Ucneurologysurvivalguide.pbworks.com



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:

4) Do NIHSS initially rather than entire exam

Acute Ischemic Stroke

Sources: Ischemic Stroke AHA guidelines from Chest 2003, Kissela lecture

Diagnosis

Symptoms: Headache (25%); seizure (10-15%)

Exam: cortical signs (aphasia, neglect, extinction, visual cut, graphesthesia), crossed findings (suggests brainstem)

NIHSS

1) LOC: 0 =keenly responsive 1=arousable by minor stim 2=not alert, requires strong stim to respond 3=unresponsive or posturing

1a) LOC ? (month/age): 0=both correct 1=1 correct 2=neither correct

1b) LOC commands (close eyes/fist): 0=both correct 1=1 correct 2=neither

2) Gaze: 0=nl, 1=partial gaze palsy, 2=forced deviation

3) Visual: 0=nl, 1=partial hemianopia, 2=complete hemianopia, 3=blind

4) Facial: 0=nl, 1=minor paralysis, 2=partial paralysis (lower face), 3=complete

5&6) Motor: 0=no drift, 1=drift but doesn’t hit bed, 2=some effort against gravity but falls to bed, 3=no effort against gravity, limb falls, 4=no movement

7) Ataxia: 0=absent, 1=one limb, 2=two limbs

8) Sensory: 0=nl, 1=mild to mod 2=severe or total sensory

9) Language: 0=nl, 1=mild-mod aphasia loss of fluency or comprehension 2=severe aphasia, all communication fragmentary, 3=mute

10) Dysarthria 0=nl, 1=mild to mod some words understandable, 2= severe aphasia, not understandable, 3=intubated or physical barrier

11) Neglect: 0=nl, 1= neglect in one modality 2=profound hemi-inattention in more than one modality

Labs: Head CT, electrolytes, CBC (plt), PTT/INR, EKG (can get MI or arrhythmia post-stroke from sympathetic release, esp. right-sided infarct)

What to look for on head CT

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

CT insensitive with: early stroke, small cortical or subcortical infarct or posterior fossa

3 CT signs of infarct (visible within 6hr in 82% of MCA infarcts): (1) hyperdense (white) MCA -> thrombus; (2) loss of gray-white junction; (3) sulcal effacement

DWI sn 88-100% sp 95-100% for detecting ischemia

DWI may be negative within the first 3 hours of stroke

DDx of stroke: seizure (hx is key), complicated migraine (headache, march of symptoms, young women), meningitis/encephalitis (fever, incr. WBC, stiff neck, severe HA), hypo/hyperglycemia, SAH, subdural or epidural hematoma, aortic dissection, neoplasm (sometimes presents acutely), abscess, multiple sclerosis/transverse myelitis

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

Complete R. MCA -> NIHSSS 16-20

Complete L. MCA -> NIHSSS 21-24

Acute Treatment (if no TPA)

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

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

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

4) Head of bed flat

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

6) BP issues. Hold BP meds to allow BP autoregulation: MAP > 100's (Mean Arterial Pressure = Diastolic BP + 1/3 (Systolic BP - Diastolic BP); MAP of 140's are not uncommon after large MCA strokes- unless on t-PA, do not aggressively manage for first 10 days. For MAP's > 140's or signs of end-organ damage, try labetalol prn or low-dose IV enalaprilat first, then nicardipine gtt. HCTZ and ACEI are preferred first line antihypertensives at discharge. Goal: to lower SBP by no more than 20 mmHg and DBP to less than 105 for the first several days.

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

8) Testing. Order fasting lipids, CBC, coags, panel-10, and U/A. Low threshold for cardiac enzymes, esp. in patients with risk factors. Order TTE for AM, keep NPO post midnight (in case of TEE). If anterior circulation stroke, order carotid dopplers. Consider MRA head and neck if symptoms localize to posterior circulation. Consider MRI if localization is uncertain. Consider checking ESR, RPR, TSH, type and screen, LFTs, and CXR as indicated. Consider transcranial dopplers to evaluate for vasospasm if prior SAH is suspected.

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

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

| | |100-150mg/d | |

|6 |300 | |200 |

| |inc 100 Qwk | | |

| |-> 300-500mg/d | | |

3) SE: Less sedating that other AEDs, nausea, dizziness, somnolence, rash (1/1,000 or 1/100 with VPA), including Stevens Johnson/TEN (rash less likely with slow titration); mild CNS effect, hypersensitivity reactions, hepatic and renal failure, DIC, arthritis, Tics and insomnia

4) PK: Liver metabolism

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

6) Drug interactions

a) increased metabolism by carbamazepine, phenytoin

b) decreased metabolism by valproic acid

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

Levetiracetam [LEV] (Keppra)

1) Therapeutic uses: Partial/generalized seizures. Adjunct or monotherapy.

