Abstract
Objective
Brain dysfunction at high altitudes can be caused by both high altitude cerebral edema (HACE) and hyponatremic encephalopathy. Differentiating them is important for proper treatment but can be difficult. We present a case series of 11 patients with hyponatremic encephalopathy, all initially misdiagnosed as HACE, and we discuss key signs and symptoms that will help clinicians differentiate the 2 pathologies.
Methods
We compiled 11 cases of patients with severe hyponatremia who were diagnosed with HACE, verified through direct patient care or referral consultation.
Results
Patients included 5 males and 6 females aged 19 to 65 y, exercising between 2100 and 4300 m. Serum Na+ concentration ranged from 112 to 127 mmol·L–1. Features included ataxia, confusion, and progression to coma without the hallmark imaging features of HACE. Clinically, the rapid progression of symptoms, moderate altitude, short duration of altitude exposure, and seizure activity suggested hyponatremia rather than HACE. All but 1 patient shared classic risk factors for exercise-associated hyponatremia: moderate to extreme exercise, rapid high volume (>5 L) fluid intake, clamminess, pallor, and nausea. Five patients suffered seizures, 4 used nonsteroidal anti-inflammatory medications, 4 had pulmonary edema, and 3 showed features of the syndrome of antidiuretic hormone secretion.
Conclusions
Severe hyponatremia should be considered in persons with encephalopathy at high altitudes. Although there is no established causal link between hypobaric hypoxia and hyponatremia, the potential for high altitude exposure to exacerbate exercise-associated hyponatremia warrants further investigation because the consequences of developing or misdiagnosing this process may be severe.
Keywords
Introduction
Patients with encephalopathy (ie, impairments in cognition and consciousness) at high altitudes present a diagnostic challenge. In the austere setting, clinicians may be quick to identify high altitude cerebral edema (HACE) as the “not to be missed” life-threatening diagnosis. However, hyponatremia may present with a similar array of neurologic symptoms and signs, including headache, nausea, confusion, ataxia, loss of consciousness, and seizure. 1 As the following case histories demonstrate, hyponatremia may be easily confused with acute mountain sickness (AMS) or HACE. 2 Distinguishing between these diagnoses is critical to guide management. Further, we consider the broader implication of whether there exists an underappreciated pathophysiologic relationship between hyponatremia and HACE.
Methods
We retrospectively analyzed 11 patients presenting with encephalopathy at altitudes ranging from 2100 to 4300 m. The patients presented were either directly managed by 1 of the authors (PH) or referred to other authors (DF or THB) for consultation over 10 y. Clinical presentations and available imaging were compared with established diagnostic criteria for HACE. Laboratory findings, particularly serum sodium concentrations ([Na+]), were reviewed to identify cases of hyponatremia (biochemically defined as a serum [Na+]<135 mmol·L–1). 1 Autopsy results were considered in the 1 fatality.
Results
Here we present 11 patients who experienced severe hyponatremia in the context of exercise at high altitude (Table 1).
Case details.
HACE, high altitude cerebral edema; HN, hyponatremia; HAPE, high altitude pulmonary edema; PO, orally; IV, intravenously; CT, computed tomography; MRI, magnetic resonance imaging; SIADH, syndrome of inappropriate antidiuretic hormone; CPM, central pontine myelinolysis
Case 1
A 19-y-old female living at 2100 m began a survival training course, reaching 2900 m. On Day 2, she drank 3 L of water with little food. By Day 3, after starting her menses and skipping breakfast, she experienced chills, nausea, and vomiting. Diagnosed with dehydration by her group's medic, she consumed 3 L of water in 75 min, temporarily improving symptoms. Later, during a 10-km trek, she developed dizziness and nausea without headaches or trouble breathing and continued drinking water. One hour after the trek, she vomited, became less alert, lost consciousness, and developed transient seizures. In the ambulance, she received 3.5 L of intravenous (IV) lactated Ringer’s solution and suffered a cardiac arrest, leading to death after 2 h. The clinical diagnosis was HACE. Autopsy revealed diffuse cerebral edema, hemorrhagic pulmonary edema, and a weight increase from 47.6 kg before the trip to 54.7 kg. Vitreous sodium was 127 mmol·L–1, toxicology was negative, and serum sodium concentration was not obtained.
