Pocket Medicine (Pocket Notebook Series)

CHANGE IN MENTAL STATUS

Consciousness/Arousal (description of patient & timing is most helpful)

• Arousal: spectrum from awake/alert → drowsy → stupor → coma. Terms vague & subjective, so most useful to describe response to increasing stimulation (eg, voice → noxious).

• Coma: lack of response to external stimuli. Degree formalized in Glasgow Coma Scale. Caused by focal lesions in brainstem (reticular activating system), thalamus, or diffuse dysfxn of both cerebral hemispheres. Mimics: locked-in synd., akinetic mutism, catatonia.

• Delirium/acute confusional state: altered attention & awareness, develops over hrs to days, often fluctuating, accompanied by cognitive Δs (eg, disorientation, memory loss, perceptual Δs); sometimes w/ sleep–wake dysregulation, autonomic Δs, emotionality

• Dementia: progressive cognitive impairment developing over mos to yrs; often affects memory, language, visuospatial, and executive function; attention often spared

Etiologies of Decreased Responsiveness
1° Neurologic (usually with focal signs)	Systemic (esp. in elderly or prior CNS injury)
Vasc: ischemic stroke/TIA, ICH, VST, PRES, vasculitis, pituitary apoplexy Seizure: postictal, status, nonconvulsive Infxn: meningitis, encephalitis, abscess Trauma: TBI, concussion, diffuse axonal injury ↑ intracranial pressure: mass, edema, hydrocephalus, herniation Autoimmune/paraneoplastic enceph. Neurodeg: late-stage (eg, Alzheimer’s) or rapidly progressive (eg, CJD)	Cardiac: global ischemia, HoTN, HTN enceph Pulmonary: ↓ PaO2, ↑ PaCO2 GI: liver failure, ↑ NH3 Renal: uremia, dialysis, ↓ or ↑ Na, ↓ or ↑ Ca Heme: TTP/HUS, DIC, hyperviscosity Endo: ↓ glc, DKA/HHNS, hypothyr., Addisonian ID: pneumonia, UTI, endocarditis, sepsis Hypothermia & hyperthermia Meds: anticholin., anti-hist., psychotrop., digoxin Toxins/withdrawal: EtOH, sedative, opiate, CO Psychiatric: catatonia, serotonin synd., NMS

Initial evaluation

• History (witness & background crucial): tempo, premorbid sx (eg, focal neuro deficits, HA, infxn, pain, falls), medical conditions (eg, dementia, epilepsy, onc, cardiac, psych, infection/immune status), accompanied by head trauma, current meds (eg, sedatives, opioids, anticoag, anticonvulsants, immunosuppressants), drug/alcohol use

• General exam: VS, breathing pattern (eg, Cheyne-Stokes), tongue bite (seizure), nuchal rigidity (meningitis, SAH; do not test if c/f trauma/cervical spine fx), ecchymoses, rash, signs of head trauma (eg, Battle sign, raccoon eyes, hemotympanum, CSF rhinorrhea), asterixis, liver disease stigmata, embolic phenomena/endocarditis, s/s drug use

• Neuro exam (see below): perform off sedatives/paralytics if possible, look for focal deficits suggesting structural cause (eg, stroke, herniation), s/s of ↑ ICP (eg, HA, vomiting, papilledema, abducens nerve palsy, unilateral dilated pupil, ↑ BP/↓ HR, fixed downgaze)

Neuro Exam in Patients with Decreased Responsiveness
Mental status	Arousal (behavioral response to ↑ intensity of stimulation, GCS)
Cranial nerves	Pupils: pinpoint → opiates, pontine lesion; midposition & fixed → midbrain lesion; fixed & dilated → severe anoxic injury, herniation, anti-cholin. Extraocular movements / vestibulo-ocular reflex tests: Oculocephalic maneuver (“doll’s eyes”): nl = eyes move opposite head movement (do not test if possible cervical spine trauma) Vestibular (cold) caloric stimulation: in coma, nl = eyes move slowly to lavaged ear, then quickly away (do not test w tymp memb perf) Corneal reflex, facial grimace to nasal tickle Gag & cough reflexes (with ET tube manipulation if necessary)
Motor	Tone, spont movements, flexor/extensor posturing of arms/legs, strength
Sensory	Response to painful stimuli: purposeful vs. reflexive/posturing
Reflexes	Deep tendon reflexes, Babinski, “triple” flexion (ankle, knee, & hip flexion to noxious stimulation → not suggestive of intact cortical function)

Glasgow Coma Scale (sum points from each of 3 categories to calculate score)
Eye Opening	Best Verbal Response	Best Motor Response	Points
		Follows commands	6
	Oriented	Localizes pain	5
Spontaneous	Confused	Withdraws from pain	4
To voice	Inappropriate words	Flexor posturing	3
To painful stimuli	Unintelligible sounds	Extensor posturing	2
None	None (intubated = 1T)	None	1

Initial treatment

• Empiric antibiotics if c/f CNS infection: vancomycin/CTX, consider acyclovir and ampicillin

• Immobilization of C-spine if concern for cervical trauma

• Thiamine 100 mg IV → dextrose 50 g IVP (this order to prevent exacerbation of Wernicke’s)

• If opiates suspected: naloxone 0.01 mg/kg; if BDZ suspected, consider flumazenil 0.2 mg IV

• If concern for ↑ ICP ↑ herniation: ↑ head of bed; osmotherapy w/ mannitol or hypertonic saline; ↑ ventilation; dexamethasone for tumor edema; c/s neurosurgery (? decompress)

Diagnostic studies (Lancet 2014;384:2064)

• All patients: check fingerstick glucose, electrolytes, BUN/Cr, LFTs, CBC, tox screen, U/A

• Based on clinical suspicion:

Labs: NH₃, TSH, cort stim, B₁₂, ABG, HIV, ESR, ANA, TPO/anti-TG, BCx, drug levels

Imaging: head CT, then MRI; CTA if c/f stroke/SAH; radiographs to r/o C-spine fracture

Lumbar puncture to r/o meningitis, SAH, or noninfectious inflammation (eg, autoimmune)

EEG to evaluate for nonconvulsive seizures, toxic/metabolic encephalopathy

Further treatment of delirium (NEJM 2017;377:1456)

• Treat underlying acute illness, eliminate precipitating factors, & provide supportive care

• Address sensory & cognitive impairments (frequent reorientation, glasses/hearing aids, etc.)

• Decrease/prevent infection/restraints if possible, remove lines/catheters if unnecessary

• Promote good sleep: reduce noise & nighttime interventions; sedative med if necessary

• Meds: consider antipsychotics (but neither haloperidol nor ziprasidone ↓ delirium duration in ICU Pts; NEJM 2018;379:2506); avoid benzos except in EtOH withdrawal or seizures

ANOXIC BRAIN INJURY (at risk if ≥5 min cerebral hypoxia)

Initial evaluation (Circulation 2010:S768)

• Neuro exam: arousal/verbal, eyes & other cranial nerves, motor response to pain

• Imaging: CT usually not informative w/in first day after arrest, but should be done prior to initiating targeted temp management if patient found down or has had head trauma

Targeted temperature management (Circulation 2015;132:2448)

• Indications: comatose (GCS <8) w/in 6 h after cardiac arrest (not isolated resp. arrest). Beneficial in both VT/VF and PEA/asystole. Also consider 6–12 h post-arrest.