2) Dose: 500mg bid -> inc. by 1000mg/d Q2wk -> 1-3gm/d -> max 5gm qday

3) PK: Not metabolized by and does not induce P450, adjust dose in renal disease

4) No drug interactions

5) SE: fatigue, dizziness, irritability, anxiety, cognitive effects, somnolence, ataxia, diplopia, depression (be cautions if starting in patients with preexisting depression/mood problems)

6) Pregnancy category: C

7) Good in elderly and pt with liver disease

8) MOA: affects synaptic vesicles

Toprimate [TPM] (Topamax)

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

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

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

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

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

6) SE: Weight loss, CNS effects (30%), impaired cognition, paresthesia, headache, fatigue, dizziness, depression, mood problems, kidney stones (2-3%), acute myopia, open angle glaucoma, metabolic acidosis (carbonic anhydrase inhibitor). Most side effects improve with time except weight loss and paresthesias.

7) PK: 70% excreted unchanged in the urine, bioavailability is 80% with half-life of 21 hours, does not appear to effects levels of other drugs, however PHT and CBZ decreases topiramate concentrations by 48 and 40% respectively. At doses >200mg/d may reduce efficacy of OCP.

8) Pregnancy category: C

Zonisamide [ZNS] (Zonegran)

1) Therapeutic use: Partial seizures. Adjunct therapy.

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

3) Sulfa derivative

4) SE: somnolence, ataxia, confusion, abnormal thinking, nervousness, dizziness, kidney stones (3%, weak carbonic anhydrase inhibitor), irritability, photosensitivity, weight loss/anorexia. Most SEs self-limited.

5) PK: liver metabolism, half-life > 60h but is shortened by drugs that induce hepatic metabolism, significant amount excreted by urine unchanged, low protein binding

6) MOA: blocks Na channel and T-type Ca channels

Ethosuxamide [ESM] (Zarotin)

1) Therapeutic uses: absence sz

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

3) Max dose: 1500mg/d

4) Level: 40-100mcg/ml

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

6) MOA: Inhibit T-type Ca channel

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

8) SE: nausea/vomiting, drowsiness, lethargy, dizziness, restlessness, agitation, anxiety, inability to concentrate, Stevens-Johnson sydrome, urticaria, leukopenia, aplastic anemia, thrombocytopenia

Tiagabine [TGB] (Gabatril)

1) Therapeutic uses: adjunctive therapy in adults/children > 12 yrs for partial seizures

2) Dose: 4 mg qday -> inc. 4mg/d Qweek -> 24-32 mg/d -> max 56mg/day (adults)

3) SE: Dizziness, asthenia, somnolence, difficulty concentrating, CNS effects (30%), nonconvulsive status, stupor, weakness

4) PK: Metabolism – CYP 3A isoform subfamily of cytochrome P-450, highly protein bound

5) MOA: GABA reuptake inhibitor

Oxcarbazine [OXC] (Trileptal)

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

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

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

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

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

6) Pregnancy category: C

Primidone [PM] (Mysoline)

1) Therapeutic uses: alternate choice in partial sz and tonic-clonic sz

2) Dose – Initially 125mg qHS x 3d, with the dose increased by 125mg q 3d until maintenance dose of 250mg TID established on day 10.

3) PK: metabolites include phenobarbital (which is usually 2-3 times higher than that of primidone) and phenylethylmalonamide; metabolism is similar to PB but is rapidly and completely absorbed after oral administration with peak concentration in 4 hours

4) SE: see phenobarbital

Pregabalin [PGB] (Lyrica)

1) Therapeutic uses – Adjunct for Partial seizures.

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

3) Metabolism – renal

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

5) Pregnancy category: C

Felbamate [FB] (Felbatol)

1) Therapeutic use: Usually reserved for severe refractory Lennox-Gastaut (reduces atonic seizures and improves global assessment scores in children with Lennox-Gastaut syndrome). Can be used for refractory partial and generalized seizure. Increases seizure threshold.

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

3) Metabolism – half-life is 15 to 20 hours with linear pharmacokinetics, time to maximum concentration is 1-4 hours, protein binding is not significant. INHIBITOR. Liver metabolized (50%) and renally excreted (90%).