Case 2
A previously healthy 28-y-old female who resided at sea level became confused and disoriented on Mt Whitney at 3670 m. She was evacuated and transported to a local hospital, where her serum sodium concentration was 118 mmol·L–1. Computed tomography (CT) scan of the head, remaining metabolic panel, and toxicology screen were normal. The diagnoses were HACE and hyponatremia, and the patient received dexamethasone, midazolam and lorazepam, furosemide, and hypertonic saline. After transfer to a higher-tiered hospital, a second CT scan and magnetic resonance imaging (MRI) of her head were normal, the serum sodium concentration normalized to 137 mmol·L–1, and her mental status normalized. Further history revealed that she consumed ∼6 L of water in the first 24 h of her climb and took 400 mg of ibuprofen with little food. She was discharged without neurologic sequelae.
Case 3
A 42-y-old male residing at 2135 m, an experienced altitude runner, completed an 80-km race at altitudes of 2500 to 2850 m. He finished in 9 h, drinking 720 mL of a 25% electrolyte and 75% water solution every 6 to 8 km, an unknown amount of the same solution at aid stations, and water after the race. Shortly after, he noted progressive nausea and chills. Suspecting dehydration, he continued drinking water without eating. His mental status deteriorated rapidly, leading to unconsciousness. At the hospital, a chest x-ray showed diffuse edema; diagnoses were high altitude pulmonary edema (HAPE) and HACE. Serum sodium concentration was 122 mmol·L–1, and he received 40 mg IV furosemide. His mental status improved over 48 h, and he was discharged neurologically intact. He later estimated that his race day fluid intake was 11.5 L.
Case 4
A 58-y-old previously healthy female living near sea level was running a high altitude marathon. While descending from 4300 m, she became confused, developed chills, and vomited. She had been drinking water but not eating during the race. Her medications included beta-blockers for glaucoma and estrogen replacement. Disoriented and hypoxemic, she seized in the emergency department (ED) and was chemically sedated and intubated. Chest x-ray identified bilateral infiltrates. Serum sodium concentration declined from 121 to 118 mmol·L–1 after she received 1 L of IV normal saline. Serum osmolality was 250 mOsm·L–1, with urine specific gravity >1.030 and spot urine sodium of 62 mmol·L–1, suggesting the syndrome of inappropriate antidiuretic hormone (SIADH). Other laboratory tests and imaging of the head and brain were normal. Diagnosed with HAPE and HACE, her mental status improved over 24 h, and she was extubated and discharged neurologically intact after 5 d.
Case 5
A 42-y-old male fell into a crevasse at 2750 m while descending Mt Denali. He had acclimatized well to the altitude and experienced no symptoms of AMS, HAPE, or HACE before the accident. With no significant trauma but a difficult extraction and risk of hypothermia, his companion lowered him hot sugar water until his rescue. The victim consumed about 6 L of water with some sugar but no electrolytes or food. On rescue, the patient was confused, which rescuers attributed to hypothermia or altitude sickness. On arrival in the ED, the patient was somnolent despite his normal body temperature and lack of frostbite. Serum sodium concentration was 124 mmol·L–1, whereas all other laboratory studies, chest x-ray, and head CT scan were normal. His mental status improved with slow correction of his hyponatremia.