• Relative contraindic.: major head trauma, coagulopathy/bleeding, major surgery <14 d; CV instability no longer viewed as contraindication, but rather something to be managed.

• Target temp: 32–37.8°C × ≥24 h, rewarm, then maintain normothermia (37°C) for ~24 hrs.

• Initial studies showing benefit w/ 32–34°C, but subsequent studies showed ≈ outcomes for 36°C or 37.8°C vs. 33°C (NEJM 2013;369:2197 & 2021;384:2283)

• ∴ prevent hyperthermia, but need for hypothermia vs. normothermia unclear

• Method: ice packs to head/neck/torso; cooling blankets; cooling vest or endovascular catheter. Goal to achieve target temp <6 h. Pts should be sedated/paralyzed while cooled. Start rewarming 24 h after cooling initiated (rewarm ≤0.5°C per h).

• Can consider higher MAP goal of >70 mmHg

• Complications

Dysrhythmias (brady most common): if significant or hemodynamic instability → rewarm

Coagulopathy (can receive lytics, GP IIb/IIIa inhibitors, etc.); monitor PT & PTT

Infection: monitor surveillance blood cultures during cooling

Hyperglycemia during cooling, hypoglycemia w/ rewarming; stop insulin if glc <200 mg/dL

Hypokalemia during cooling, hyperkalemia w/ rewarming; keep K 4–5 mEq/L

Ongoing evaluation

• Neuro exam: daily focus on coma exam. No exam finding is reliable <24 h or on sedation. Should be off sedation for adequate time (depends on dose, duration, Pt’s metabolism).

• Labs: daily CBC, PT/PTT, electrolytes. Serum neuron-specific enolase (NSE) on days 1–3.

• Imaging: noncontrast CT 24 h after arrest; if unrevealing, consider MRI around days 3–5

• EEG: consider in all to exclude seizures; greatest risk during rewarming. Unreactive background or abundant rhythmic or episodic discharges may convey poor prognosis.

• Somatosensory evoked potentials (SSEP): helpful for prediction of poor outcome if cortical responses are absent bilaterally; perform 48 h after arrest (72 h if cooled)

Prognosis (Nat Rev Neuro 2014;10:190)

• Prior to cooling era, poor prognosis at 72 h if absent pupillary & corneal reflexes and no motor response to pain; or absent SSEPs at 48 h. With cooling, unclear if prior measures as reliable. Overall ~12% survive to hosp. d/c; VT/VF 25-40%, PEA ~10%, asystole ~2%.

• Prognosis requires multifactorial assessment based on age, exam, comorbidities, ancillary data. Poor signs: absent brainstem reflexes, Rx-resistant myoclonus, EEG w/ absent background/reactivity, NSE >101, MRI w/ diffuse hypoxic injury. If doubt, err on more time.

SEIZURES

Definitions & clinical manifestations (Epilepsia 2017;58:522)

• Seizure: transient neurologic symptoms due to excessive synchronous neuronal activity; may be provoked by a reversible factor lowering the seizure threshold, or unprovoked

• Epilepsy: ≥2 unprovoked seizures occurring >24 h apart or 1 unprovoked seizure w/ ≥60% probability of further seizures over the next 10 y (see below for prognostication)

• Generalized seizures (involves brain diffusely)

Tonic-clonic (grand mal):

Aura (sec to mins): premonition with paresthesias, focal motor contractions, abnormal smells/tastes, fear, depersonalization, déjà vu, autonomic changes, automatisms

Ictal period (sec to mins): lateral gaze and head deviation, tonic contraction of muscles → intermittent relaxing and tensing of muscles, tongue biting, urinary incontinence, pooling of secretions

Postictal period (mins to h): slowly resolving period of confusion, disorientation, and lethargy. May be accompanied by focal neurologic deficits (Todd’s paralysis).

Absence (petit mal): transient lapse of consciousness w/o loss of postural tone, usu pedi

Myoclonic (infantile spasms & juvenile myoclonic epilepsy): sudden, brief contraction

• Focal seizures (involves discrete brain area, often associated with a structural lesion)

w/o impaired awareness: focal motor/autonomic sx (formerly “simple partial seizure”) or focal sensory/psychic symptoms (eg, aura)

w/ impaired awareness: dyscognitive features (formerly “complex partial seizure”)

evolving to bilateral, convulsive seizure (formerly “secondarily generalized seizure”)

• Status epilepticus: continuous convulsive seizure ≥5 min or >2 seizures w/o resolution of postictal encephalopathy; life threatening

• Nonconvulsive status epilepticus: alteration of awareness (ranging from confusion to coma) w/o motor manifestations of seizure; dx with EEG

Differential diagnosis

• Syncope (Lancet Neurol 2006;5:171)

Feature	Seizure	Syncope
Aura	Unusual behavior/automatisms	Diaphoresis, nausea, tunnel vision
Convulsions	Variable duration	Usually <10 sec
Postictal state	Yes; can be ≥30 min	None or short
Other clues	Tongue biting, incontinence	Skin pallor, clamminess

• Nonepileptic seizure (aka “psychogenic”): may see side-to-side head turning, asymmetric large-amplitude limb movements, hip thrusting, diffuse shaking w/o LOC, crying/talking during event; diagnosis requires spell capture on EEG with no EEG correlate

• Other: metabolic disorders (eg, alcoholic blackouts, hypoglycemia), migraine, TIA, transient global amnesia, narcolepsy (cataplexy), nonepileptic myoclonus, tics, asterixis

Etiologies of seizures (vary strongly by age)

• Without focal lesion: genetic predisposition to seizures or epilepsy syndrome; alcohol withdrawal, illicit drugs; meds (eg, β-lactams, bupropion, fluoroquinolones, tramadol, MNZ, meperidine, CsA); electrolyte (hyponatremia) & other metabolic (eg, uremia, liver failure, hypoglycemia); autoimmune encephalitis, idiopathic (~60%)

• With focal lesion: tumor, trauma, stroke, subdural hematomas, posterior reversible encephalopathy syndrome, mesial temporal sclerosis, abscess, focal cortical dysplasia

Clinical evaluation (JAMA 2016;316:2657)

• History key in differentiating seizure from other causes of transient loss of consciousness. Must talk to witnesses. Ask about prodrome, unusual behavior before spell, type & pattern of abnl movements incl. head turning & eye deviation (gaze preference usually away from seizure focus), loss of responsiveness.

• Recent events: illnesses/fevers, head trauma, sleep deprivation, stressors

• PMH: prior seizures or ⊕ FHx; prior CNS infection, stroke or head trauma; dementia

• Medications (new or noncompliance), alcohol and illicit drug use

• General physical exam should include the skin, looking for neuroectodermal disorders (eg, neurofibromatosis, tuberous sclerosis) that are a/w seizures

• Neurologic exam should look for focal abnormalities → underlying structural abnormality

Diagnostic studies (Neurology 2007;69:1996)

• Lab: full lytes, BUN, Cr, glc, LFTs, CK, lactate, tox screen, AED levels (except levetiracetam level rarely useful unless ? noncompliance), illicit drug screen, prolactin if drawn immediately after event (w/in 10–20 min)

• Routine EEG (~30 min): may help determine risk of seizure recurrence after 1^st-time unprovoked seizure. Caveat: interictal EEG nl in 50% of Pts w/ epilepsy, and interictal epileptiform activity (spikes or sharp waves) seen in up to 2% of nl population; EEG w/in 24 h, sleep deprivation and repeated studies ↑ dx yield of EEG.

