HACE is a life-threatening encephalopathy representing the end-stage of acute mountain sickness (AMS), characterized by ataxia and altered mental status in an unacclimatized individual ascending to high altitude. It is rare below 3,500–4,300 m (~11,500–14,000 ft) and carries a prevalence of approximately 0.5–1.0% at 4,000–5,000 m. [1-2] Without treatment, coma can ensue within 12–24 hours of ataxia onset, followed by death from brain herniation. [1-2]
The following figure illustrates the proposed pathophysiological cascade from high-altitude hypoxemia to cerebral edema:
1. History
- Ascent profile: Altitude reached, rate of ascent, sleeping altitude, number of rest days — rapid ascent is the primary risk factor [4]
- Preceding AMS symptoms: Headache, nausea, vomiting, fatigue, dizziness — HACE is usually preceded by AMS, though not always [2][5]
- Timing: Onset typically within the first 2–5 days after ascent above 4,000 m; can occur earlier with concurrent HAPE [1-2]
- Symptom progression: Worsening headache poorly responsive to NSAIDs, persistent vomiting, increasing drowsiness, confusion, unsteady gait [2]
- Functional decline: Inability to perform self-care, apathy, irritability, lassitude [5]
- Important negatives: Ask about cough/dyspnea (concurrent HAPE), seizures, focal weakness (suggests alternative diagnosis), medication/substance use, carbon monoxide exposure, oral intake (hypoglycemia risk) [1][6]
2. Alarm Features
- Truncal ataxia — often the earliest neurologic sign of HACE [2][5]
- Altered mental status: Confusion, disorientation, drowsiness resembling alcohol intoxication [1]
- NSAID-refractory headache with vomiting — signals progression from AMS to HACE [2]
- Rapid deterioration to coma within 12–24 hours without intervention [1-2]
- Concurrent HAPE signs: Dyspnea at rest, cyanosis, pink frothy sputum — HACE frequently co-occurs with severe HAPE [1][4]
- Focal neurologic deficits or seizures are rare in HACE and should prompt consideration of intracranial lesion, seizure disorder, or hyponatremia [1]
3. Medications
- Dexamethasone is the cornerstone pharmacologic treatment:
- HACE dose: 8 mg loading dose (PO/IV/IM), then 4 mg every 6 hours until symptoms resolve or descent achieved [1][5]
- Pediatric: 0.15 mg/kg/dose every 6 hours (max 4 mg) [7]
- Acetazolamide (250 mg q12h) may be used as adjunct but does not treat HACE directly and does not replace dexamethasone [5][7]
- Medications to avoid: Opioids (respiratory depression at altitude), sedatives/hypnotics (may mask neurologic deterioration)
- Prophylaxis (for future ascents): Acetazolamide 125 mg q12h or dexamethasone 2 mg q6h for moderate-to-high-risk profiles [4][7]
- Dexamethasone does not facilitate acclimatization — further ascent should not be attempted while on dexamethasone [5]
4. Diet
- Hydration: Maintain adequate hydration; dehydration mimics AMS symptoms. Forced overhydration is not beneficial and increases hyponatremia risk [7]
- Avoid alcohol: Exacerbates dehydration, impairs judgment, and may mask neurologic signs
- Adequate caloric intake: Anorexia is common with AMS/HACE; encourage small, frequent, carbohydrate-rich meals
- No specific dietary triggers are established for HACE
5. Review of Systems
- Neurologic: Headache quality/severity, gait instability, confusion, vision changes, seizures
- Pulmonary: Cough (dry → productive), dyspnea at rest, exercise intolerance — screen for concurrent HAPE [4]
- GI: Nausea, vomiting, anorexia
- Constitutional: Fatigue, lassitude, sleep disturbance
- Psychiatric: Apathy, irritability, behavioral changes (may be subtle early signs) [5]
6. Collateral History and Family History
- Collateral from climbing partners: Observed behavioral changes, gait abnormality, confusion, inability to self-care — patients with HACE may lack insight into their own deterioration
- Prior altitude illness: Personal history of AMS, HACE, or HAPE is a major risk factor for recurrence [4]
- Family history: No strong hereditary component for HACE specifically, though individual susceptibility to altitude illness varies and may have a genetic basis [8]
- Social context: Experience level, group dynamics (pressure to continue ascending), access to descent/evacuation
7. Risk Factors
- Rapid ascent rate — the primary modifiable risk factor; sleeping altitude increasing >500 m/night above 3,000 m [4]
- Prior history of altitude illness [4]
- Lack of acclimatization — lowlanders ascending directly to high altitude [5]
- Concurrent HAPE — HACE frequently develops secondary to severe hypoxemia from HAPE [1]
- High target altitude — rare below 3,500 m; prevalence increases above 4,000 m [2]
- Individual susceptibility — possibly related to cranial CSF-to-brain volume ratio ("tight fit" hypothesis) [9-10]
- Vigorous exertion at altitude before acclimatization
- Physical fitness does not protect against altitude illness [4]
