on a small percentage of pts with post-dural puncture headaches.
4. A traumatic or “bloody” tap from inadvertent puncture of the spinal venous plexuses is possible. This is self-limiting in the
majority of pts, but could lead to a spinal hematoma in pts with bleeding disorders. Some uthorities recommend sending the first
and fourth tubes for cell ct (RBCs and WBCs with diff) if a traumatic tap is suspected. The RBC ct will decrease from tube one to
tube four in the case of a traumatic ta. A correction can be made for SDF leukocytes and CSF protein if the tap is traumatic. For
each 700 RBCs, CSF leukocytes increases by one and CSF protein rises 1mg/100ml.
5. Brain herniation from a suptratentorial mass or increased ICP is another complication. Always check the fundi for papilledema
before performing LP. If a tumor, an intercranial bleed, or marked increased ICP is suspected, an emergent HCT should be done
before LP to reduce changes of herniation.
6. Paresthesias in the lower extremities are usually transient, but rare cases can last for more than a year.
7. Local pain in the back may be due to injury of the periosteum or the spinal ligaments.
8. Nerve root aspiration is possible. Replacing the stylus before withdrawing the needle may prevent aspiration of nerve roots.
Very rarely, nerve root diverticula can rupture as a result of LP, causing a brief CSF leak and a spinal headache.
9. Infection/meningitis
Procedure:
1. Position pt near edge of bed/exam table in the lateral recumbent or sitting position. Slightly flex the neck anteriorly. If lying, ask
pt to “roll up into a ball: with knees drawn up to the abdomen. Shoulders and pelvis should be aligned vertically w/o forward or
backward tilt. Identify L3-L4 interspace ( a line drawn b/w the superior aspect of the iliac crest intersect the body of L4). If
necessary, the L2-L3 or L4-L5 interspaces can be used.
2. Open spinal ray in a sterile manner. Put on sterile gloves and reassemble the manometer. Open numbered test tubes and placed
them upright, in order, in the slots provided in the plastic tray.
3. Prepare the skin at the selected interspace with an antiseptic solution. Cover the area with fenestrated drape.
4. Draw 3 ml of 1% lidocaine into the syringe with the 0- to 23- gauge needle.
Administer local anesthetic with the skin needle and raise a wheal over the L3-L4 interspace. Inject a small amount deeper into the
posterior spinous region, in the direction that the spinal needle will follow.
5. Palpate the posterior spinous process. Using this and the umbilicus s landmarks, insert a 20- or 22- gauge spinal needle through
the skin. Angle the needle about 15 degrees cephalad, toward the umbilicus, keeping it level with the sagittal midplane of the needle
parallel to the longitudinal is of the sine. If bone is encountered, withdraw the needle slightly and change its angle. Depending on
the size of the patient, after the needle has advanced about 3 to 4 cm, stop, withdraw the stylus and check the hub for fluid. If
there is no fluid, replace the stylus and advance another fraction before repeating this again. Usually a slight “pop” is felt as the
spinal needle penetrates the dura. Advance the needle 1 to 2 mm farther and withdraw the stylus. Rotating the needle 90 to 180
degrees is sometimes helpful if no fluid returns. If the patient experiences pain radiating down one leg or the tap is “dry” remove
the needle completely and make an attempt at a different interspace. A “dry” tap is more often due t a poorly positioned patient or
an improperly placed needle than to an obliterated subarachnoid space. Reposition the patient from lying to sitting or vice versa.
6. Once fluid is obtained, place the end of the stopcock with the attached manometer on the hub of the needle. Have the patient
straighten their legs and relax so that the opening pressure is not artificially elevated. The CSF should rise in the manometer to the
level of the OP. Note the color of the fluid and the OP. CSF pressure should oscillate slightly with the pulse and with respiration.
7. In case the fluid is bloody and does not clear after the first few drops of fluid (bloody tap), replace the stylus and remove the
spinal needle. Select an alternative lumbar interspace above or below the current level and re-attempt. Bloody CSF due to SAH will
not clot. Also, after spinning in a centrifuge, the supernatant is xanthochromic.
8. Turn the stopcock to allow the CSF to flow into the test tubes. Keep track of the order in which they are filled. Fill at least three
test tubes with 2-3ml of CSF each. Label each tube in the order it was collected. A 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, 2nd ed. 2003.