Adenosine triphosphate (ATP) is a high-energy phosphate compound necessary for normal muscle function.₅ It is required for muscular contraction and relaxation, facilitation of calcium ion influx into the myocyte, and maintenance of the critical ionic gradients across the myocyte membrane via ATP dependant ion-transport pumps.₆ As ATP is utilized, three mechanisms are available to replenish myocyte stores. ATP can be generated from adenosine diphosphate by the enzyme CK, but this route can only briefly sustain muscular function. The other two methods involve the glycolytic pathway utilizing intracellular glycogen, and mitochondrial oxidation utilizing acetyl CoA derived from the breakdown of glucose and triglycerides.⁶ Depletion of ATP, whether due to sustained muscular contraction (i.e., status epilepticus) or blockage of a metabolic pathway necessary for ATP production, leads to devastating shifts of the intracellular electrolyte balances due to the inability of the myocyte to maintain the transmembrane ion gradients.⁶ One of the primary electrolyte disturbances is of intracellular calcium.₇ This occurs from failure of a calcium-ATPase driven efflux, resulting in an increase of intracellular calcium, leading to disruption of normal intracellular calcium sequestration by the sarcoplasmic reticulum and ultimately to toxic levels of calcium present inside the myocyte.⁶,₈ These elevated intracellular calcium levels then activate proteases, phospholipids, and other enzymes which damage the cell membrane,⁸ and the calcium damaged mitochondria result in the formation of free radicals and further oxidative insult, with eventual myocyte lysis and the escape of intracellular toxins into the systemic circulation.⁶,₉ This muscle damage also causes a local invasion of neutrophils, which contribute to the release of proteases and free radicals and result in a self-sustaining myolytic reaction and necrosis. This process is known as the syndrome of rhabdomyolysis.

The first reference to rhabdomyolysis is thought to have been in the Bible, where the Israelites suffered a mass plague following ingestion of quail (Book of Numbers 12:31-34). Rhabdomyolysis occurring after quail consumption during the spring in the Mediterranean region is a recognized phenomena, and is thought to be a direct result of hemlock intoxication, on which the quails feast during their spring migration.⁷ Bywater and Beall, however, are credited with the earliest modern research on the syndrome of rhabdomyolysis. They described a crush syndrome and major clinical sequelae following victims of a World War II bombing raid in London.¹,⁷ Rhabdomyolysis has since been associated with over 60 traumatic and non-traumatic causes (Appendix B), such as contact sports, hypothermia, cocaine usage, sepsis, electrolyte abnormalities, and the direct myotoxic effects of alcohol.₁₀ Several sequelae have also been recognized, with acute renal failure and compartment syndrome causing the most morbidity and mortality.₁₁

Compartment syndrome, as occurred in our patient, is a self-perpetuating series of events further damaging compromised muscles that exist in a non-communicating fascial compartment.₁₂ An example of fascial compartments that are intolerant of increased local pressures is in the forearm, which contains both a volar and dorsal compartment.₁₃ As muscle damage ensues and acute swelling takes place, the increase in intracompartmental pressures compromise perfusion to the compartment, causing further disturbances of the muscular metabolic processes. The increased local pressure leads to increased myolysis, which in turn leads to extravasation of intracellular components capable of drawing even more fluid into the compartment and further increasing compartment pressures, with potential complications of entire compartmental ischemic necrosis and distal vascular and neurologic compromise.₁₄ While controversy exists in the literature as to exactly what intracompartmental pressure values can be tolerated, it is generally agreed that once compartment pressures rise to within 10-30 mmHg below diastolic blood pressure an emergent fasciotomy for compartmental release should be performed to minimize permanent disability.¹²,₁₅

While the etiology of this patient's seizures may have been a combination of factors, three obvious and proven possibilities are 1) alcohol withdrawal, 2) hyponatremia,₁₆,₁₇ and/or 3) hypocalcemia.₁₈,₁₉,₂₀ Abrupt cessation of alcohol intake as a causative factor in first-time seizures has been well established.19 This is a consideration in this patient since he reports an intake of at least 6 beers per day, confirmed by the patient's roommate along with his mother. His chronic alcoholism, however, may also have contributed to formation of two other possible factors leading to his admission: hyponatremia and hypocalcemia.

