Abstract
Abstract
Maa, Edward H. How do you approach seizures in the high altitude traveler. High Alt. Med. Biol. 12:13–19, 2011.—Counseling patients who suffer first-time or break- through seizures can be difficult, particularly when controllable external factors may be contributing to the lowering of their seizure threshold. High altitude as a potential trigger for seizures is a common question in our epilepsy clinics in Colorado, and this article reviews the existing anecdotal literature, presents our local experience with high altitude seizures (HAS), offers possible mechanisms to explain how high altitude may trigger seizures, and suggests an initial work-up and prophylactic strategies for future high altitude exposures.
Introduction
A Case Presenting to the Altitude Research Center
Ms. R., a 50-year-old woman with no prior seizure history or family history of seizure was en route from Miami, Florida, to Santa Cruz, Bolivia, with a layover in La Paz (4100 m). Toward the end of the 90-min layover when the cabin was depressurized to allow passengers to disembark and luggage to be inspected, the woman suddenly felt nauseated and closed her eyes. Her next memory was a flight attendant asking if she was okay, because she had just had a seizure. The plane had taken off prior to the seizure, and witnesses reported noisy hyperventilation, clawing at the air, and urinary incontinence. Paramedics in Santa Cruz documented a blood pressure of 100/80, and she was released to the care of her physician friend with whom she was visiting. He agreed that she had probably had a seizure, with her history of altered awareness, uncontrolled limb movements, urinary incontinence, and postictal lethargy. She had previously traveled to Mexico City (2200 m), Bogota, Columbia (2500 m), and Quito, Ecuador (3000 m), without incident. She seeks recommendations for a work-up to characterize the event, determine her risk for further seizures in similar high altitude settings, and recommendations to prevent future seizures. How would you counsel this patient?
What We Know about Seizures at Altitude
Seizures are the final common pathway from a variety of inherited and/or acquired imbalances of neuronal excitation and inhibition, which suggests that each person has his or her own inherent seizure threshold. Seizures can be thought of as resulting from abnormal synchronized firing of a small population of neurons that recruit ever-increasing numbers of neighboring neurons as the synchronized population grows. A seizure terminates when a sufficient number of aberrantly firing neurons becomes refractory to further excitation, thereby desynchronizing and inhibiting further ictal activity. Seizures are seen in a number of medical and neurological disease states, as are toxic and metabolic disturbances. Given the broad array of known and yet-to-be-described physiological mechanisms for inducing seizures in humans, it seems plausible that high altitude might also provoke seizure in the susceptible patient. In fact, the medical literature provides some of these interesting cases (Table 1).
EEG, electroencephalogram; CT, computed tomography; HACE, high altitude cerebral edema; MRI, magnetic resonance imaging; CTH, computed tomography of head.
Seizures have been documented in the literature between the moderately high altitudes (2400 to 3600 m) through the extremely high altitudes (>5500 m), with roughly equal numbers of men to women and spanning the ages from 11 to 70. The cases of generalized convulsions reported in the literature do not appear to favor any specific epidemiological group. Intuitively, one might assume that seizures would be seen more frequently in high and extremely high altitude exposures. Given the large disparity of visitors, inversely proportional to the elevation visited, Table 1 appears to be in alignment with intuition. Despite having only “moderately high altitudes,” the 22.5 million people who visit the Colorado Rocky Mountains annually should translate into a substantial signal of provoked, high altitude seizures (Longwoods International, 2005). In fact, this question prompted a retrospective chart review of seizure cases treated in the Summit County Emergency Department, which receives all emergency medical transports from the ski resort towns of Breckenridge, Keystone, and Arapahoe Basin. Summit County's visitor bureau reports almost 2 million visitors annually, and from October 2001 to October 2005, 27 visitors whose home elevation was lower than 2000 m were evaluated in the emergency department and are summarized in Table 2.
N/R, not reported; Sz, seizure; GTC, generalized tonic clonic seizure; PMH, past medical history; EtOH: alcohol use, POx, pulse oximetry reading; CTH, computed tomography scan of the head; crani, craniotomy.