Case 6
A 32-y-old previously healthy male was evacuated from 2600 m on Mt Adams in Washington. He had previously attempted Mt Rainier but stopped due to severe headache and lethargy, suggestive of AMS. To prevent these symptoms, he aggressively hydrated, drinking 7 L of water on the way to camp. That evening, he felt weak and nauseated, developed a headache, and became combative. Six hours later he was unarousable, required evacuation by helicopter, seized en route, and was intubated in the ED. Head CT scan was normal, serum sodium concentration was 122 mmol·L–1, and creatine phosphokinase level was 1073 units. Toxicology showed opiates and benzodiazepines (the patient later recalled taking codeine for a headache and a “sleeping pill”). Electrocardiogram and chest x-ray were normal. Suspecting HACE, providers administered IV dexamethasone. The patient’s serum sodium concentration corrected to 135 mmol·L–1 over 24 h, and his mental status improved to allow discharge. Follow-up neurologic and pulmonary evaluations were normal.
Case 7
A 21-y-old male with a history of mild asthma and viral encephalitis as a child ran a 10-km race over 3 h at 2850 m. He had acclimatized 3 wk prior at ∼2800 to 3600 m. Immediately after the run, he ingested 6 L of water without food. Soon after, he developed chills, nausea, vomiting and seized. The patient was evacuated by helicopter to a hospital at 2000 m, where his mental status fluctuated between lethargy and combativeness. Serum sodium concentration was 116 mmol·L–1, Creatine phosphokinase was elevated at 905 IU/L, and serum chloride concentration was 90 mmol·L–1, with negative urine toxicology and a total CO2 of 19 mmol·L–1. Urine sodium concentration was 9 mmol·L–1. Chest x-ray was normal, whereas head CT scan identified cerebral edema. The patient was diagnosed with HACE and hyponatremia and received IV dexamethasone. His fluids were restricted. Serum sodium concentration corrected over 12 h to 133 mmol·L–1, but he remained mildly lethargic and confused during his 3-d hospital stay.
Case 8
A previously healthy 27-y-old male traveled from sea level to Colorado, spending the first night at 2000 m. The next day, he attempted to climb a 3950-m peak without eating but drinking 5 to 7 L of water. He demonstrated ataxia and confusion at 3350 m 24 h after arriving at altitude. The mountain guide administered 500 mg acetazolamide and 400 mg ibuprofen and evacuated the somewhat combative patient to a hospital at 2000 m. In the ED, the patient was ambulatory and oriented to date and place but not to the day's events, with slow perseverative speech and difficulty following commands. Neurologic exam identified ataxia, dysmetria, and mild papilledema. His lungs were clear. Head CT scan and chest x-ray were reported as normal. Serum sodium concentration was 126 mmol·L–1. After admission to the ICU, the patient became more combative and required a propofol drip along with IV dexamethasone, acetazolamide, and furosemide. Eight hours later his sodium concentration improved to 132 mmol·L–1. He was transferred to a lower elevation hospital (340 m), where his serum sodium concentration normalized, and he rapidly returned to neurologic baseline.
Case 9
A healthy 37-y-old female traveled to Aspen, CO, for a hiking trip. On Day 2 or 3 of hiking around 3360 m, she developed weakness, nausea, and vomiting, followed by altered mental status. She became progressively obtunded and seized, falling from standing height. She required intubation in the field and evacuation. There was no reported history of significant water intake. On arrival at the ED, she was unresponsive with a Glascow Coma Scale score of 6. The patient's sister reported that the patient had migraines just prior to the trip. Chest x-ray revealed left-sided atelectasis vs consolidation. Serum sodium concentration was 113 mmol·L–1, with a normal head CT scan. Initial urine output was 5100 mL, with elevated urine sodium and osmolality. After admission to the ICU, a brain MRI revealed several nonspecific foci of T2 hyperintensities in bilateral cerebral white matter. Electroencephalogram indicated toxic/metabolic encephalopathy. After starting a normal saline IV infusion at 100 mL·h–1, her sodium concentration increased to 126 mmol·L–1 but later dropped to 119 mmol·L–1 after starting desmopressin. Her urine output and osmolality raised concern for SIADH, but her urine volume and concentration quickly corrected without specific treatment. She recovered well in the ICU; over 36 h, her sodium concentration corrected to 133 mmol·L–1. She was discharged 5 d after admission. Two and a half years after this event, the patient reported ongoing daily migraines, insomnia, and symptoms of an “overactive sympathetic system,” although she had no focal neurologic sequela.