The causes of hyponatremia are extensive,₂₁ but the underlying pathophysiology involves a rate of water intake that exceeds the rate of free-water renal excretion.₂₂ Free water is generated by the kidney in the diluting segments through the process of re-absorbing salt without water, so that hypo-osmolar water is formed and excreted. Therefore, hyponatremia and hypotonicity can develop whenever there is a primary increase in water intake, when the ability of the kidney to produce a maximally dilute urine is compromised, or when a combination of these factors exist.21

The rate of free water reabsorbption is regulated mostly by the hormone arginine vasopressin (AVP), also known as anti-diuretic hormone (ADH), so that the greater the concentration of AVP present, the greater the rate of free water reabsorbption.21 In the absence of AVP, a dilute urine is produced but the minimal osmolality of the urine has been shown to be about 50 mOsm/kg H₂O.²¹,²² Thus, if the fluid presenting to the collecting duct is more dilute than this minimum, free water will be reabsorbed even in the absence of AVP. This is the case in both psychogenic polydipsia and a condition called beer potomania.22 These conditions occur due to either decreased sodium intake or increased water consumption, with both probably contributing in this patient.

From the perspective of the kidney, if less salt is delivered to the dilutional segments, then less free water is generated. This is best demonstrated by a simplified equation: Healthy individuals excrete between 600 and 1000 mOsmol of solute per day,₂₃ and maximally dilute urine is 50 mOsmol/kg of H₂O. This means that a maximum of I L of free water can be excreted for 50 mOsmol of solute.21 Thus, on a normal diet, containing about 800 mOsmol of solute, a healthy person can excrete a maximum urine volume of 16 L (800 mOsmol/50 mOsmol/L = 16 L).²³ The problem in chronic beer consumption, beer potomania, is that the diet typically consist largely of beer, with little salt or other solute.22 It is not uncommon for these individuals to excrete less than 250 mOsmol of solute per day. In this case, the maximal urine volume is 5 l/day assuming a maximal dilutional capacity of 50 mOsmol/kg (250/50 = 5 L).²³ If this same individual then consumes more than 5 L of electrolyte-free water, the excess will be retained even in the absence of AVP, resulting in a dilutional, hypotonic hyponatremia.²²,²³

Our patient was found to be hypotonic and had a low urine osmolality, which further strengthens the case for hyponatremia due to excessive free-water intake. The low urine osmolality also helps to exclude SIADH, in which case we would have expected a high urine osmolality due to an inappropriate excess of AVP (ADH) concentrating the urine.²¹,₂₄ Available literature on hyponatremia suggests that neurologic symptoms (nausea/vomiting, twitching, stupor, convulsions) can occur at a serum sodium concentration of less than 127 mmol/L, and are most likely to occur when hyponatremia develops rapidly.²,³,⁸,¹⁷,²¹,²⁴,₂₅,₂₆,₂₇ Our patient was in this range with a serum sodium of 117 on admission.

Hyperglycemia can cause a pseudohyponatremia by an osmotic shift of water from the cells. This is due to the hypertonicity of the extracellular fluid present with hyperglycemia, and an inadequate amount of free water available in the plasma for compensation. However, we have established that the extracellular fluid was expanded in this case and caused hypotonicity due to increased free water consumption.²⁰,²¹

One of the other electrolyte disturbances in this patient was hypocalcemia. Calcium in the blood is approximately 40% bound to protein, 10% complexed to citrate, phosphate, and sulfate ions, and 50% ionized.₂₈ There are several reasons to explain hypocalcemia in this case. First, he was found to have a concurrent hypomagnesiemia, which results in decreased parathyroid hormone secretion.²⁸ Hypomagnesiemia is common amongst the alcoholic population, approaching 30% in one study,₂₉ and is believed to be a result of a direct magnesiuric effect of acute alcohol consumption, alcohol withdrawal syndrome, and/or poor nutritional status.²⁰,₃₀