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

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

6) Not sedating; minimal cognitive effects

Headache

Source: UpToDate, Nicolas lecture, Neurology 2000;55:754-763, Heal Your Headache; Continuum, Lecture notes & AAN Pocket guidelines 2005-2006, 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. Age20ml)

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 22%

Atypical features, including no light perception or absence of pain, were protective

When to admit MS patient

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

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

When not to admit MS patient

1) No objective neurologic finding (i.e. more than pain)

2) Symptoms due to infection or anamnestic response

3) Patient can be treated at home with IV steroids and the diagnostic work-up (including LP) can be performed at outpatient basis by urgent referral to the Waddell Center for MS

Treatment

1) For exacerbations

a) IV steroids

i) Indication for IV steroids: definite change in function affecting vision, motor or cerebellar systems, not recrudescence of old symptoms due to infection. Treat early, when the symptoms are developing, not when they are already improving.

ii) Methylprednisolone 1000mg IV Qday x 3-5 days, followed by prednisone 60mg qday x 3 days, then decreased by 10mg/day Q3days

iii) Improves rate of recovery but not final outcome

iv) SEs: mental changes, unmasking of infections, gastric disturbances, anaphylactoid reactions, arrhythmias, aseptic necrosis of joints

v) Contraindicated by pregnancy

b) Plasma exchange (if steroids fail)

2) Disease modifying treatments

a) Glatiramer acetate (Copaxone)

i) Dose: 20mg SC Qday

ii) Most effective for patients with low inflammatory MS

iii) Efficacy: Lowers 2-year relapse rate 1.19 vs 1.68; reduced disability (decrease 1.5 EDSS) in 140 weeks, 22% vs 41%; reduces new T2 lesions ( Neurology 1995 Jul;45(7):1268-76.; Neurology 1998 Mar;50(3):701-8.; Ann Neurol 2001 Mar;49(3):290-7.)

iv) Fewest side effects (local injection reactions, chest pain, flushing, dyspnea, palpitations, anxiety)

v) Pregnancy B

vi) No lab monitoring

vii) MoA: mixture of random polymers of four amino acids, which is antigenically similar to myelin basic protein; glatiramer is thought to expand regulatory T cells that mediate bystander suppression of encephalitogenic T cells. Because GA-specific T cells also produce BDNF, theoretically GA may have some neuro-restorative potential

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

i) IFN-beta-1a = Avonex, Rebif; IFN-beta-1b = Betaseron

ii) Avonex dosing: 30mcg IM qweek

iii) Rebif dosing: 8.8mcg sc 3x/wk x 8 week -> 22mcg x 8 week -> 44mcg x 8 week

iv) Betaseron dosing: 0.0625mg SC QOD -> inc by 0.0625mg qweek -> goal 0.25mg QOD

v) Efficacy

1) Betaseron: Reduces freq of relapses 0.84/year vs 1.27/year; reduced disease progression at 5-yr 35% vs 46%; 5-yr MRI burden remained the same whereas it increased 30% for placebo (Neurology 1993 Apr;43(4):655-61.; Neurology 1995 Jul;45(7):1277-85.)

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

3) Rebif: Reduction in relapse rate over 2 years 27% vs 33%; reduced MRI burden 3.8% vs 10.9% (Lancet 1998 Nov 7;352(9139):1498-504.)

vi) Instructions: Take APAP or NSAID prn before each dose to reduce flu-like symptoms; if missed a dose, take it ASAP, but not within 48 hours of another dose, report depression or SI, report black and blue at injection site

vii) Caution in psychiatric illness because can cause severe psychosis or depression

viii) Side effects: flulike symptoms, fever, myalgia (reduced by premedication with NSAID); injection site reactions, mild lymphopenia, hepatotoxic/elevated LFTs (rarely requires discontinuation)

ix) Pregnancy C

x) Interactions Rebif/Avonex: ACEI (monitor CBC), hepatoxic drugs, warfarin (increased effect), zidovudine (increased levels)

xi) Interactions Betaseron: theophylline (increases levels)

xii) Monitor CBC/LFTs at 1, 3, and 6 mo, then periodically -> if high LFTs or low WBC, reduce dose 20-50%

xiii) Monitor TSH if has thyroid disease

b) 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 34 repeats |

|SCA 3 |20.8 % |Gaze-evoked nystagmus; prominent spasticity or neuropathy; Parkinsonism; fasiculations; absent |

| | |reflexes; extensor plantar responses; bulging eyes; limited EOM; muscle atrophy; peripheral |

| | |neuropathy (54%) |

| | |Ataxin-3 (14q) CAG > 56 repeats |

|SCA 6 |15.2 % |Pure cerebellar syndrome; -ve family history; dementia; frontal lobe signs; peripheral neuropathy; |

| | |seizures |

| | |27% sporadic; onset 30-50 |

| | |CACNL1A (19p13) CAG > 21 repeats |

|SCA 7 |4.5 % |Retinal degeneration; visual loss; ophthalmoplegia (70%); slow saccades; pyramidal signs; Hearing |

| | |loss; Onset in 1st decade; no peripheral neuropathy |

| | |Ataxin-7 (3p21) CAG > 38 repeats |

Muscle diseases

Metabolic myopathy

1) Glycogen

2) Lipids

3) Purines

4) Mitochrondrial

Glycogen Storage Diseases

Acid maltase deficiency

Source: Continuum 6/06

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

Epidemiology: Autosomal recessive, chromosome 17

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

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

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 ). The motor subscale is a convenient way to measure change in exam over time.