In this cohort of patients:
The average age was 38 ± 2.3 yr.
Seizures occurred more frequently in men by 2:1 (which likely reflects the demographic of an outdoor, high-country vacation population).
The average time to seizure from arrival was 2.5 days.
A prior history of seizure was seen in 44%.
First-time seizures were seen in 56%.
A family history of seizure was reported in only 1 patient.
All 27 cases were convulsive seizures, without partial onset, with more reports of tongue biting and urinary incontinence and clustering of convulsions when compared to seizures from local residents.
Seventeen of the 27 cases had computed tomography (CT) of the head, with only 3 “abnormal” scans: nonspecific atrophy, prior craniotomy, and a previously diagnosed brain mass.
No comorbid diagnoses of high altitude pulmonary or cerebral edema (HAPE/HACE).
As would be expected in a general visitor population:
Sleep disturbances and headaches were more frequently reported.
Postictal oximetry showed hypoxic readings (less than 90% saturation) twice as frequently when compared with seizures from local residents.
Possible Mechanisms of High Altitude Seizures
As suggested by the generalized tonic clonic seizures reported by Colorado visitors (rather than focal seizures that then secondarily generalize), metabolic derangements may act in a diffuse way to lower overall seizure threshold. Some specific pathophysiological mechanisms may be implicated: (1) high altitude cerebral edema, (2) sleep deprivation, (3) hyperventilation, and (4) direct effects of hypobaric hypoxia.
Neurological symptoms associated with high altitude are quite common. Acute mountain sickness (AMS), which includes headache, fatigue, sleeplessness, and anorexia, has been found to occur in as many as 25% of a population visiting moderate to high altitudes (Honigman et al., 1993). At the other extreme of the same continuum is high altitude cerebral edema (HACE), a metabolic encephalopathy characterized by headache, ataxia, and alteration of mental status ranging from hallucinations to coma, and if left untreated, death (Hacket and Roach, 2004). It is associated with radiographic and clinical evidence of vasogenic edema of midline white matter structures, including the splenium of the corpus callosum, the magnetic resonance imaging (MRI) hallmark of this condition; CT findings include attenuation of white matter signal with compression of sulci and flattening of gyri (Hackett and Roach, 2004). Although seizures are seen in HACE, their frequency is exceedingly rare, and the mechanism of edema and its contribution to epileptogenesis are unknown (Hackett and Roach, 2001). In the largest series of 44 patients with HACE, no cases of convulsions were reported (Dickinson, 1983). In their review, Hackett and Roach (2004) agree that “seizures appear to be rare,” and report four representative cases, none of which presented with seizure. A retrospective study looking at HACE in Colorado by Yarnell and colleagues (2000) revealed just 13 cases in 13 yr, and only 2 of the cases were associated with seizure. Our own retrospective review and clinical experience suggest that far more seizures are occurring than would be expected if HACE were the sole etiology of high altitude seizures (HAS).
As the body acclimatizes during ascent, the hypoxic ventilatory response attempts to compensate for hypoxia in the setting of hypobaria, which produces the phenomenon of periodic breathing. This physiological Cheyne–Stokes breathing pattern is responsible for the central sleep apnea observed in some healthy individuals during ascent to altitudes above 2400 m (Kale and Anholm, 2006). Periodic breathing can result in a high frequency of microarousals, and many travelers report sleep disturbances during their first few nights at altitude. Central sleep apnea may decrease total sleep time, increase sleep fragmentation, and cause intermittent hypoxemia. Obstructive sleep apnea can be exacerbated by lower environmental oxygen concentration and also leads to poor sleep quality. Sleep disturbances caused by either form of apnea can contribute to worsened seizure control or possibly increase the potential for epileptic phenomenon (Malow, 2004; Badawy et al., 2006).