He was also found to have a hyperphosphatemia, and this could have contributed to his hypocalcemia. Phosphate is the major intracellular anion, and any cause of marked tissue breakdown, as in rhabdomyolysis, causes an acute phosphate load to be excreted into the extracellular fluid,²⁰,²⁸ where the phosphate binds with calcium and is then precipitated in the tissues.7

When evaluating hypocalcemia it is important to consider whether the reduction is one of total calcium or ionized calcium. The ionized fraction affects neuromuscular function and is therefore the only clinically relevant parameter when evaluating symptoms of hypocalcemia, such as tetany.₃₁ This is due to the fact that a low calcium ion concentration in the extracellular fluid allows for cellular sodium channels to become easily opened, resulting in a highly excitable nerve fiber. The nerve fiber can then begin to discharge repetitively without provocation, and this continued spontaneous discharge is manifested as muscular rigidity, which constitutes tetany.₃₂

The clinical consequences of hypocalcemia are also affected by acid-base status. Hypocalcemia and alkalosis seem to potentiate each other in causing tetany, whereas an acidotic state seems to have a protective effect in the face of hypocalcemia. This is due to decreased albumin binding in acidosis, which increases the ionized fraction of calcium and lessons the clinical impact of hypocalcemia.20

Hypoalbuminemia was also present in this patient. This would mean less protein available for binding with calcium, mitigating the effect on the ionized calcium of the overall hypocalcemia, as described above.²⁰,³¹

This patient in fact had an ionized calcium of 1.20 on admission, with a range of about 1.16 – 1.27 mmol/L defining normal.₃₃ He also failed to show the classic electrocardiogram finding associated with hypocalcemia, which is QT segment elongation.20 Therefore, it would appear that his condition was due to some pathologic process aside from hypocalcemic-induced tetany.

New onset diabetes mellitus was considered as a possible contributing factor due to the hyperglycemia and acid-base disturbances on admission. The patient was in a state of metabolic acidosis, based on blood gas values of pH 7.073 (range 7.35 – 7.45), Pco₂ 34.9 mmHg (range 35-45), and HCO₃ 10.0 mEq/l (range 20 – 26). While this could have been due to a ketoacidosis secondary to new onset diabetes mellitus, it most likely resulted from a lactic acidosis. This is based on the fact that his urine failed to show the presence of ketones, and his hyperglycemia resolved without exogenous insulin intervention, helping to exclude the possibility of new onset diabetes. Therefore, the acidosis was felt to be lactic in nature, as a direct result of his impaired tissue oxygenation, forcing the muscles to utilize anaerobic pathways for ATP generation where lactate is a by-product.20

Another electrolyte disturbance to consider was potassium, which our patient was found to actually not have on lab values. However, a review of the role of potassium in muscle oxygenation shows that his normal serum potassium may indeed have been a falsity. Muscle fiber contraction releases potassium into the extracellular environment where it acts to dilate the local microvasculature and increase blood flow to the muscle.⁸ During periods of sustained muscular contractions (e.g., seizure activity), the intracellular potassium becomes depleted and therefore no longer available for extracellular release, resulting in failure of the local microvasculature to dilate and increase blood flow to the area, causing muscle ischemia and myocyte injury.11 This can lead to myolysis, at which time all remaining intracellular electrolytes, including potassium, are released from the cell on a large scale and into the systemic circulation.21

This sudden release of large quantities of potassium from the injured muscles into the extracellular space should have acutely raised the potassium level, and the fact that this patient's serum potassium was in the low normal range suggests that he may have been hypokalemic prior to the onset of rhabdomyolysis. Since hypokalemia is frequently encountered in chronic alcoholism (usually due to poor nutritional intake), and also has been shown to be associated with both neuromuscular irritability21 and rhabdomyolysis,11 this was yet another possible contributor to his current admission.

The one other differential mentioned earlier is neuroleptic malignant syndrome, which may occur with administration of psychoactive medications and presents with the triad of muscular rigidity, confusion, and pyrexia.₃₄ This was excluded on account of the normothermic status of this patient, and the fact that he had been on the same psychoactive medications for several years without prior complication.