8. Differential Diagnosis
Must-exclude diagnoses in the setting of altered mental status at altitude: [1][6]
- Carbon monoxide poisoning — from stoves/heaters in enclosed tents or shelters
- Hypothermia — overlapping altered mentation, ataxia
- Hypoglycemia — from exertion and poor intake
- Hyponatremia — from forced overhydration; can cause seizures and encephalopathy
- Drug/alcohol intoxication — HACE presentation mimics alcohol intoxication
- Stroke/intracranial hemorrhage — focal deficits favor this over HACE
- Seizure disorder — seizures are rare in HACE
- Dehydration/exhaustion — may mimic AMS but lacks neurologic signs
- Meningitis/encephalitis — fever, neck stiffness, though mild fever can occur in HACE [2]
Key distinguishing feature: HACE produces global encephalopathy (ataxia + altered mentation) without focal neurologic deficits. Focal findings should prompt urgent evaluation for alternative diagnoses. [1][4]
9. Past Medical History
- Prior episodes of AMS, HACE, or HAPE — strongest predictor of recurrence
- Neurologic conditions: Migraine, seizure disorder, prior stroke — may confound diagnosis
- Cardiopulmonary disease: May predispose to more severe hypoxemia at altitude
- Medications: Acetazolamide allergy (anaphylaxis or Stevens-Johnson from sulfonamides is a contraindication) [7]
10. Physical Exam
- Vital signs: Tachycardia, low SpO₂ (expected at altitude but markedly low with HACE/HAPE), mild fever is common; assess for hypothermia [2]
- Neurologic exam:
- Heel-to-toe (tandem) gait — the most useful bedside test; truncal ataxia is often the earliest sign [5]
- Mental status: GCS, orientation, ability to follow commands
- Fundoscopy: Papilledema may confirm cerebral edema; retinal hemorrhages are common at extreme altitude [5]
- Focal deficits: Should be absent — if present, consider stroke or intracranial lesion [1]
- Pulmonary: Crackles (concurrent HAPE), cyanosis
- General: Assess for signs of dehydration, hypothermia, frostbite
11. Lab Studies
HACE is a clinical diagnosis — there are no characteristic laboratory findings. [5] Labs are primarily used to exclude mimics:
- Point-of-care glucose — rule out hypoglycemia
- Basic metabolic panel — assess sodium (hyponatremia), renal function, dehydration
- ABG/VBG — if available; assess for severe hypoxemia, acid-base status
- CBC — polycythemia expected at altitude; leukocytosis may suggest infection
- Carboxyhemoglobin — if CO poisoning suspected
- Lactate — if concern for sepsis or severe tissue hypoxia
12. Imaging
- Not required for diagnosis in the field — HACE is a clinical diagnosis based on context and exam [5]
- MRI (gold standard) when available post-evacuation:
- T2/FLAIR hyperintensity in white matter, especially the splenium of the corpus callosum and centrum semiovale [2][11]
- Microhemorrhages on SWI (best seen at 3T), extending beyond areas of edema, persisting long-term as hemosiderin deposits — the "HACE footprint" [12]
- Changes are reversible with treatment [11]
- No gray matter abnormalities typically seen [11]
- CT head: May show diffuse cerebral edema, small ventricles, effaced sulci; less sensitive than MRI [13]
- Imaging is most useful to exclude alternative diagnoses (hemorrhage, mass lesion) when focal deficits or seizures are present
13. Special Tests
- Lake Louise AMS Score: Useful for grading AMS severity (scores 3–5 mild, 6–12 moderate-severe); not directly applicable to HACE but informs the clinical spectrum [5]
- Tandem gait test (heel-to-toe walking): Simple, reproducible field test for ataxia — the most practical bedside assessment [5]
- Pulse oximetry: SpO₂ expected to be low at altitude; markedly low values suggest concurrent HAPE or severe illness. Target SpO₂ >90% with supplemental O₂ [6]
- Optic nerve sheath diameter (ONSD) by POCUS: May change with altitude gain but is not reliable for diagnosing AMS or HACE [5]
- Portable hyperbaric chamber (Gamow bag): Simulates descent of ~1,500–2,500 m; therapeutic rather than diagnostic, but clinical response supports the diagnosis
14. ECG
- No specific ECG findings for HACE
- ECG may show sinus tachycardia, right heart strain patterns (P-pulmonale, right axis deviation) if concurrent HAPE is present
- Obtain ECG if available to rule out cardiac causes of syncope or altered mentation
- Arrhythmias at altitude are uncommon but may occur with severe hypoxemia or hypothermia
15. Assessment
HACE represents a neurologic emergency — the end-stage of the AMS-HACE continuum. [1][8] Key assessment points:
- Severity stratification: Any ataxia or altered mental status in the context of recent altitude gain = HACE until proven otherwise [5]
- Typical presentation: Unacclimatized traveler, 2–5 days after ascent above 4,000 m, with progressive headache → confusion → ataxia → coma [2]
- Atypical presentations: HACE without preceding AMS symptoms; HACE at lower altitudes when concurrent HAPE causes severe hypoxemia [1-2]