• Long-term EEG monitoring (hrs to days): if suspicion for nonconvulsive status or non-epileptic seizures; video monitoring may help w/ nonepileptic seizures

• MRI to r/o structural abnormalities; ↑ Se w/ fine coronal imaging of frontal & temporal lobes

• LP (if no space-occupying lesion on imaging): if suspect meningoencephalitis (eg, fever, ↑ WBC, nuchal rigidity), autoimmune encephalitis, and in all HIV ⊕ Pts

Treatment (Neurology 2015;84:1705; Lancet 2015;385:884)

• Treat any underlying precipitants, including CNS infections, intoxication, withdrawal, discontinuing provoking med, etc.

• Antiepileptic drug (AED) Rx usually reserved for Pts w/ ≥2 unprovoked seizures, single seizure w/ high risk of recurrence (see below), or underlying structural abnormality. Provoked seizures generally treated by addressing underlying cause; consider AED if status epilepticus on presentation, focal neuro exam, postictal Todd’s paralysis.

• After 1^st unprovoked sz, weigh risks of recurrence vs. AED. ↑ risk of recurrence if abnl EEG, MRI, or nocturnal sz. If EEG & MRI nl → 65% sz-free at 5 y (Lancet Neurol 2006;5:317).

• Immediate treatment w/ AED after 1^st unprovoked seizure ↓ risk of recurrence over 2 y, but does not Δ long-term prognosis

• If AED Rx indicated, choice dependent on type of seizure, side effects, cost, mechanism of elimination (if hepatic or renal insufficiency), teratogenesis, and drug interactions

• Introduce gradually, monitor carefully

• Individual state laws mandate seizure-free duration before being allowed to drive

Antiepileptic Drugs and Side Effects
Medication	Avg Daily Dose	Common Side Effects
		Systemic	Neurologic (all: sedation)
Carbamazepine	400–1600 mg	Aplastic anemia, ↓ WBC, rash, hepatotoxicity, ↓ Na	Diplopia, confusion, ataxia
Ethosuximide	500–1500 mg	Rash, BM suppression	Behavioral Δs
Gabapentin	900–3600 mg	GI upset, wt gain	Nystagmus, ataxia
Lacosamide	200–400 mg	Prolonged PR interval	Dizziness, diplopia
Lamotrigine	100–300 mg	Rash (Stevens-Johnson)	Tremor, HA, blurred vision, insomnia
Levetiracetam	1000–3000 mg	GI upset (rare)	Emotional lability
Oxcarbazepine	600–2400 mg	Hyponatremia, rash	Diplopia, dizziness
Phenobarbital	50–200 mg	Rash	Cognitive slowing
Phenytoin	200–400 mg	Gum hyperplasia	Dizziness, ataxia
Topiramate	100–400 mg	↓ wt, hypohidrosis, kidney stones, glaucoma, met acid	Cognitive slowing
Valproic acid	500–2500 mg	Hepatotox, ↑ NH3, ↑ wt, ↓ hair	Tremor
Zonisamide	200–600 mg	↓ wt, hypohidrosis, nephrolith	Cog slowing, fatigue

(NEJM 2008;359:166; Lancet Neurol 2011;10:446)

Status epilepticus (Epilepsy Curr 2016;16:48)

• ABCs: vital signs, oral airway or endotracheal intubation. Place Pt in semiprone position to ↓ risk of aspiration. Obtain IV access. Give thiamine, dextrose, IV normal saline.

• STAT POC glc, metabolic panel, CBC, tox screen, CK, lactate, AED levels, consider head CT, LP

• Start standing AED after loading dose.

Treatment of Status Epilepticus
Time (min)	Antiepileptic	Dosing Regimen	Typical Adult Dose
5–20	Lorazepam or Midazolam or Diazepam*	0.1 mg/kg IV>IM 0.2 mg/kg IM 0.2 mg/kg IV or 0.2–0.5 mg/kg PR	2–4 mg IV pushes, up to 8 mg Up to 10 mg x1 Up to 10 mg IV; up to 20 mg PR
20–40	Phenytoin or Fosphenytoin or Valproate or Levetiracetam	20 mg/kg 20 mg PE/kg 40 mg/kg 20–40 mg/kg	1.0–1.5 g IV (max 1.5 g) over 20 min 1.0–1.5 g PE IV over 5–10 min 1.0–1.5 g IV (max 3 g) over 5–10 min 2g IV (max 4.5 g) over 10–15 min
	Subsequent steps mandate intubation, EEG monitoring, and ICU admission
40–60	General anesthesia with continuous midazolam, pentobarbital, or propofol

PE, phenytoin equivalents. ^*Consider PR diazepam if no IV access and IM midazolam is contraindicated.

ALCOHOL WITHDRAWAL

Clinical manifestations

• Minor withdrawal: 6–48 h after last drink; mild anxiety, tremulousness, HA

• Withdrawal seizures: typically w/in 48 h after last drink; if unRx’d, 1/3 → delirium tremens

• Alcoholic hallucinosis: isolated hallucinations (typically visual) 12–48 h after last drink

• Delirium tremens (DT): disorientation, agitation, hallucinations, ↑ HR & BP, fever, diaphoresis; begins 48–96 h after last drink, lasts 5–7 d

• Consider other dx: CNS infxn or bleed, sz, drug O/D, co-ingestions, acute liver failure, GIB

• Ten-item scale (CIWA-Ar) used to assess and manage alcohol withdrawal (see Appendix)

Treatment (J Addict Med 2020;14:1)

• Benzodiazepines:

Drug: diazepam preferred (long-acting; ↓ risk of recurrent withdrawal), lorazepam (short-acting), chlordiazepoxide, oxazepam (no active metab; good if cirrhosis)

Dosing: typically start w/ diazepam 10–15 mg IV q10–15min (or lorazepam 2–4 mg IV q15–20min) until appropriate sedation achieved, then titrate to CIWA-Ar scale, evaluating q1–4 h until score <10 × 24 h, then q4–8 h × 24 h, and if stable, then q4 h

• Phenobarbital: adjunctive use in severe withdrawal may ↓ hospital stay, mech ventilation

• Avoid βB (mask sx)

• Mechanical restraints as needed until chemical sedation achieved

• Volume resuscitation as needed; thiamine then glc to prevent Wernicke’s encephalopathy (ataxia, ophthalmoplegia, short-term memory loss); replete K, Mg, PO₄

• Ppx: if min sx or asx (ie, CIWA score <8) but prolonged heavy EtOH consumption or h/o withdrawal seizures or DTs → chlordiazepoxide 25–100 mg q6 h × 24 h, then taper

DIZZINESS

Differential diagnosis

• Includes a variety of sx. Disequilibrium: sense of imbalance, gait disturbance; vertigo: perception of spinning; near syncope: lightheadedness due to cerebral hypoperfusion.