-Can have associated dementia (PD patients have up to six times higher likelihood than general population of developing cognitive impairment; 25% of PD patients will develop a subcortical frontal-predominant type of dementia)

                        •Treatment:

-Dopamine Agonists (non-ergots: Ropinerole, Pramipexole; ergots: Pergolide [recently discontinued due to induction of drug-induced valvulopathy], Bromocriptine [almost never used]). Direct stimulation of post-synaptic receptors. Can be used alone or as supplement to levodopa. Titrate dose slowly, not well tolerated in patients with underlying psychiatric disease or in the elderly. Side effects include nausea, psychotic symptoms, daytime somnolence, sleep attacks, and impulse control disorders (excessive shopping, compulsive gambling, hypersexuality).  Ergots can cause pulmonary/retroperitonial fibrosis and restrictive valvular heart disease (esp w/pergolide).

-Levodopa: Most effective treatment for PD, increases dopamine precursor availability. Paired with carbidopa to prevent peripheral breakdown of levodopa. Comes in IR and CR formulations. Start with low doses (25/100mg, ½ tab po TID) and titrate slowly. Side effects include nausea, postural hypotension, psych sx. At least 50% of patients treated with levodopa for 5 years will develop significant motor fluctuations (on-off symptoms, dyskinesias, freezing)

-COMT inhibitors:(Entacapone, Tolcapone): Mostly unable to cross the BBB, they are used only in conjuction with levodopa to prevent its peripheral decarboxylation into dopamine outside the brain, allowing more levodopa to follow its concentration gradient into nigrostriatal pre-synaptic terminals. May increase amount of “on” time and diminish severity of motor fluctuations as it extends the area under the curve for levodopa. Tolcapone is more potent but used less frequently due to risk of fatal hepatotoxicity and hematologic abnormalities (requires informed consent and frequent monitoring of LFTs). 

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

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

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

•Management of mental status changes in PD: Can occur as mild confusion, cognitive difficulty, behavioral disturbance, delirium, psychosis. General approach is to rule out infectious or metabolic process, and review any recent medication changes. Then, if present, attempt at reducing or eliminating anticholinergic drugs, amantadine, and dopamine agonists, in that order if necessary. Replacement of dopamine agonists with levodopa may often be sufficient to control behavioral difficulties. Finally, if the above steps are not successful, low doses of seroquel or, if ineffective, clozapine may be necessary. Risperdone and olanzapine are generally avoided as these “atypical” antipsychotics behave in typical neuroleptic fashion. Avoid haldol and use ativan as a last resort in acute situations. Often see some improvement if doses of dopamine agonists can be reduced.

•Surgical Treatments/DBS: 

-Indicated for patients with idiopathic PD, patients with good response to

levodopa (need to undergo documented on/off evaluation), and patients who have significant intractable symptoms and/or significant drug-induced dyskinesias and wearing-off.

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

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

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

-Prior surgeries focused on ablation of BG or thalamic regions. Now most commonly see placement of deep brain stimulators (DBS) with targets for lead placement in subthalamic nucleus (most common) or internal segment of globus pallidus.                                                                                                                                                         

b. Multiple system atrophy (MSA): atypical Parkinsonism characterized by varying degrees of destruction of nigrostriatal system, cerebellum, autonomic system (usually 3 phenotypes as below). Average age of onset around 50, rapid progression with death in 5-10 years.

•MSA-P (previously striatonigral degeneration): prominent parkinsonian features at onset

•MSA-C (previously sporadic olivopontocerebellar atrophy): prominent cerebellar signs at onset

•MSA-A (previously Shy-Drager syndrome): progressive autonomic failure

c. Diffuse Lewy body disease: characterized by prominent visual hallucinations, parkinsonism, fluctuating mental status (episodic confusion with lucid intervals), dementia (typically with severe impairment of visual-spatial deficits with memory less affected), behavior disturbance. Pathology shows Lewy bodies (intraneuronal cytoplasmic inclusions that stain with PAS and ubiquitin) throughout cortex, amygdala, cingulated cortex, SN. May respond to anticholinesterase medications. Visual hallucinations should never be treated with antypsychotics as paradoxical worsening occurs. Rivastigmine is best used for this purpose.