- Complications: Brain herniation and death (without treatment), long-term cognitive impairment, persistent microhemorrhages on MRI [12][14]
- Concurrent HAPE is common and worsens prognosis — always assess for pulmonary edema [1]
16. Treatment Plan
Initial stabilization (field or ED)
- Immediate descent is the most important intervention — descend at least 300–1,000 m (1,000–3,300 ft) [2][7]
- Supplemental oxygen: Target SpO₂ >90% (2–4 L/min by nasal cannula) [2][6]
- Dexamethasone: 8 mg loading dose (PO/IV/IM), then 4 mg every 6 hours [1][5]
- Portable hyperbaric chamber (Gamow bag): If descent is not feasible, pressurize for 2–4 hours; simulates descent [1][6]
- Acetazolamide 250 mg q12h: May be added as adjunct to facilitate acclimatization [7]
If in a resourced medical facility
- Supplemental oxygen and dexamethasone; descent may not be necessary if adequate monitoring and O₂ are available [6]
- Airway management if GCS deteriorating
- Treat concurrent HAPE with oxygen ± nifedipine 30 mg SR q12h [2]
- No role for diuretics, mannitol, or hypertonic saline in HACE management [2]
Pediatric dosing: Dexamethasone 0.15 mg/kg/dose q6h (max 4 mg); acetazolamide 2.5 mg/kg q12h (max 250 mg) [1][7]
17. Disposition
- All patients with HACE require evacuation to lower altitude and medical observation [5-6]
- Admission criteria: Altered mental status, persistent ataxia, concurrent HAPE, inability to descend, coma
- ICU-level care: For patients with GCS ≤8, respiratory failure from concurrent HAPE, or hemodynamic instability
- Observation: Patients who improve rapidly with descent and dexamethasone may be observed at a lower-altitude facility
- Discharge criteria: Full resolution of neurologic symptoms, stable mental status, ability to self-care, at a safe altitude
- Specialist consultation: Neurology if focal deficits, seizures, or failure to improve; pulmonology/critical care if concurrent severe HAPE
- Do not allow reascent until fully asymptomatic off dexamethasone [5-6]
18. Follow Up / Return Precautions
- Follow-up timing: Neurology follow-up within 1–2 weeks post-recovery; consider MRI to document resolution of edema and assess for residual microhemorrhages [12][14]
- Cognitive assessment: Some patients experience persistent cognitive impairment; neuropsychological testing may be warranted [14]
- Return precautions (counsel patient):
- Return immediately if headache worsens, confusion recurs, gait becomes unsteady, or new neurologic symptoms develop
- Do not reascend until fully recovered and off all medications
- Future ascents require slow ascent profile, pharmacologic prophylaxis (acetazolamide), and awareness of personal susceptibility [4]
- Expected recovery: Most patients recover fully with prompt treatment; MRI white matter changes typically resolve, though microhemorrhages may persist as hemosiderin deposits [11-12]
- Prognosis: Excellent if recognized and treated early; fatal if untreated [1-2]
References
1. High-Altitude Travel and Altitude Illness. — Peter H. Hackett and David R. Shlim CDC Yellow Book. 2025.
2. Acute High-Altitude Illnesses. — Bärtsch P, Swenson ER. The New England Journal of Medicine. 2013.
3. High-Altitude Illness. — Hackett PH, Roach RC. The New England Journal of Medicine. 2001.
4. Medical Conditions and High-Altitude Travel. — Luks AM, Hackett PH. The New England Journal of Medicine. 2022.
5. Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update. — Luks AM, Beidleman BA, Freer L, et al. Wilderness & Environmental Medicine. 2024.
6. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2019 Update. — Luks AM, Auerbach PS, Freer L, et al. Wilderness & Environmental Medicine. 2019.
7. Acute Altitude Illness: Updated Prevention and Treatment Guidelines from the Wilderness Medical Society. — American Academy of Family Physicians (2020). 2020.
8. Altitude Illnesses. — Gatterer H, Villafuerte FC, Ulrich S, et al. Nature Reviews. Disease Primers. 2024.
9. High-Altitude Illness. — Basnyat B, Murdoch DR. Lancet. 2003.
10. Cerebral Spinal Fluid Dynamics: Effect of Hypoxia and Implications for High-Altitude Illness. — Lawley JS, Levine BD, Williams MA, et al. Journal of Applied Physiology. 2016.
11. High-Altitude Cerebral Edema Evaluated With Magnetic Resonance Imaging: Clinical Correlation and Pathophysiology. — Hackett PH, Yarnell PR, Hill R, et al. The Journal of the American Medical Association. 1998.
12. Acute and Evolving MRI of High-Altitude Cerebral Edema: Microbleeds, Edema, and Pathophysiology. — Hackett PH, Yarnell PR, Weiland DA, Reynard KB. AJNR. American Journal of Neuroradiology. 2019.
13. The Cerebral Effects of Ascent to High Altitudes. — Wilson MH, Newman S, Imray CH. The Lancet. Neurology. 2009.
14. Improved Neuroimaging Findings and Cognitive Function in a Case of High-Altitude Cerebral Edema. — Urushida Y, Kikuchi Y, Shimizu C, et al. Internal Medicine. 2021.