• Dizziness can occur with PNS & CNS injury (vide infra) or in hematologic (eg, anemia), CV (eg, arrhythmia, orthostasis) & endocrine (eg, ↓ glc, thyroid) disorders, or due to meds

• Vertigo Ddx:

Peripheral (inner ear/CNVIII)

BPPV: dislodged canaliths in semicircular canal; episodic rotatory vertigo (<1 min episodes), triggered by changes in position; Rx: Epley/BBQ roll maneuver

Meniere’s disease: ↑ endolymphatic pressure in inner ear; episodic rotatory vertigo (min-hrs), N/V, aural fullness, hearing loss, tinnitus; Rx: diuretics, ↓ salt

Vestibular neuritis: sudden-onset w/ gait ataxia; severe for 24–48 hrs followed by gradual improvement, often post-viral; w/ hearing loss = labyrinthitis

Central (brainstem/cerebellum)

Posterior circulation stroke/TIA: “5 Ds” of dizziness, diplopia, dysarthria, dysphagia, dystaxia; sudden onset (resolves after mins in TIA, persists in stroke)

Other: migraine, Chiari, epilepsy, MS, tumors, drugs/meds, concussion

Initial evaluation

• Hx: ask open-ended questions (description by Pt may be unreliable), pace of illness, episodic vs. chronic, meds, other sx of posterior circ including diplopia, dysarthria, ataxia

Exam	Peripheral Causes	Central Causes
Orthostatics	⊕ in orthostatic syncope	Typically absent
Eye movements	Nystagmus unidirectional if present, never vertical, suppressed w/ fixation	Nystagmus bidirectional, often vertical, not suppressed w/ fixation
Hearing	May be impaired in some peripheral causes of vertigo	Normal (rarely unilat. hearing loss in AICA-territory stroke)
Coord./gait	Normal	May reveal limb, trunk, gait ataxia

• HINTS testing (Stroke 2009;40:3504)

Head Impulse test: Pt fixates on examiner’s nose during rapid passive head turn of ~10–20°; presence of “catch-up saccade” supports peripheral dysfunction to side of turn

Nystagmus (see table above)

Test of Skew: vertical refixation saccade on alternating eye cover supports central cause

• Dix-Hallpike test: Pt sitting → lying back w/ 45º head tilt; elicits rotatory nystagmus after delay of secs; fatigues if repeated; ⊕ suggests BPPV w/ affected ear down

• Supine Roll test: nystagmus elicited by head turn while patient supine; when ⊕ suggests BPPV w/ affected ear down (lateral canal, 8% of cases)

• Studies: orthostatic VS, basic labs, ECG; if concerning s/s HINTS → MRI brain

• Rx: Epley for BPP; vestib. PT; anti-hist., sedative or anti-emetic, steroid for vestib. neuritis

STROKE

ISCHEMIC STROKE

Etiologies

• Embolic: artery → artery, cardioembolic (~30% due to AF; NEJM 2014;370:2478), paradoxical

• Thrombotic: large vessel (atherosclerosis) vs. small vessel (“lacunar,” lipohyalinosis of small arteries, often related to smoking, HTN, hyperlipidemia, & DM)

• Other: hypoperfusion, dissection, vasculopathy (vasculitis, radiation), vasospasm, hypercoag, hematologic (sickle cell, hyperviscosity), endocarditis, venous

Clinical manifestations

• Timing: embolic → sudden onset; thrombotic → may have stuttering course

Stroke Syndromes by Vascular Territory
Artery	Deficits
ICA → Ophth	Amaurosis fugax (transient monocular blindness)
ACA	Hemiplegia (leg >arm), abulia, urinary incontinence, primitive reflexes
MCA	Hemiplegia (face & arm >leg); hemianesthesia; homonymous hemianopia Aphasia if dom. hemisphere: sup. div. → expressive; inf. div → receptive Apraxia & neglect if nondom. hemisphere.
PCA	Macular-sparing homonymous hemianopia; alexia w/o agraphia Thalamic syndromes with contralateral hemisensory disturbance
Vertebral, PICA	Wallenberg syndrome = numbness of ipsilateral face and contralateral limbs, diplopia, dysarthria, dysphagia, ipsilateral Horner’s, hiccups
Basilar	Pupillary Δs (midbrain=dilated, pons=pinpoint), long tract signs (quadriplegia, sensory loss), CN abnl, cerebellar dysfxn. Top of basilar → ”locked in” synd.
Cerebellar	Vertigo, N/V, diplopia, dysarthria, nystagmus, ipsilateral limb ataxia
Lacunar (arterioles)	5 major syndromes: pure hemiplegia, pure hemianesthesia, ataxic hemiparesis, dysarthria + clumsy hand, mixed sensorimotor

Transient ischemic attack (TIA)

• Sudden deficit due to cerebral ischemia; no stroke on imaging; most resolve in <1 h

• Ddx: seizure, migraine, hypoglycemia, amyloid spells, TGA, anxiety

• Risk of subsequent stroke ~2% by 1 wk (NEJM 2016;374:1533). Can stratify based on ABCD₂: Age ≥60 y (+1); BP ≥140/90 (+1); Clin features: unilat. weak. (+2), speech impair. w/o weakness (+1); Duration ≥60 (+2) or 10–59 min (+1); DM (+1)

Physical exam

• General: murmurs, carotid & subclavian bruits, peripheral emboli, endocarditis stigmata

• Neurologic exam, NIH stroke scale (http://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf)

Acute workup

• Electrolytes, Cr (relevant for contrast); glc, CBC, coags (see exclusion criteria for lysis)

• Cardiac biomarkers, 12-lead ECG, tox screen

• STAT CT to r/o ICH prior to lysis (Se ICH ≈ MRI, CT faster). Early signs of stroke: hyperdense artery, loss of gray-white differentiation, edema, insular ribbon. CT can be nl initially, & not Se for small or brainstem stroke. CTA if possible endovascular Rx.

Acute treatment of ischemic stroke (Stroke 2019;50:e344; JAMA 2021;325:1088)

• Thrombolysis (IV): tPA 0.9 mg/kg (max 90 mg), w/ 10% as bolus over 1 min, rest over 1 h

consider if onset w/in 4.5 h, Ø contraindic. (incl. current/prior ICH; head trauma or stroke w/in 3 mo; intracranial neoplasm, AVM or aneurysm; recent intracranial/intraspinal surgery; active internal bleeding; noncompressible arterial puncture; ↑ BP; multilobar infarct; plt <100k, INR >1.7, on Xa inhib, PTT >40, glc <50)

0–3 h: 12% absolute ↑ in good neuro outcome (min/no disability), 5.8% absolute ↑ in ICH, trend toward 4% absolute ↓ mortality

3–4.5 h: 7.4% absolute ↑ in good neuro outcome, 1.8% absolute ↑ in ICH, Ø mortality benefit (nb, trial excluded patients with previous strokes + DM)

Data for tenecteplase (TNK), Rx up to 9 h or unknown timing, and for MRI imaging to guide Rx (NEJM 2018;378:1573 & 379:611; 2019;380:1795; Lancet 2020;396:1574)

• BP: lower to <185/110 to consider lysis; if lyse keep <180/105 × 24 h (consider IV labetalol or nicardipine), o/w permissive HTN unless >220/120 or sx; if sx HoTN consider vasopressors

• Initiate ASA w/in 24–48 h; avoid anticoagulation w/in 24 h of lysis; see below for long-term Rx

• Cerebral edema → herniation: 1–5 d post large MCA or cerebellar strokes, ↑ risk in young. Elevate HOB >30°; mannitol ± 23% NaCl. Hemicraniectomy ↓ mortality (NEJM 2014;370:1091). Neurosurgery consult in select MCA and all large cerebellar strokes.