Case 10
A 65-y-old female with hypertension on lisinopril developed confusion 24 h after arriving in Cusco, Peru (3400 m). She preacclimatized by spending 4 d at 2400 m and taking 125 mg of acetazolamide twice daily. The night before symptom onset, she ingested ∼500 mL of water. The next morning, she ingested ∼500 mL of fluids (tea, coffee, and electrolyte-infused water). That day, participating in a 2-h walking tour, she developed a headache, took 400 mg of ibuprofen, and refused lunch and dinner. That evening, she became confused and was evaluated by a physician in her hotel who administered 25 mg sublingual captopril for high blood pressure (160/90 mm Hg). Her mentation deteriorated overnight, requiring descent and hospitalization the next morning. She arrived in the ED with a Glascow Coma Scale score of 9 and was uncooperative. Before losing consciousness, a head CT scan was negative for cerebral edema. An initial arterial blood gas report revealed a sodium concentration of 112 mmol·L–1, an oxygen saturation of 96%, and creatinine concentration of 1.08 mg·dL–1. Treated with 5 L of normal saline IV plus ten 20-mL ampules of 20% sodium chloride, she regained consciousness 28 h later when her sodium concentration reached 130 mmol·L–1. She was discharged 48 h later without cognitive impairment.
Case 11
A 41-y-old female with a history of hypothyroidism on levothyroxine sodium developed headache, vomiting, malaise, and diarrhea while ascending from Lima (sea level) to Machu Picchu (2430 m). A local physician administered metoclopramide, acetazolamide, ciprofloxacin, and IV normal saline for a presumed diagnosis of gastroenteritis exacerbated by high altitude illness, which initially provided the patient with relief. After consuming an estimated 9 L of free water overnight, her headache and nausea worsened. The next morning, she became increasingly confused and demonstrated seizure-like activity before becoming unresponsive and cyanotic. Bystander cardiopulmonary resuscitation was administered before rapid transport to the local clinic, where the patient was intubated and treated with IV dexamethasone for presumed HACE. Chest x-ray showed infiltrates, and brain CT scan revealed generalized edema and effacement of both ventricles and gyri. Her serum sodium concentration was 103 mmol·L–1, prompting administration of hypertonic saline and transfer to Lima. Her sodium concentration corrected to 133 mmol·L–1 over 3 d, and she was extubated as her mental status improved. Her mental status continued to improve over 2 wks before she was evacuated to the United States. Follow-up MRI and neurologic evaluations were normal without any evidence of central pontine myelinolysis or HACE despite an initial diagnosis of central pontine myelinolysis.
Discussion
This case series highlights an emergent need for practitioners to consider hyponatremic encephalopathy in the differential diagnosis of encephalopathy presenting at high altitudes. Despite speculation that hyponatremia can masquerade as HACE, only 2 previous cases have been suggested.2,3 The pathophysiologic processes that cause encephalopathy due to HACE (hypobaric hypoxia) and hyponatremia (hypoosmolality) differ with potentially catastrophic consequences when misdiagnosed (see Case 1).