The hyperventilatory portion of periodic breathing may itself be a seizure- provoking maneuver. Hyperventilation (HV) has long been used to elicit primary generalized absence seizures as well as to increase interictal epileptiform discharges during routine electroencephalograms (EEG). The data supporting this time-honored tradition have been controversial. In a large prospective study of HV in patients with known epilepsy, only 2 seizures were elicited in 433 patients exposed to a single HV period of 5 min (Holmes et al., 2004). Conversely, an epilepsy monitoring unit (EMU) study looking retrospectively at the HV response demonstrated at least one provoked seizure in a quarter of the patients studied (Guaranha et al., 2005). Because EMUs are utilized to evaluate focal epilepsy syndromes for ablative surgery, these findings suggest that HV may affect both primary generalized and focal epilepsies. The mechanism of HV-provoked seizures is unknown, but may be related to neuronal hyperexcitability caused by hypocapnia (Laffey and Kavanagh, 2002). Hyperventilation as a seizure-provoking maneuver may simply require the longer duration of several nighttimes of periodic breathing.
Hypoxia may exert an independent influence in seizure provocation. In a well- accepted mouse model of obstructive sleep apnea, relatively mild intermittent hypoxia (alternating 10% O2 with room air every 90 sec) has been shown to cause architectural disorganization in the cerebral cortex and the CA1 region of the hippocampus (a highly ictogenic region) and upregulation of stress-induced, metabolic, and apoptotic proteins in these same regions (Gozal et al., 2002). Tissue hypoxia has also been shown to increase neuronal excitability; specifically, K+ and Ca2+ channels show aberrant ion flux, which may promote seizure threshold lowering as a result of glutamate-mediated cellular damage (Neubauer and Sunderram, 2004).
Recommendations
The available evidence for high-altitude-provoked seizures is observational and anecdotal and, given the relative rarity currently reported, prospective trials will likely be difficult to accomplish. However, the potential consequences and immediate seriousness of an individual seizure and/or an unmasking of epilepsy warrant thoughtful consideration for the identification, treatment, eventual diagnosis, and counseling of prophylaxis.
Identification
Because generalized convulsions were the most frequent description of seizures at high altitude, witness accounts of the event can be very valuable. Of interest, note from Tables 1 and 2 that the only seizures involving unilateral clonic movements prior to secondary generalization were patients in which focal masses were eventually discovered. The primary differentials of large-amplitude, rhythmic body movements with alteration of awareness are syncopal convulsions and nonepileptic seizures (NES; previously referred to as psychogenic). Parkinsonian tremors and other neurogenic movement disorders typically retain awareness. Syncopal convulsions occur after falling to the ground, involve a few quick myoclonic jerks, and, assuming the patient was able to acquire a position in which the heart and brain were close to the same elevation, rapid recovery without prolonged postictal confusion is expected. Nonepileptic seizures are often difficult to confidently diagnose without the aid of an EMU; however, forced eye closure during the clonic phase of the seizure usually correlates with NES. A family history of epilepsy should increase suspicion; however, our observational data did not suggest this was strongly predictive.
In remote settings, including high altitude climbing expeditions, symptoms of HACE presenting on waking or seizures in sleep suggest that shared sleeping quarters may promote rapid identification of these potentially fatal neurological problems.
Treatment
As a potential neurological emergency, a generalized convulsion should be terminated before irreversible neuronal injury occurs. Most convulsive seizures will cease on their own after 2 to 3 min of clonic activity, and supportive management is all that is needed: loosen restrictive clothing, clear the area of hard objects, protect the head from striking hard objects, and do not insert objects in the mouth under any circumstances. Turn the patient into a supine or lateral recumbent position following the convulsion, and carefully inspect the mouth for foreign objects.
If the convulsion persists beyond 5 min, treatment for status epilepticus (a neurological emergency) should be entertained, because the likelihood of autocessation decreases. In locales where emergency medical services are available, they should be activated. The mainstay of emergency seizure management is the rapid administration of benzodiazepines, preferably lorazepam (2 to 4 mg by mouth or intravenously, up to 0.1 mg/kg if intubation services are available) for its fast onset and long anticonvulsant effect. Diazepam (5 to 10 mg by mouth, intramuscularly, or intravenously, up to 0.2 mg/kg if intubation services are available) has even faster onset, but an anticonvulsant effect that is only minutes long. Treatment with an antiepileptic agent follows the benzodiazepine to maintain a seizure-free state.