• Endovascular thrombectomy if w/in 6 h of sx onset, pre mRS 0-1, occlusion in ICA or MCA, NIHSS ≥6, ASPECTS ≥6 (CT-based likelihood of recovery). May extend to 6–24 h if mismatch between infarct size and clinical deficits or stroke penumbra (NEJM 2018;378:11 & 708).

Workup to assess for etiology/modifiable risk factors

• Cardiac: monitor for AF (inPt and extended outPt); TTE to r/o thrombus/veg, w/ bubble study to r/o PFO/atrial septal aneurysm if suspect embolic

• Vessel imaging: CTA or MRA head/neck; carotid U/S w/ Doppler if contraindic to CTA/MRA

• Labs: lipids, HbA1c, TSH, homocysteine, Lp(a), hypercoag w/u (if <65 y or cryptogenic stroke; ideally drawn before starting anticoag), ESR/CRP, blood cx if s/s systemic infection

• MRI helpful if dx of stroke unclear (esp. post circ) or to define stroke subtype, age, exact size

DWI bright/ADC dark = earliest finding in acute ischemia (~w/in mins, up to days)

T2-FLAIR: hyperintense w/in about 6 hrs, persists for wks; PWI differentiates irreversibly infarcted core vs. viable penumbra; T1 fat-sat (neck vessels) if suspicious for dissection

Secondary stroke prevention (Stroke 2021;52:e364)

• Antiplatelet therapy: different agents likely have similar efficacy

ASA ↓ death & repeat stroke; equal to warfarin in nonembolic stroke (NEJM 2001;345:1444)

clopidogrel: marginally superior to ASA, slightly ↑ ICH (Lancet 1996;348:1329)

P2Y₁₂ (clopi or ticag) + ASA (vs. ASA alone): Rx for 1–3 mos in minor strokes or TIA w/ high ABCD² → ↓ risk of ischemic stroke, ↑ ICH (NEJM 2018;379:215 & 2020;383:207). Rx for 90 d if stroke due to intracranial athero (NEJM 2011;365:993).

• Anticoagulation (AC): consider for AF (qv), cardiac/paradoxical emboli (except bacterial endocard); large extra-dural dissections; hypercoag; bridge to CEA in sx carotid stenosis

Hold off on AC in large strokes for ~2–4 wk given risk of hemorrhagic conversion

• Long-term SBP target <130/80 mmHg

• ↓ LDL-C (<< 70 mg/dL): ↓ recurrence w/ statin PCSK9i added to statin (NEJM 2017;376:1713)

• Carotid revascularization (NEJM 2013;369:1143)

CEA (if surgical morbidity & mortality ≤6%) indicated for:

sx stenosis 70–99% (benefit ↑ for males, >75 y, ≤2 wk from stroke) → 65% ↓ RR of repeat stroke, slight benefit for 50–69% stenosis (NEJM 1991;325:445; Lancet 2004;363:915)

asx stenosis 70–90%, <79 y: 50% ↓ RR of repeat stroke (Lancet 2010;376:1074)

Stenting: c/w CEA, ↑ periprocedural stroke (esp. in elderly) & ↓ MI (but many asx); subseq. ≈ rates of fatal or disabling stroke, but ↑ non-disabling stroke (Lancet 2021;398:1065)

Patent foramen ovale (PFO; in ~25% of population) (NEJM 2005;353:2361)

• ↑ stroke risk: ≥4 mm separation, R→L shunting at rest, ↑ septal mobility, atrial septal aneurysm

• Risk scores assess likelihood stroke related to PFO. RoPE score: age (+1 for each decade <70); cortical stroke on imaging (+1); HTN, DM, h/o stroke/TIA, smoker (+1 for each absent risk factor). PASCAL classification also includes large shunt or atrial septal aneurysm.

• If PFO & stroke/TIA: no benefit of warfarin vs. ASA, but consider if high risk for or has DVT/PE

• Closure ↓ recurrence by ≥50%, with magnitude of benefit dependent on risk classification (RoPE ≥7 or PASCAL classification of possible or probable) (JAMA 2021;326:2277)

INTRACRANIAL HEMORRHAGE (ICH)

Classification by location

• Hemorrhagic strokes: intraparenchymal hemorrhage (IPH) & subarachnoid hemorrhage (SAH)

• Other ICH: epidural hematoma (EDH) & subdural hematoma (SDH)

Etiologies

• AVM, aneurysm, cerebral venous sinus thrombosis → IPH or SAH

• HTN (basal ganglia, cerebellum, brainstem), cerebral amyloid (lobar), tumor (esp. w/ melanoma, renal cell CA, chorio-CA, thyroid CA) → IPH

• Trauma → all locations (nb, IPH or SAH caused by trauma technically not a stroke)

Clinical manifestations (Lancet 2017;389:655 & NEJM 2017;377:257)

• ↓ consciousness, N/V, HA, progressive focal neurologic deficits

• SAH: thunderclap HA, onset w/ exertion; nuchal pain/rigidity; LOC. EDH: initial lucid interval.

Workup (Acad Emerg Med 2016;23:963)

• STAT CT brain, angio (CT-A or conventional) if suspicious for vascular source

• ? LP for xanthochromia if no evid of ICH on CT (although ⊖ LR 0.01) & suspicious for SAH

• Coags (PT, PTT, INR)

Management (Crit Care Med 2016;44:2251; JAMA 2019;321:1295)

• Reverse coagulopathy, INR <1.4. Plt >100k, no need for plt tfn if on antiplt Rx (? if ↑ ICH), DDAVP if uremic. 2–3 mo after recovers, can restart antiplt mono Rx (Lancet 2019;393:2013).

• BP control w/ art line, nicardipine or labetalol gtt. SBP goal <140 for 1^st 24 h, then <160 (NEJM 2013;368:2355 & 2016;375:1033), though BP goals controversial (NEJM 2016;375:1033)

• SAH: endovasc coiling vs. surg clipping (depends on location, comorbid.; Lancet 2015;385:691) of aneurysm/AVM; nimodipine to ↓ risk of vasospasm (monitor w/ TCDs), seizure Ppx

• Surg evac: EDH; SDH if >1 cm or rapid ↑, Rx-resistant epilepsy; IPH: no obvious benefit

• Venous sinus thrombosis: start anticoagulation, manage ↑ ICP and seizures as needed

WEAKNESS & NEUROMUSCULAR DYSFUNCTION

PERIPHERAL NEUROPATHIES

Etiologies based on presentation

• Mononeuropathy (1 nerve): acute → trauma; chronic → entrapment, compression, DM, Lyme. Common: median nerve (carpal tunnel); ulnar (elbow or wrist); radial (spiral groove); com. peroneal (fibular head w/ leg crossing); lat. femoral cutan. (inguinal lig)

• Mononeuropathy multiplex (axonal loss of multiple, noncontig. nerves): vasculitic synd. (eg, PAN, EGPA, GPA, SLE, RA, Sjögren’s, cryo, HCV), DM, Lyme, HIV, leprosy, hereditary neurop. w/ pressure palsies, infiltrative (sarcoid, lymphoma, leukemia)

• Polyneuropathy (multiple symmetric nerves, generally length dependent): 30% idiopathic;

W/ autonomic features: DM, EtOH, paraneoplastic, B₁₂ def, amyloid, chemo, 1° dysauto

Painful (small fiber nerves): DM, EtOH, amyloid, chemo, sarcoid, heavy metals, porphyria

Demyelinating. Acute: AIDP (Guillain-Barré), diphtheria. Subacute: meds (taxanes), paraneoplastic. Chronic: idiopathic, DM, CIDP, anti-MAG, HIV, hypothyroidism, toxins, paraproteinemia, hereditary (eg, CMT).