Despite having similar symptoms and findings, both HACE and severe hyponatremia demonstrate key differences in clinical history, signs, and symptoms (Table 2). Hyponatremic encephalopathy is more abrupt, rapidly progressive, and more often associated with concurrent clamminess, chills, pallor, nausea, vomiting, and seizures. HACE nearly always progresses from AMS over days rather than hours or can be a complication of HAPE, which itself typically takes 1 to 2 d to develop. 4 HACE most often presents as ataxia, drowsiness, and confusion, with clinical decline progressing over 12 to 24 h if remaining at the altitude of onset. Seizures are not commonly reported in HACE. Importantly, most of our patients did not experience sufficient high altitude exposure to develop HACE or HAPE. Furthermore, each case describes a rapid progression of illness from symptom onset to encephalopathy over hours rather than days, and many of our patients resided above 2000 m at baseline, and some were in the process of descent as their symptoms developed and progressed.1,5,6
Clinical features of hyponatremic encephalopathy vs high altitude cerebral edema.
NSAIDs, nonsteroidal anti-inflammatory drugs
Obtaining an accurate history of the absolute altitude, rate of ascent, and duration at altitude is crucial in differentiating HACE from hyponatremia. Although hyponatremia can develop at any altitude, HACE is extremely rare below a sleeping altitude of 4000 m unless associated with HAPE. For example, it has never been verified in Colorado except as a complication of HAPE. In a recent series of 8 patients with severe HACE admitted to a hospital in Colorado, all had HAPE, and there were no cases of HACE without HAPE at the modest altitudes of Colorado resorts. 7 Furthermore, altitude illness is unlikely to develop during descent from high altitude and nearly always improves immediately with descent. In contrast, half these patients worsened or did not respond to descent (see Cases 2, 4, 5, 8, 9, and 11). Finally, the lack of response to the standard treatment of HACE with steroids, oxygen, and descent should suggest alternative diagnoses such as hyponatremia.
As noted earlier, HAPE often precedes HACE, whereas the neurogenic pulmonary edema of hyponatremia is thought to be secondary to cerebral edema. 8 Noncardiogenic pulmonary edema was documented in 4 of our 11 patients (36%). Another case series reported a runner at sea level, as well as 2 patients from previous reports, who developed severe hyponatremia, cerebral edema, and pulmonary edema following exposure to similar circumstances as Cases 3, 4, 7, and 11 in our series. Hemodynamic measurements confirmed noncardiogenic pulmonary edema, presumably on a neurogenic basis from the cerebral edema. 9
Additionally, HAPE typically develops over 48 to 72 h and generally presents with weakness and cough. The pulmonary edema of hyponatremia is more abrupt, developing over a few hours. Although the large fluid resuscitation may have contributed to the pulmonary edema in Case 1, it is unlikely that the edema can be explained solely based on volume overload. None of the 4 patients with pulmonary edema in our series experienced sufficient altitude exposure to develop HAPE.
HACE and hyponatremic encephalopathy may demonstrate similar patterns of cerebral edema with attenuation of sulci and smaller ventricles on CT scan. However, MRI may differentiate the 2 processes. MRI in HACE reveals a characteristic white matter T2 hyperintensity, most prominently in the corpus callosum, associated with increased fluid-attenuated inversion recovery and microbleeds. Restricted diffusion is often noted in the splenium.7,10 None of the MRIs reported in our series of hyponatremia patients identified findings characteristic of HACE. Additionally, on pathologic exam, HACE usually exhibits petechial hemorrhages, especially in the white matter, whereas hyponatremia does not. No such hemorrhages were found in the autopsy report for Case 1. The cause of death in both acute hyponatremia and HACE is herniation of the brain, as documented in Case 1 by symmetric uncal grooving on autopsy.
Factors favoring a variant of exercise-associated hyponatremia were clearly present in our cases.11,12 Exertion was a component of every case, with 3 patients having finished strenuous endurance activities immediately prior to the onset of their symptoms. All but 1 patient had reported excessive fluid intake during their event or the day of hiking or climbing. Six patients reported drinking only water, and half reported little to no food intake. Half the patients specifically reported chills and had seizures, uncommon in HACE. In addition to the factors described earlier, environmental conditions such as high heat, high relative humidity, and intense sun exposure can further contribute to hypovolemia and electrolyte losses. These climate factors can exacerbate fluid and sodium imbalances through increased sweat production and insensible water losses, potentially compounding the risks of both hypovolemic and dilutional hyponatremia. Unfortunately, detailed climate data were not consistently available for most of the cases in this review. This lack of data limits our ability to fully analyze the influence of environmental conditions on the observed outcomes and underscores the need for future studies to incorporate precise climate and weather measurements.