In remote settings, especially at high and extremely high altitudes involving climbing expeditions, seizure management offers a special challenge. Not only is access to appropriate medications limited, but the extremely sedating effects of these medications can impair individuals from assisting with their own descent, thereby jeopardizing the safety of fellow climbers. Since hypobaric hypoxia and periodic breathing may be contributing to a diffuse seizure-threshold-lowering mechanism, it is reasonable to initiate supplemental oxygen and acetazolamide (250 mg initially and then twice daily) after the seizure has terminated. In an epileptic patient off medications, it is reasonable to restart them immediately; in an epileptic patient already on medications, it is reasonable to add acetazolamide to the existing regimen until neurological follow-up is obtained. Our data suggest that clusters of convulsions are possible, so evacuation is strongly advised, because the risk for additional seizures will only increase the likelihood of accident and death. If evacuation is logistically delayed, supplemental oxygen should be administered for as long as feasible, with artificial descent with a portable hyperbaric bag if available.
Status epilepticus in remote locations should also be managed with benzodiazepines for seizure stoppage, followed by initiation of antiepileptic medications if available or acetazolamide if they are not. Evacuation in this setting will be challenging, because the patient will be unlikely to assist with descent and may even be combative while postictal or under the influence of benzodiazepines. Airlifting the patient to medical services would be appropriate if possible. Because subradiographic cerebral edema is another hypothesized mechanism for seizures at high altitude, dexamethasone (8 mg intramuscularly) could theoretically be attempted if no other anticonvulsant or antiepileptic agent is available for the treatment of an ongoing seizure.
Diagnosis
Once the seizure is stopped and the patient is transported to medical attention at a lower elevation, a diagnostic work-up should begin. This includes a comprehensive electrolyte panel, urine toxicology screen, urine pregnancy test, lumbar puncture (if meningitis, sepsis, or encephalitis is suspected), neuroimaging, and EEG. MRI is the preferred evaluation tool because of its ability to assess for multiple sclerosis, acute stroke, varying ages of blood products, cortical migration defects, meningioma, and mass lesions. However, CT is more readily available and gives good information about the presence of acute blood, large-mass lesions causing edema and/or shift, ventricular architecture, and general parenchymal morphology. EEG, being a functional rather than anatomical study, has poor negative predictive value, and nonlocalizing results are the norm. EEGs are typically repeated 2 to 3 times over the course of a few months to boost the yield of this test.
Many patients elect to return to their homes for further evaluation and, although timeliness may be sacrificed, more advanced diagnostic techniques and subspecialty care should be available. Continuing acetazolamide 250 mg twice daily and bridging transport with scheduled lorazepam 1 to 2 mg every 12 h for 3 to 4 days should offer enough protection to reach home, with minimal risk of further seizures en route. The choice of accompanied travel is probably situational, depending on the resources of the traveler, but hardly mandatory assuming that the patient has stabilized and is not exhibiting further seizures. Once home, cessation of lorazepam is advised, along with a taper of acetazolamide. One possible scheme is described later.
Diagnosis should reveal whether this event was provoked by some toxic, metabolic, or neurological insult or the unmasking of previously undiagnosed epilepsy. With those entities ruled out or undetermined, the possibility of a seizure provoked by high altitude remains. In the setting of a suspected diagnosis of epilepsy, antiepileptic medications would be recommended for repeat exposures to similar altitudes and considered for ongoing prophylaxis; seizure precautions would be observed for a period of 3 months. During that time if seizures recurred, especially at home elevation, prophylaxis would be strongly recommended. If the seizure occurring at altitude was in a known epileptic patient, the breakthrough seizure might warrant an increase in prophylactic medication, but could also be considered provoked. In the latter case, changes in medication might not be offered unless repeat exposure was anticipated. This management decision should be made between the patient and the treating neurologist or epileptologist.
Counseling and prophylaxis
Travelers planning high altitude expeditions should be counseled regarding the small possibility of seizures occurring in previously healthy people. This discussion can be presented along with education about acute mountain sickness, pulmonary edema, and cerebral edema symptoms.