3. Tauopathies

a.       Progressive supranuclear palsy (PSP): usual age of onset in 60’s or 70’s, progression to

death in 5-10 years. Characterized by a symmetric akinetic rigid tremorless parkinsonism with prominent early balance problems (postural instability occurs much earlier than in classic PD), frontal-type cognitive impairment. Also see abnormalities of voluntary eye movements, initially in vertical planes, with normal VOR (supranuclear vertical gaze palsy).                                                                                                                                                                            

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

c. Frontotemporal dementia (FTD): age of onset 50-70. Behavioral symptoms predominate in early stages (disinhibition, apathy, compulsions) but later develop dementia (usually affects higher functions with relative sparing of memory), parkinsonism, apraxia. Primary progressive aphasia (PPA) due to left frontal and temporal atrophy, and semantic dementia (or fluent PPA) due to left anterolateral temporal atrophy (or prosopagnosia if similar lesion on the right) are non behavioral FTD variants. “Pick’s disease” was the former nomenclature of these variants, named for the Pick’s bodies (inclusions that stain with silver).  

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

 

UPDRS Motor Subscale

18. Speech

0 = Normal.

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

2 = Monotone, slurred but understandable; moderately impaired.

3 = Marked impairment, difficult to understand.

4 = Unintelligible.

19. Facial Expression

0 = Normal.

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

2 = Slight but definitely abnormal diminution of facial expression

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

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

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

0 = Absent.

1 = Slight and infrequently present.

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

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

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

21. Action or Postural Tremor of hands

0 = Absent.

1 = Slight; present with action.

2 = Moderate in amplitude, present with action.

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

4 = Marked in amplitude; interferes with feeding.

22. Rigidity

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

0 = Absent.

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

2 = Mild to moderate.

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

4 = Severe, range of motion achieved with difficulty.

23. Finger Taps

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

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

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

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

4 = Can barely perform the task.

24. Hand Movements

(Patient opens and closes hands in rapid succesion.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

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

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

4 = Can barely perform the task.

25. Rapid Alternating Movements of Hands

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

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

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

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

4 = Can barely perform the task.

26. Leg Agility

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

3 inches.)

0 = Normal.

1 = Mild slowing and/or reduction in amplitude.

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

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

4 = Can barely perform the task.

27. Arising from Chair

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

0 = Normal.

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

2 = Pushes self up from arms of seat.

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

4 = Unable to arise without help.

28. Posture

0 = Normal erect.

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

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

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

4 = Marked flexion with extreme abnormality of posture.

29. Gait

0 = Normal.

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

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

3 = Severe disturbance of gait, requiring assistance.

4 = Cannot walk at all, even with assistance.

30. Postural Stability

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

0 = Normal.

1 = Retropulsion, but recovers unaided.

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

3 = Very unstable, tends to lose balance spontaneously.

4 = Unable to stand without assistance.

31. Body Bradykinesia and Hypokinesia

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

0 = None.

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

amplitude.

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

amplitude.

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

4 = Marked slowness, poverty or small amplitude of movement

Serotonin Syndrome

Source: NEJM 2005;352;11:1112

History and Exam

Spectrum of severity from very mild to life-threatening

Rapid onset (present within 6 hours)

Ataxia, myoclonus, hyperreflexia more common in SS than in NMS

Hyperthermia and rigidity milder in SS than in NMS

Fever, diarrhea, vomiting common in prodrome of SS unlike NMS

Tremor, clonus and akathisia without other EPS is suggestive

History of offending agent, including OTCs, herbal and drugs of abuse

Mental status changes, autonomic hyperactivity, neuromuscular abnormalities

Delirium, agititation, hypervigilance, pressured speech

Autonomic signs: tachycardia, shivering, diaphoresis, mydriasis, hyperthermia, HTN, diarrhea/hyperactive bowel sounds

Tremor, myoclonus, hyperreflexia (worse in lower extremities), ocular clonus

Seizures

Poorly treated hyperthermia -> metabolic acidosis, rhabdomyloysis, high LFTs, renal failure, seizures, DIC

Exam: Reflexes, Clonus, Muscle rigidity, Pupils, Dryness of oral mucosa, Bowel sounds, Skin color, Diaphoresis

Offending medications: MAOIs, TCA, SSRI, opiods, OTC cough medicines, antibiotics, weight reduction agents, antiemetics, antimigraine agents, drugs of abuse, herbal products, meperidine, MDMA (“ecstasy”), dextromethorphan, trazadone, nefazadone, buspirone, clomipramine, venlafaxine, phenelzine, valproate, fentanyl, tramadol, pentazocine, ondansetron, metoclopramide, sumatriptan, sibutramine, linezolid, ritonavir, LSD, tryptophan, St. John’s wort, ginseng, lithium