A potential causal relationship between high altitude and hyponatremia, associated with SIADH secretion, remains unclear.13–15 Cases 1, 4, 7, and 9 through 11 suggest that hyponatremia was associated with nonosmotic arginine vasopressin secretion, likely due to a variety of stimuli, including hypovolemia, interleukin-6 secretion, pain, and/or nausea that can occur at altitude. 1 Persistent secretion of arginine vasopressin facilitates fluid retention, which explains why even modest fluid intakes (as in Case 10) may cause profound hyponatremia. Forced fluid intake beyond thirst should be avoided at altitude and at sea level to avoid the fatal consequences of hyponatremia.8,15,16 Of note, mathematical modeling, 17 field trials, 18 and studies on patients with SIADH 19 collectively suggest that modest sodium supplementation offers limited protection against the development of dilutional hyponatremia when excess fluids (ie, beyond the capacity of free water excretion) are ingested and/or administered. In the less common hypovolemic (depletional) variant of hyponatremia, sodium supplementation may be helpful, 20 although most of these cases appear to be dilutional.
A bidirectional relationship between hyponatremia and altitude illness also could exist, but we were unable to find reports suggesting this in the literature. Elevated antidiuretic hormone levels resulting from AMS could predispose to hyponatremia, but this has not been reported. Low serum sodium concentration has never been reported as a feature of altitude exposure or altitude illness. Work by Vexler et al21 showed the aggravating effects of hypoxia on hyponatremia-induced cerebral injury. Their team studied cats who were made hyponatremic and developed brain edema. When the animals were further subjected to hypoxia, a major increase in cerebral edema and mortality resulted. The authors suspected that hypoxia interfered with the brain's normal compensatory mechanism of managing hyponatremia: adjusting sodium transport to reduce cellular swelling. 21
Although there is no established causal link between hypobaric hypoxia and hyponatremia, the potential for high altitude exposure to exacerbate exercise-associated hyponatremia warrants further investigation because the consequences of developing or misdiagnosing this process may be severe.
Conculsions
Our series demonstrates the importance of considering hyponatremia in individuals presenting with encephalopathy at high altitude. Obtaining a careful clinical history is key to making the appropriate diagnosis and administering the correct treatment. In our cases, the total altitude exposure (the combination of altitude gained, final altitude, and duration at altitude) was insufficient to cause severe altitude illness, and all patients had typical factors associated with hyponatremia. Our findings suggest a need for immediate consideration of this diagnosis, with emergent serum sodium testing when available and potential intervention when confirmation testing is not available. Once hyponatremia is diagnosed or strongly suspected, intravenous administration of hypotonic or isotonic fluids should be avoided in favor of prompt administration of hypertonic saline.1,2,8 Recent evidence suggesting that slower rates of serum sodium correction are associated with increased mortality highlights the importance of early recognition and prompt correction of hyponatremia. 22
Future research should investigate the potential interplay between hypoxia and sodium homeostasis and the role of gender in susceptibility to hyponatremia. Our analysis calls for integrating hyponatremia into existing high altitude medical protocols to enhance patient safety and outcomes. Because treatment with hypertonic saline is appropriate for both high altitude cerebral edema and hyponatremic encephalopathy, its use should be considered in the management of encephalopathy at high altitude.
Footnotes
Acknowledgments
The authors acknowledge the people who referred cases for this analysis: Kimberly Johnson, the US Air Force Academy, William Hilty, Christopher Davis, and Sheryl Olson.
Author Contribution(s)
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