Axonal. Acute: acute motor axonal neuropathy, porphyria, vasculitis, uremia, critical illness. Subacute: EtOH, sepsis, paraneoplastic, meds (cisplatin, paclitaxel, vincristine, INH, ddI, amio). Chronic: DM, uremia, lead, arsenic, HIV, paraproteinemia, B₁₂ defic.

Clinical manifestations

• Weakness, fasciculations, cramps, numbness, dysesthesias (burning/tingling), allodynia

• ↑ Autonomic dysfxn (orthostasis, constipation, urinary retention, impotence, abnl sweating)

• Depressed or absent DTRs (may be normal in small fiber neuropathy)

Diagnostic studies

• Distal symmetric polyneuropathy: CBC, lytes, BUN/Cr, Hb_A1C, B₁₂, ESR, SPEP + IF

• EMG/NCS (often no change in 1^st 10–14 d or in small-fiber neuropathy)

• Based on H&P: LFTs, celiac Abs, ANA, anti-Ro/La, HIV, Cu, Lyme, RPR, UA, UPEP+IF, ACE, ANCA, heavy metals, LP (AIDP/CIDP), cryo, paraneoplastic Abs, genetic testing. Autonomic testing/skin bx (small fiber), nerve bx (mononeuropathy multiplex), fat pad bx (amyloid).

• MRI if possible radiculopathy or plexopathy (after EMG)

Pharmacologic treatment of neuropathic pain (Lancet Neurol 2015;14:162)

• Gabapentin, pregabalin, TCAs (nortriptyline, amitriptyline), SNRIs (duloxetine, venlafaxine)

• 2^nd line: tramadol, topicals (lido, capsaicin); 3^rd line: nerve block, botulinum toxin A

GUILLAIN-BARRE SYNDROME (GBS)

Definition & epidemiology (Lancet 2021;397:1214)

• AIDP (60–80%); acute motor axonal neuropathy (AMAN; 7–30%; a/w anti-GM1, anti-GD1a Abs; worse prognosis); Miller Fisher synd. (ophthalmoplegia & ataxia; a/w anti-GQ1b Ab)

• Incidence 1–2 per 100,000; most common acute/subacute paralysis

• Precipitants in 60%: viral illness (influenza, CMV, EBV, HIV, Zika, COVID-19), URI (Mycoplasma), gastroenteritis (Campylobacter), Lyme, immunizations, immune checkpoint inhibitors, surgery

Clinical manifestations (Nat Rev Neurol 2019;15:671)

• Pain (55–90%), distal sensory dysesthesias & numbness often 1^st sx, back pain common

• Progressive symmetric paralysis in legs and arms over hrs to days; plateau in 1–4 wk

• Hypoactive then absent reflexes. <10% w/ reflexes on presentation, but all develop hypo/areflexia during course. Minority of AMAN w/ preserved reflexes throughout.

• Resp failure requiring mech vent occurs in 25%; autonomic instability & arrhythmias in 60%

Diagnostic studies (results may be normal in first several days)

• LP: albuminocytologic dissociation = ↑ protein w/o pleocytosis (<10 WBCs) seen in up to 64% of Pts. ↑ protein in ½ in 1^st wk, ¾ by 3^rd wk of sx. Unlikely to be GBS if WBC >50

• EMG/NCS: ↓ conduction velocity, conduction block, abnl F-waves; can be nl in 1^st 2 wk

• FVC & NIF: to assess for risk of resp. failure (cannot rely on P_aO₂ or S_aO₂ alone)

Treatment

• Plasma exchange or IVIg of equal efficacy (Neuro 2012;78:1009); steroids not beneficial

• Supportive care with monitoring in ICU setting if rapid progression or resp. failure

• Watch for autonomic dysfunction: labile BP, dysrhythmias, urinary retention, ileus

• Erasmus GBS outcome score can help w/ prognostication (Lancet Neurol 2007;6:589). Most recover near baseline in 1 y; 3–5% mortality. Residual deficits: pain, fatigue.

MYASTHENIA GRAVIS (MG)

Definition & epidemiology (Lancet Neurol 2015;14:1023; NEJM 2016;375:2570)

• Autoimmune disorder with Ab against acetylcholine receptor (AChR, 80%), muscle-specific kinase (MusK, 4%), lipoprotein-related protein 4 (LRP4, 2%), or other NMJ proteins

• Prevalence: 150–250 per million; all ages, peak incidence 20s–30s (F), 60s–70s (M)

• 15% of AchR MG a/w thymoma; 30% of pts w/ thymoma develop AchR MG

Clinical manifestations

• Fluctuating weakness w/ fatigability (worse w/ repetitive use, relieved by rest)

• Cranial muscles involved early → 60% present initially w/ ocular sx (ptosis, diplopia); 15% confined to ocular sx; 15% w/ bulbar (difficulty chewing, dysarthria, dysphagia)

• Limb weakness proximal >distal; DTRs preserved; minimal/no atrophy

• MusK MG (F >>M): more severe limb/facial/bulbar weakness, muscle atrophy

• Exacerb. triggers: URI, surgery, preg/postpartum, meds (eg, Mg, AG, macrolides, FQ, procainamide, phenytoin, D-penicillamine, β-blocker). Prednisone can worsen sx acutely.

• Myasthenic crisis = sx exacerbation, risk of respiratory compromise

• Cholinergic crisis = excessive Rx with anticholinesterases: salivation, cramping, diarrhea

Diagnostic studies

• Bedside: ptosis, worse after >45 sec of sustained upgaze; improved with ice pack over eyes for 2–5 min (Se 77%, Sp 98%), ophthalmoplegia, weakness

• Neostigmine test: temporary ↑ strength; false ⊕ & ⊖ occur; premedicate w/ atropine

• EMG: ↓ response with repetitive nerve stimulation (vs. ↑ response in Lambert-Eaton)

• Anti-AChR Ab (Se 80%, 50% if ocular disease only, Sp >90%); muscle specific receptor tyrosine kinase (MuSK) Ab; AchR modulating Ab

• CT or MRI of thorax to evaluate thymus (65% hyperplasia, 10% thymoma)

Treatment (Neurology 2021;96:114)

• Thymectomy if thymoma and in Ab ⊕ Pts w/o thymoma (NEJM 2016;375:511)

• Cholinesterase inhibitor (eg, pyridostigmine) is most rapid acting (30–60 min). Less effective for MusK MG. Side effects: cholinergic stim (brady, diarrhea, drooling).

• Immunosuppression: prednisone (benefit in wks; don’t start during crisis) + steroid-sparing agent: AZA (benefit in 6–15 mo), MMF. Refractory: rituximab, MTZ, eculizumab.

• Myasthenic crisis: treat precipitant; d/c cholinesterase inhibitor if suspect cholinergic crisis. IVIg or plasmapheresis; if no response, high-dose glucocorticoids (monitor for initial worsening). ICU if rapid or severe (follow FVC, NIF).

