Differential Diagnosis: First-Time Seizure with Severe High Anion Gap Metabolic Acidosis in a 13-Year-Old
This 13-year-old girl has severe high anion gap metabolic acidosis (bicarbonate 11 mmol/L, anion gap 26 mEq/L) that caused her seizure, and the most likely diagnoses are toxic ingestion (salicylates, methanol, ethylene glycol, isoniazid), diabetic ketoacidosis (including euglycemic DKA), inborn errors of metabolism, or severe lactic acidosis from sepsis or tissue hypoperfusion.
Understanding the Clinical Picture
The combination of first-time seizure with profound metabolic acidosis (bicarbonate 11 mmol/L) and markedly elevated anion gap (26 mEq/L) indicates a life-threatening metabolic emergency. 1 An anion gap >12 mEq/L signifies accumulation of unmeasured anions such as lactate, ketoacids, uremic toxins, or ingested toxins. 2, 3
Normal CT and CBC help exclude structural brain lesions and infection as primary causes, but the seizure is almost certainly secondary to the severe acidosis itself. 4
Primary Differential Diagnoses
Toxic Ingestions (Highest Priority)
Salicylate toxicity typically presents with metabolic acidosis and respiratory alkalosis, though severe cases can cause seizures, altered mental status, and anion gaps in this range. 2
Methanol or ethylene glycol poisoning produces severe high anion gap acidosis with anion gaps frequently >20 mEq/L; an anion gap of 26 mEq/L warrants immediate consideration of toxic alcohol ingestion and emergent hemodialysis evaluation. 1, 2
Isoniazid overdose causes severe metabolic acidosis, hyperglycemia, and intractable seizures within 30 minutes to 3 hours of ingestion, with anion gap elevation and acetonuria as typical findings. 5
Obtain immediate toxicology screening, serum osmolal gap calculation (elevated osmolal gap >10 mOsm/kg strongly suggests toxic alcohol), salicylate level, acetaminophen level, and urine organic acids. 1, 6, 7
Diabetic Ketoacidosis or Euglycemic DKA
Standard DKA is defined by glucose >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L (this patient has bicarbonate 11 mmol/L, indicating moderate-to-severe DKA), and positive ketones. 8
Euglycemic DKA can occur with SGLT2 inhibitor use (increasingly prescribed off-label in adolescents) or starvation ketosis, presenting with normal or near-normal glucose but severe acidosis and elevated anion gap. 1
Measure serum glucose, beta-hydroxybutyrate (>3 mmol/L confirms ketoacidosis), urine ketones, and hemoglobin A1c immediately. 8, 6
Lactic Acidosis
Type A lactic acidosis from tissue hypoperfusion (septic shock, cardiogenic shock, severe anemia) or Type B lactic acidosis from medications (metformin), toxins, or mitochondrial disorders can produce anion gaps of this magnitude. 2, 9
Measure serum lactate immediately; levels >4 mmol/L indicate severe lactic acidosis and are associated with high mortality. 2, 9
Assess for signs of sepsis (fever, tachycardia, hypotension), obtain blood cultures, and evaluate perfusion status (capillary refill, skin mottling, blood pressure). 9
Inborn Errors of Metabolism
5-oxoproline (pyroglutamic) acidosis can present in adolescents with chronic acetaminophen use, malnutrition, or sepsis, causing severe high anion gap acidosis with anion gaps typically 20-30 mEq/L. 6, 7
Organic acidemias (methylmalonic aciduria, propionic acidemia) can present with first seizure in adolescence during metabolic decompensation triggered by illness or fasting. 6
Send urine organic acids, plasma amino acids, and acylcarnitine profile; consider 5-oxoproline measurement if other causes are excluded. 6, 7
Uremic Acidosis