Diagnostic criteria (sn 84% sp 97%)

Has exposure to serotonergic drug in last 5 weeks AND any one of the following

1) tremor + hyperreflexia

2) spontaneous clonus

3) muscle rigidity + T > 38 C + (ocular clonus or inducible clonus)

4) (ocular clonus or inducible clonus) + (agitation or diaphoresis)

Labs: coags, LFTs, ck, pan culture, CXR, Head CT, +/- LP

Treatment

1) Remove precipitating drug…usually resolves within 24 hours

2) Supportive care: IVF, correct vital signs

3) Control agitation: benzodiazepines (lorazepam 1-2mg, then titrate to eliminate agitation), no restraints

4) Control autonomic instability

a) norepi or phenylephrine for hypotension

b) esmolol or nitroprusside for hypertension

5) Control hyperthermia:

a) Eliminated excessive muscle activity with benzos (moderate cases) or neuromuscular paralysis (severe cases T > 41.1 C)

b) No role for antipyretics

6) If above measures fail, try 5HT2A antagonists

a) First line: Cyproheptadine 12mg PO x 1, then 2mg Q2 if symptoms persist, maintenance dose 8mg Q6

b) Olanzapine 10mg SL

c) Chlorpromazine 50-100mg IM (not if hypotensive or if has NMS)

7) Propranolol (5HT1A antagonist) not recommended because of hypotension + bradycardia

8) Bromocriptine not recommended because may worsen NMS or serotonin syndrome

9) Dantrolene not recommended because no effect on survival in animal models

Neuroleptic Malignant Syndrome

Idiopathic reaction to dopamine antagonists

Slow onset (over several days)

Bradykinesia, lead pipe rigidity, hyperthermia, fluctuating consciousness, autonomic instability

*Ask what meds they got, get vital signs, what has been done so far

*Results from dopaminergic blockade, usually assoc. with haldol, can also be seen with PD patients when holding their dopamine agonist or sinemet (known as NMS-like syndx)

*Clincally: Fever, rigidity, elevated CK, rhabdomyolysis, mental status change, dysautonomia

*Needs comprehensive lab w/u,

*TX: Stop offending agent. May try bromocriptine 5 mg TID or dantrolene 0.5-3 mg/day, amantidine 100 mg/q12H is alternative to bromocriptine

Depression

Epidemiology

10-15% prevelance

2:1 F:M, onset age 30-40s

Diagnosis

DSM IV criteria

2 weeks of depressed mood or anhedonia plus 4 of SIGECAPS

Sleep disturbance

Interest decreased

Guilty

Energy decreased

Concentration impaired

Appetite changes

Psychomotor retardation/agitation

Suicidal thoughts

Rule out other causes: substance use (EtOH, sedative, cocaine withdrawal, steroids, Acutane, beta-blockers, hypothyroid, syphilis, mono, HIV)

Neuro disorders causing depression: MS, PD, seizures, CVA, trauma, tumors

Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) Lancet Neurol 2006;5(5):399

Choose the best answer of the following:

4=Always or often

3=Sometimes

2=Rarely

1=Never

1) Everything is a struggle

2) Nothing I do is right

3) Feel guilty

4) I’d be better off dead

5) Frustrated

6) Difficulty finding pleasure

Score > 15 suggests depression (range 6-24)

Antidepressants

Ask about mania before starting antidepressants

Efficacy for all of them 60-75%

SSRIs

SEs: headache, stomach upset, loose stools, serotonin syndrome, sexual side effects (1/3, most likely decreased libido or delayed orgasm), alopecia, hyponatremia, decreased plt aggregation

Citalopram/Escitalopram: Fewest side effects, sedating for some people, escitalopram requires ½ dose compared to citalopram

Sertraline: generic available, fewest side effects

Paroxetine & fluoxetine inhibit 2D6 -> increased beta blocker, TCA, antipsychotics

Paroxetine: weight gain, sedation

Flouxetine: better for noncompliant, longest half-life (30 hrs, 2-3 weeks for metabolite)

SNRI (5HT & NE reuptake inh)

Venlafaxine: can increased BP at higher dose (has more NE effect @ higher dose), SEs include HA, GI upset, sexual SEs

Duloxetine (Cymbalta): also indicated for diabetic peripheral neuropathy, dose 30mg x 7 days, then 60mg qday, can increase BP

OTHERs

Mirtazapine (Remeron): MOA: blocks alpha-2 receptor on presynaptic increasing 5HT/NE release, sedation and weight gain occur at lower doses