MYOPATHIES

Etiologies (Front Neurol 2011;2:49)

• Hereditary: Duchenne, Becker, limb-girdle, myotonic, metabolic, mitochondrial

• Endocrine: hypothyroidism, hyperparathyroidism, Cushing syndrome

• Toxic: statins, fibrates, steroids, zidovudine, EtOH, cocaine, colchicine, penicillamine

• Infectious: HIV, HTLV-1, trichinosis, toxoplasmosis, COVID-19

• Inflammatory: polymyositis, dermatomyositis, inclusion body myositis, anti-HMGCR

Clinical manifestations

• Progressive or episodic weakness (not fatigue)

• Weakness most often symmetric, proximal >distal (stairs, rising from sitting, etc.)

• ↑ Myalgias (though not prominent or frequent), cramps, myotonia (impaired relaxation)

• May develop either pseudohypertrophy (dystrophies) or mild muscle atrophy

• Assoc. organ dysfxn: cardiac (arrhythmia, CHF), pulmonary (ILD), dysmorphic features

Diagnostic studies

• CK, aldolase, LDH, electrolytes, ALT/AST, PTH, TSH, ESR, HIV

• Autoantibodies: ANA, RF, anti-Jo1, antisynthetase, anti-Mi-2, anti-SRP, anti-HMGCR, 5TN1CA (in inclusion body myositis)

• EMG/NCS: low-amplitude, polyphasic units w/ early recruitment, ↑ fibrillation potentials

• Muscle biopsy, molecular genetic testing (where indicated)

• Age-appropriate cancer screening if polymyositis or dermatomyositis suspected

HEADACHE

Primary headache syndromes (Cephalgia 2018;38:1)

• Tension-type: bilateral, pressure-like pain of mild–mod intensity, not throbbing or aggravated by physical activity. A/w photophobia or phonophobia, not N/V. Freq a/w myofascial sensitivity in neck/head. Triggers: stress, sleep deprivation, dehydration, hunger. Episodic HA Rx: NSAIDs, acetaminophen (risk of med overuse HA); chronic HA Rx: TCAs.

• Cluster HA and other trigeminal autonomic cephalalgias (TACs) (Continuum 2018;24:1137)

Characterized by unilateral headache a/w ipsilateral autonomic sx (rhinorrhea, red/tearing eye, miosis, ptosis, lid edema, sweating), subtypes differentiated by timing.

Cluster: ♂ >♀, unilateral pain w/ autonomic sx & restlessness; attacks 15 min–3 h, up to 8/d (circadian). Rx: high-flow O₂ (12–15 L/min), sumatriptan. Ppx: CCB (verapamil).

Paroxysmal hemicrania: similar to cluster, but ♀ >♂, attacks 2–30 min. Rx: indomethacin.

Hemicrania continua: ♀ >♂, ice pick–like pain lasting >3 mo. Rx: indomethacin.

Short-lasting unilateral neuralgiform HA (SUNA/SUNCT): ♂ >♀, excruciating, stabbing, electrical pain, 5 sec–4 min, up to 200×/d. Rx: lamotrigine, gabapentin, topiramate.

• Migraine: see below

Secondary causes of headaches (Neurology 2019;92:134)

• Traumatic: post-concussion, SAH, SDH, postcraniotomy

• ↑ ICP: mass (tumor, abscess, vascular malformations, ICH), hydrocephalus, idiopathic intracranial hypertension (pseudotumor cerebri), altitude-associated cerebral edema

• ↓ ICP: post-LP headache, CSF leak/dural tear, overshunting

• Vascular: stroke (esp. posterior circ), dissection, vasculitis (incl. temporal arteritis), reversible cerebral vasoconstriction syndrome (RCVS), ICH, venous sinus thrombosis

• Meningeal irritation: meningitis, SAH

• Extracranial: sinusitis, TMJ syndrome, glaucoma

• Systemic: hypoxia (OSA), hypercapnia, dialysis, HTN, cardiac cephalalgia, hypoglycemia, ↓ TSH, pheo, medication overuse (analgesics), withdrawal (caffeine, opioids, estrogen)

Clinical evaluation (Neurology 2019;92:134 & JAMA 2021;325:1874)

• Hx: onset (sudden vs. gradual), quality, evolution (progressive), severity, location, duration, triggers, alleviating factors, positional, hormonal (menstruation), preceding trauma, assoc. sx (visual Δs, “floaters,” N/V, photophobia, focal neuro sx), meds (new, analgesics), substance abuse (opioids, caffeine), personal/family hx of HA; neoplasm, preg

• General and neurologic exam (including funduscopic exam, visual fields). Headache diary.

• Warning signs (should prompt neuroimaging)

Explosive onset (vasc); “worst HA of life” (SAH, RCVS); meningismus (SAH, infxn)

Positional: lying >standing (↑ ICP); N/V (↑ ICP; migraines); coughing/bearing down (↑ ICP)

Visual sx: diplopia, blurring, ↓ acuity (GCA, glaucoma, ↑ ICP); eye pain (glaucoma, trigeminal autonomic cephalalgia, optic neuritis)

Abnl exam (struct. lesion, poss. in migraine); ↓ consciousness; systemic sx (fever)

Age >65 y; immunosuppression (CNS infections, PRES)

• Imaging: CT or MRI; consider CTA (beading in vasculitis/RCVS/vasospasm), CTV/MRV

• LP if ? SAH (✓ for xanthochromia), idiopathic intracranial HTN (✓opening press); image first!

MIGRAINE (NEJM 2017;377:553)

Definition & clinical manifestations (Lancet 2018;391:1315 & Continuum 2021;27:586)

• Epidemiology: affects 15% of women and 6% of men; onset usually by 30 y

• Migraine w/o aura (most common): ≥5 attacks lasting 4–72 h with both (a) N/V or photophobia & phonophobia, and (b) ≥2 of following: unilateral, pulsating, mod–severe intensity, or aggravated by routine activity

• Migraine w/ aura: ≥2 attacks w/: (a) aura defined as ≥1 fully reversible sx: visual Δs (flickering spots, visual loss), sensory sx (paresthesias, numbness), speech disturbance; and (b) unilateral progression of sx over ≥5 but ≤60 min; and (c) HA w/in 60 min of aura

• Aura may occur w/o HA (“acephalgic migraine”), must r/o TIA/stroke (typically rapid onset)

• If motor weakness, consider sporadic or familial hemiplegic migraine: aura of reversible motor weakness (up to 24 h), a/w CACNA1A, ATP1A2, or SCN1A mutations

• Precipitants: stress, foods (cheese, chocolate, MSG), fatigue, EtOH, menses, exercise

Treatment (Lancet 2021;397:1505 & Continuum 2021;27:613)

• Abortive Rx: 5-HT₁ agonists (triptans) effective if given early in migraine attack; contraindicated if motor aura, CAD, prior stroke. Also consider acetaminophen, caffeine, NSAIDs (ketorolac), steroids, Mg, metoclopramide, prochlorperazine, valproate, dihydroergotamine (caution if CAD, recent triptan use). Avoid butalbital, opioids.

• Prophylaxis: AEDs (topiramate, VPA), β-blockers (propranolol first-line), TCAs (amitriptyline), Mg, B2, botox, anti-CGRP, & receptor mAbs (Lancet 2021;397:51)

BACK AND SPINAL CORD DISEASE

Differential diagnosis of back pain

• Musculoskeletal: involving spine (vertebra, facet joints), paraspinal muscles & ligaments, sacroiliac joint, or hip joint. Spondylolisthesis, vertebral fx, OA, inflam. spondyloarthritis (qv), musculoligamentous “strain,” myofascial pain syndrome, trochanteric bursitis.