Severe chronic kidney disease can cause high anion gap acidosis, but the anion gap is typically mild (15-20 mEq/L) and bicarbonate rarely falls below 12 mmol/L unless acute kidney injury is superimposed. 2, 3, 9
Check BUN and creatinine; if elevated, obtain renal ultrasound and consider acute-on-chronic kidney disease. 3
Immediate Diagnostic Workup Algorithm
First-Line Laboratory Tests (Stat)
Arterial or venous blood gas (pH, PaCO2, PaO2) to confirm metabolic acidosis and assess respiratory compensation. 8
Serum glucose, beta-hydroxybutyrate, lactate, BUN, creatinine, and calculate corrected anion gap for albumin. 8, 7
Serum osmolality and calculate osmolal gap: (measured osmolality) - (2[Na] + glucose/18 + BUN/2.8); osmolal gap >10 mOsm/kg suggests toxic alcohol. 1, 6
Comprehensive toxicology screen including salicylate, acetaminophen, ethanol, methanol, ethylene glycol levels. 1, 2
Urine ketones and urine organic acids (for 5-oxoproline and organic acidemias). 6, 7
Second-Line Tests Based on Initial Results
If osmolal gap elevated or toxic ingestion suspected: immediate nephrology consultation for emergent hemodialysis (anion gap >27 mmol/L with potassium-inclusive calculation indicates severe toxicity requiring dialysis). 1
If ketones positive: hemoglobin A1c, C-peptide, insulin level, and assess for new-onset type 1 diabetes versus euglycemic DKA. 8
If lactate elevated: blood cultures, chest X-ray, echocardiogram, and consider mitochondrial workup if no obvious cause of hypoperfusion. 2, 9
If all common causes excluded: plasma amino acids, acylcarnitine profile, and consider genetic/metabolic consultation. 6
Critical Management Principles
Immediate Stabilization
Ensure airway protection and adequate ventilation; seizures from severe acidosis may recur until pH improves. 4
Establish IV access and begin isotonic saline (0.9% NaCl) at 15-20 mL/kg/h to restore perfusion and renal function. 8
If isoniazid overdose suspected (seizures + acidosis + hyperglycemia): give IV pyridoxine 5 grams (or 80 mg/kg in children) over 30-60 minutes immediately. 5
If toxic alcohol suspected (elevated osmolal gap + severe acidosis): initiate fomepizole immediately and arrange emergent hemodialysis. 1, 6
Bicarbonate Therapy Considerations
Bicarbonate therapy is generally not indicated for DKA unless pH <6.9-7.0, as insulin and fluid resuscitation correct the underlying acidosis. 8
For toxic ingestions (isoniazid, salicylates, methanol, ethylene glycol), bicarbonate may be needed to maintain pH >7.1 while arranging definitive therapy (antidotes, dialysis). 5, 2
Monitor serum potassium every 2-4 hours during any bicarbonate or insulin therapy, as alkalinization drives potassium intracellularly and can cause life-threatening hypokalemia. 8
Seizure Management
The American Academy of Neurology recommends EEG as part of the neurodiagnostic evaluation for first unprovoked seizure in children. 4
Antiepileptic drugs may be needed acutely, but definitive seizure management requires correcting the underlying metabolic acidosis. 4
Common Pitfalls to Avoid
Failing to calculate osmolal gap in severe high anion gap acidosis can miss toxic alcohol ingestion, delaying life-saving hemodialysis. 1, 6
Assuming DKA based on glucose alone without checking ketones can miss euglycemic DKA or lead to inappropriate insulin therapy in non-ketotic conditions. 1
Overlooking 5-oxoproline acidosis in patients with chronic acetaminophen use (even therapeutic doses) and negative standard toxicology screens. 6, 7
Stopping insulin when glucose normalizes in DKA before anion gap closes (<12 mEq/L) and bicarbonate rises (≥18 mmol/L) can cause rebound ketoacidosis. 8
Giving excessive bicarbonate without adequate ventilation can worsen intracellular acidosis by generating CO2 that cannot be eliminated. 5, 9