Buproprion: NE/DA reuptake inhibitor, decreases seizure threshold, contraindicated in eating disorders, is activating “like having too much caffeine”, don’t use in agitated depression, good in amotivational depression, fewer sexual SEs, SE includes anxiety

Tazadone: 5HT reuptake inhibitor & 5HT2A blocker, SEs include sedation, orthostasis, priapism, better for insomnia than depression

Fewest sexual SEs: bupropion, mirtazapine, nefazadone

Imaging Tips

Blood on MRI

|Timing |Type of hemoglobin |T1 |T2 |

|Hyperacute (0-24hr) |oxyhemoglobin |Isodense |Bright |

|Acute (1-3 d) |deoxyhemoglobin |Isodense |Dark |

|Subacute (3-7 days) |intracellular methemoglobin |Bright |Dark |

|Chronic (2 weeks) |hemosiderin |Dark |Dark |

Bright on T1: fat, methemoglobin, calcium, enhancement, proteinaceous fluid

DWI positive: infarct, hypercellularity (some tumors), demyelination

ICU tips

Fever workup in NSICU (per Dr. Shutter): Cult blood, urine, BAL (no sputum); ABG; CXR; LP; LE Dopplers; Echo; LFTs - chole is forgotten cause of ICU fever b/c tube feeds

Antibiotics in ICU (per Dr. Shutter)

When to start abx: (Must have >2)

1) Fever

2) Leukocytosis

3) HR > 90

4) RR > 30

5) Hypotensive (MAP < 70)

or Altered Mental Status +

Abnormal CXR

PaO2/FiO2 < 300

Purulent secretions

For ventilator PNA: Vanc 1.5 gm q12 hrs + Cefepime 2 gm q12 hrs +/- tobramycin (7 day course or 14 days if drug resistant- put stop date in when writing order)

For meningitis: Vanc + CTX

For UTI: Nitrofurantoin 7 days

Bacteremia: Vanc and cefepime

Bugs needing double coverage: SPACE: Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter

Pressors in ICU

1) No pressors until you have given at least 2 L

2) Levophed 2 mcg/min; max 10 mcg/min

3) Consider adding vasopressin .04 u/min

4) Add inotrope- dobutamine, epinephrine

5) Consider hydrocortisone 50 mg dose

Opiod Dosing

|Opioid |Parenteral |Oral Equivalent dose |Duration of analgesia |Onset (min) |Notes |

| |Equivalent dose |(mg) |(hours) | | |

| |(mg) | | | | |

|Morphine |10 |30 |3-4 |PO | |

| | | | |15-60 | |

|Oxycodone |NA |30 |3-4 |PO |Safe in renal |

| | | | |10-15 |insfx. |

|Hydromorphone |1-1.5 |6 |3-4 |PO | |

|(Dilaudid) | | | |15-30 | |

|Fentanyl |0.1 |NA |IV 0.5-1 |IV 1-2 |Patch: 25, 50, |

| | | |TM 1-2.5 |TM 5-8 |and 75 mcg |

|Meperidine |75-100 |300 |2-3.5 |SC 10-15 |Avoid in seizure |

|(Demerol) | | | | |patients |

|Hydrocodone |NA |30 |3-4 |PO | |

| | | | |10-20 | |

|Codeine |120-130 |200 |3-4 |PO | |

| | | | |30-60 | |

Falls

Etiology

1) Central processing: dementia

2) Neuromotor: Parkinson's disease, stroke, myelopathy, cerebellar degeneration, peripheral neuropathy

3) Vision: cataracts, glaucoma, age-related macular degeneration

4) Vestibular: PPV

5) Proprioception: peripheral neuropathy, vitamin B12 deficiency

6) Musculoskeletal: arthritis, foot disorder, muscle weakness

7) Systemic: postural hypotension, metabolic disease (thyroid), cardiopulmonary disease, other acute illness

8) Medications

a) Reduce alertness or retard central processing: analgesics (narcotics), psychotropics (TCA, benzo, phenothiazine)

b) Impair cerebral perfusion: antihypertensives, antiarrhythmics

c) Direct vestibular toxicity: AMG, high dose loop diuretics

d) Extrapyramidal syndromes: phenothiazes

Plan

-evaluate pt to get details of fall

-assess for any trauma (esp any abrasions, cuts, localized pain, ROM at hip) and do quick neuro check

-check serum osm & calculate serum osm, if gap present then hidden substrate

-XRAY limbs/pelvis or head CT if indicated by exam

-consider if new organic cause (MI, Sz, agitation from pain, MS changes, over sedation)

-make sure to leave a cross-cover note

Lumbar Puncture

Indications:

Suspected CNS infection (meningitis, encephalitis)

Suspected SAH (HCT 1st to exclude increased ICP.