• Spinal cord (myelopathy)/nerve root (radiculopathy):

Degenerative/traumatic: disc herniation, foraminal or lumbar stenosis, spondylolisthesis

Neoplastic: lung, breast, prostate, RCC, thyroid, colon, multiple myeloma, lymphoma

Infectious: osteomyelitis/discitis, epidural abscess, zoster, Lyme, CMV, HIV, spinal TB

Vascular: spinal cord ischemia, dural AV fistula

• Referred pain from visceral disease:

GI: PUD, cholelithiasis, pancreatitis, pancreatic cancer

GU: pyelonephritis, nephrolithiasis, uterine or ovarian cancer, salpingitis

Vascular: aortic dissection, leaking aortic aneurysm

Initial evaluation (Lancet 2017;389:736 & Continuum 2021;27:12)

• History: location, timing (acute/subacute/chronic), worse w/ Valsalva, radiation, trauma, wt loss, cancer, fever, immunocompromised, IVDU, neurologic sx, saddle anesthesia, Lhermitte phenomenon, bowel/bladder/sexual sx (retention, incontinence)

• General physical exam: local tenderness, ROM, signs of infection or malignancy; paraspinal tenderness or spasm in musculoskeletal strain

• Signs of radiculopathy (sharp/lancinating pain radiating into limb):

Spurling sign (cervical radiculopathy): radicular pain w/ downward force to extended & ipsilaterally rotated head; 30% Se, 93% Sp

Straight leg raise (sciatica or lumbosacral radiculopathy): radicular pain at 30–70°; ipsilateral: 92% Se, 28% Sp; crossed (contralateral leg raised): 28% Se, 90% Sp

Patrick/FABER test (SI joint synd): severe pain on hip ext rotation; 70% Se, 100% Sp

Neurogenic claudication in lumbar stenosis (see table on next page)

• Neuro exam: full motor (incl. sphincter tone); gait; sensory (temp/pain, position, vibration; ↑ perineal; ? dermatomal); reflexes incl. bulbocavernous, anal wink (S4), cremasteric (L2)

• Red flags: acute change (pain, weakness), upper motor neuron signs (hyperreflexia, upgoing toes), cauda equina or conus medullaris syndromes (saddle anesthesia, bowel/bladder or sexual dysfunction, reduced rectal tone, loss of sacral reflexes), dyspnea when flat (C3–C5), pain at rest or at night

• Laboratory (depending on suspicion): CBC w/ diff, ESR/CRP, Ca, PO₄, CSF, BCx

• Neuroimaging: low yield if nonradiating pain, high false ⊕ rate (incidental spondylosis); depending on suspicion: X-rays, CT or CT myelography, MRI, bone scan

• EMG/NCS: may be useful to distinguish root/plexopathies from peripheral neuropathies

SPINAL CORD COMPRESSION

Clinical features (Continuum 2021;27:163)

• Etiologies: tumor (vertebral mets, intradural meningioma/neurofibroma), epidural abscess/ hematoma, vascular malformation (dural AV fistula), degen. dis. (spondylosis), trauma

• Acute: flaccid paraparesis and absent reflexes (“spinal shock”)

• Subacute–chronic: spastic paraparesis and hyperreflexia (upgoing toes ± ankle clonus)

• Posterior column dysfunction in legs (loss of vibratory and/or proprioceptive sense)

• Sensory loss below level of lesion (truncal level ↑ bilateral leg sx is clue for cord process)

Evaluation & treatment

• Empiric spine immobilization (collar, board) for all trauma patients

• STAT MRI (at and above clinical spinal level, with gadolinium) or CT myelogram

• Emergent neurosurgical and/or neurology consultation. Urgent radiation therapy ↑ surgery for compression if due to metastatic disease (Lancet Oncol 2017;18:e720).

• Empiric broad-spectrum antibiotics ± surgery if c/f epidural abscess

• High-dose steroids depending on cause:

Tumor: dexamethasone 16 mg/d IV (usually 4 mg q6 h) with slow taper over wks

Trauma: methylprednisolone 30 mg/kg IV over 15 min then 5.4 mg/kg/h × 24 h (if started w/in 3 h of injury) or × 48 h (if started 3–8 h after injury) (Cochrane 2012:CD001046)

NERVE ROOT COMPRESSION

Clinical features (NEJM 2015;372:1240 & Continuum 2021;27:163)

• Radicular pain aggravated by activity (esp. bending, straining, coughing), relieved by lying

• Sciatica = radicular pain radiating from buttocks down lateral aspect of leg, often to knee or lateral calf ± numbness and paresthesias radiating to lateral foot. Caused by compression of nerve roots, plexus, or sciatic nerve.

Pathophysiology

• <65 y: 90% from disc herniation. ≥65 y also w/ more degenerative contributors: ligamentous hypertrophy, osteophyte formation, facet arthropathy, neural foraminal narrowing

• Spinal stenosis: central canal narrowing → root compression via direct impingement, CSF flow obstruction, vascular compromise

Nb, lumbar disc protrusion tends to compress the nerve root that exits 1 vertebral level below the protrusion.

Neurogenic vs. Vascular Claudication
Features	Neurogenic Claudication	Vascular Claudication
Cause	Lumbar spinal stenosis (with nerve root compression)	Peripheral artery disease (with limb ischemia)
Pain	Radicular back/buttock pain Radiating down legs	Cramping leg pain Mostly in calves; radiating up legs
Worse with	Walking & standing Hyperextension/lying prone	Walking Biking
Better with	Bending forward, sitting	Rest (standing or sitting)
Other sx	Numbness/paresthesias	Pale, cool extremity
Exam	± Focal weakness, ↓ reflexes ↓ Lumbar extension Preserved pulses	Diminished/absent pulses (dorsalis pedis/posterior tibialis) Pallor
Diagnostic studies	MRI lumbar spine CT myelogram (if no MRI) EMG/NCS	Arterial Doppler studies Ankle-brachial index (ABI) Arteriography
Treatment	PT (flexion exercise), NSAIDs, epidural steroid injections (ESI) Surgery (if other Rx fails)	Modify vascular risk factors, exercise rehab, antiplatelet Rx, revascularization

Nb, diagnosis complicated by overlap between presentations & possibility of both diagnoses in the same patient.

Evaluation & treatment of nerve root compression (NEJM 2016;374:1763)

• MRI if sx not improved after 6 wk of conservative tx; if nondiagnostic, consider EMG/NCS

• Conservative: avoid bending/lifting; soft collar (cervical radiculopathy); NSAIDs; muscle relaxants; lidocaine patch/ointment; Rx neuropathic pain (see “Peripheral Neuropathies”); physical/occup therapy. Insufficient evidence for oral steroids.

• Avoid opiates when possible; risks outweigh benefits in noncancerous back pain

• Spinal epidural steroid injections (ESI): limited short-term relief of refractory radicular pain

• Surgery: cord compression or cauda equina syndrome; progressive motor dysfunction/EMG/NCS pathologic findings; bowel/bladder dysfunction; intractable pain w/ failure to respond to conservative Rx after 3 mo