Counseling can be complicated in the case of Ms. R, an incidental traveler to altitude who suffered a seizure and worries about the risk of future provocation. If an epilepsy syndrome or causative lesion is discovered, prophylaxis with antiepileptic therapy may be recommended. If the work-up is unrevealing, several precautions can be considered for future exposures. Recommendations similar to those for the prevention of AMS seem reasonable:
Staged ascent
Avoid tobacco, alcohol, sleeping pills, and narcotics
Avoid strenuous activity for the first 24 h after arrival to each new altitude
Limit gains of elevation to 300 m/day and for every 1000 m spend a day to acclimatize
Climb high, sleep low
Good hydration: as much as 3 to 4 quarts of free water a day
Prophylactic medications for a history of prior high altitude spectrum illnesses (Maa, 2010)
Seizure prophylactic options should include acetazolamide. A carbonic anhydrase inhibitor, this diuretic accelerates acclimatization by pharmacologically blocking bicarbonate formation and creating a metabolic acidosis that counters the respiratory alkalosis induced by hypoxia. Dosing between 125 and 250 mg twice daily starting 1 to 2 days prior to ascent is suggested. The duration of treatment should continue throughout the exposure, followed by a taper after returning home. Halving the twice-daily dose for 3 to 5 days, followed by discontinuing the morning dose for another 3 to 5 days, and then discontinuing the medication entirely is one possible tapering scheme. Tapering acetazolamide and other antiepileptic medications is advised owing to the possibility of a rebound or withdrawal effect that may promote additional seizures; it is supported by general clinical experience in epilepsy management and anecdotally in a high altitude seizure patient (Privitera, 1995).
Acetazolamide has long been known to have broad spectrum but unfortunately transient antiepileptic effects (Millichap et al., 1955) and therefore is not considered a mainstay of chronic antiepileptic therapy. The medications topiramate and zonisamide are effective antiepileptic medications and are believed to modulate at least a part of their antiseizure activity through a similar carbonic anhydrase inhibitor moiety, but their activity is only 25% that of acetazolamide. Because of this reduced efficacy of carbonic anhydrase inhibition, the severe paresthesias frequently seen with acetazolamide are dramatically reduced with topiramate and zonisamide. Therefore, in high altitude travelers who cannot tolerate the paresthesias of acetazolamide, who are diagnosed with epilepsy but not on medication, or who had a seizure at high altitude despite medication, topiramate (25 to 50 mg twice daily) or zonisamide (100 to 200 mg nightly), started 2 to 3 days prior to ascent, may be considered a possible option to prevent seizures associated with future exposures, although the ultimate success of an individual prophylaxis regimen will vary by patient.
For remote high altitude expeditioners who have a prior history of epilepsy but are no longer taking medications, it would be reasonable to bring a supply of medications previously used or consult with their physician prior to the expedition. For the incidental traveler who has documented seizures with sudden changes in airplane cabin pressures or high altitude layovers or who has uncontrolled epilepsy and desires to travel by air, scheduled lorazepam is an option. The antiseizure effect of a single administration of lorazepam is roughly 12 h, and 1 to 2 mg taken upon boarding (depending on benzodiazepine naïveté and weight) is usually sufficient for a plane ride or layover.
Conclusion
It is not currently possible to predict with any certainty which patients are susceptible to seizures at high altitude, and more data are sorely needed. It is the hope of the author and his collaborators that these cases be collected and reported in a central repository, such as the HAPE database at <http://www.altitude.org/hape.php>. For the time being, contacting the author with questions and cases can serve as the nidus for a similar online database reporting tool (
Footnotes
Disclosure
The author has no conflicts of interest or financial ties to report.
Acknowledgments
The author thanks Andrew Luks for his referral of Ms. R, who became the focus of this review and graciously granted her permission to use her story. He also wishes to thank his collaborators at the Altitude Research Center at the University of Colorado, Peter Hackett and Robert Roach, for continuing to send him fascinating cases from around the world.