Pseudotumor cerebri (therapeutic) or NPH (diagnostic)

Guillian-Barre syndrome (very high protein level > 200mg/100ml)

Multiple sclerosis (elevated IgG index and OCBs present on electrophoresis)

Spinal analgesia

SLE

Acute demyelinating disorders (encephalomyelitis, transverse myelitis)

Dementia

Meningeal carcinomatosis

Staging of lymphoma

Diagnosis of tertiary syphilis

Unexplained neurologic disorders if CT is negative

Contraindications:

Local skin infections (absolute CI)

Raised ICP (ok for pseudotumor or suspected NPH)

Suspected venous sinus occlusion

Supratentorial mass lesions (HCT 1st)

Severe bleeding dithesis, coagulopathy, or anticoagulated patient (relative CI)

Platelet count les than 50,000/mm3

Precautions:

Pt w/ coma, focal neurological findings, or papilledema should have a CT w/ IV contrast prior to the procedure

Imaging rarely indicated in pts w/ suspected acute meningitis, esp if pt is immunocompetent w/ no h/o CNS lesions, a normal neuro exam, & no clinical evidence of ICP (no papilledema & nl SBP)

Instituting antibiotic therapy one to two hrs before LP will not decrease diagnostic sensitivity if the culture of the CSF is done in conjuction w/ testing of CSF fluid for bacterial antigens and w/ blood cultures

Risks/Complications:

1. Post-LP headache: HA occurs in 10-25% of pts and is usually self-limited. The HA usually lasts for a few days, but may last longer than a week and can be debilitating. Spinal HA usually occurs w/I 48 h following dural puncture, but it may occur up to 12d later. It is exacerbate by sitting upright and is relieved by lying down. The incidence is reduced by using a 20- gauge or smaller needle; by keeping the bevel of the needle oriented parallel to the long axis of the ts spine, thereby spreading rather than cutting the fibers of the ligamenta flava; by telling the pt to remain at bed rest following the procedure. Oral and IV caffeine benzoate can be used to treat refractory HA. IV doses of 500mg are given over a few minutes. A repeat dose can be given in an hour for an 85% chance of alleviating symptoms. Epidural blood patch can be performed for those refractory to caffeine. This is done by injecting 15 ml of autologous blood into the dural space.

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

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

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

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

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

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

8. Nerve root aspiration is possible. Replacing the stylus before withdrawing the needle may prevent aspiration of nerve roots. Very rarely, nerve root diverticula can rupture as a result of LP, causing a brief CSF leak and a spinal headache.

9. Infection/meningitis

Procedure:

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

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

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

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

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

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

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

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

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

9. Once you have obtained enough CSF, replace the stylus and withdraw the needle. Cover the puncture site with a sterile dressing. Have the pt turn to the supine position and remain there for the next 2 hours.

10. For a therapeutic LP, remove enough spinal fluid to reduce the closing pressure to 100 mm H20) or less (usually 25-35 ml of CSF). For diagnostic table, removal of 3-50 ml may result in transient improvement in gait or cognition for suspected NPH.

Processing CSF fluid:

Tube 1: Cell count, diff, gram stain, culture (bacterial, fungal, TB, viral)

Tube 2: Glucose, protein, protein electrophoresis (need concurrent serum study)

Tube 3: Save the fluid until further notice

Tube 4: Cell count and diff; Optional studies (VDRL, India ink, cryptococcal antigen, cytology, oligoclonal bands, myelin basic protein, countercurrent immunoelectrophoresis, serologic and genetic tests for other microorganisms)

Consider additional tests

a. Bacterial cultures

b. N meningitides, H influenza, S pneumoniae antigens

c. Assay for cryptococcal antigens in immunocompromised pts

d. Oligoclonal banding, IgG index and assay for myelin basic protein are useful to dx MS

e. VDRL for syphilis

f. AFB stain, TB culture, and PCR for TB

g. India ink for cryptococcus

h. Lyme titer

i. Fungal or viral cultures

j. Cytology

k. HSV PCR

l. MS serology

Role of repetitive LPs for f/u

1. Aseptic meningitis

2. Subacute/chronic meningitis of proven etiology

3. Bacterial meningitis which does not respond to Rx

Normal CSF values:

Opening pressure 50-200mm H20

WBC < 5/mm3

Neutrophils none

Glucose 60-70 blood glucose levels

Protein level 15-45mg/100ml

REF: Pfenninger & Fowler, Procedures for Primary Care, 2nd ed. 2003.

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