Most likely causes, in order of concern

• Valproate can raise ammonia even at normal drug levels and with normal liver tests. Ammonia above 80 μg/dL (35 μmol/L) can cause profound encephalopathy (Washington Manual of Medical Therapeutics, Pathophysiology, Toxicology chapter).
• Typical features are vomiting, lethargy and falling consciousness.
• Phenytoin is an enzyme inducer and raises the risk. This patient takes both, so VHE is high on the list.
• Carnitine depletion after decades of valproate is a likely contributor. In psychiatric patients with this syndrome, IV L-carnitine has been shown to lower ammonia (Sleisenger and Fordtran's GI and Liver Disease, Valproic Acid).

• Valproate displaces phenytoin from albumin and slows its metabolism, so the free level can be high even when the total level looks normal.
• Plasma levels of 30-40 mg/L cause ataxia, slurred speech, nausea and vomiting. Above 40 mg/L they cause lethargy and confusion (Tintinalli's Emergency Medicine, Table 197-4).
• Check for nystagmus and ataxia.
• Ask about any recent antibiotic or antifungal, since this patient has a UTI history. Co-trimoxazole, metronidazole, fluconazole and ciprofloxacin can all raise phenytoin levels.

• UTI history, a cold body and reduced alertness fit sepsis, and hypothermia is a sepsis sign.
• He cannot report dysuria, flank pain or fever. A normal pulse does not exclude it.

• Olanzapine can cause hyperglycemia and DKA (vomiting, drowsiness). It can also cause constipation or ileus and bowel obstruction through its anticholinergic effect. Neuroleptic malignant syndrome is less likely with a cold body, but check for rigidity and CK.
• Valproate-related pancreatitis or hepatotoxicity. Pancreatitis is a recognised valproate effect (Tintinalli's).
• Nonconvulsive status epilepticus, which is easily missed in a non-verbal patient with intellectual disability.
• Clobazam accumulation, or the opposite problem: missed doses from vomiting leading to benzodiazepine or antiepileptic withdrawal and seizures.
• Hypoglycemia, hyponatremia, other electrolyte disturbance, AKI, hypothyroidism or adrenal crisis.
• Intracranial causes: head injury or subdural hematoma after a fall, meningoencephalitis, raised intracranial pressure.
• Wernicke encephalopathy, given prolonged vomiting. The Washington Manual also lists it as a mimic of valproate toxicity.

Immediate investigations

• Bedside glucose, temperature and GCS.
• Venous blood gas with lactate, electrolytes, urea and creatinine, calcium, magnesium, and ketones.
• Blood ammonia. Send it on ice and run it quickly. It is the key test.
• Liver function tests, lipase, CBC, CRP, CK.
• Total and free valproate level, and total and free phenytoin level with albumin.
• Urine microscopy and culture, and blood cultures.
• ECG. Olanzapine can prolong QT, and vomiting can cause electrolyte disturbance.
• CT head and an abdominal film or ultrasound. Arrange EEG if the cause is unclear or drowsiness persists.
• TSH and cortisol if the picture is still unexplained.

Initial management

• Keep him nil by mouth, with IV access, aspiration precautions and continuous monitoring. A high-dependency bed is appropriate.
• Give IV isotonic fluids, adding dextrose if glucose is low. Give thiamine before dextrose if Wernicke is a concern.
• If sepsis is suspected, take cultures and start empirical antibiotics within the first hour.
  • Avoid carbapenems (such as meropenem). They can drop valproate levels sharply and trigger seizures.
  • Avoid fluoroquinolones where possible, because they lower the seizure threshold.
• For antiemetics, ondansetron is reasonable once the QT interval is checked. Avoid metoclopramide, prochlorperazine and haloperidol. They lower the seizure threshold and add to olanzapine's extrapyramidal and QT effects.
• Do not stop antiepileptics abruptly because of the withdrawal-seizure risk. If oral intake fails, give IV phenytoin or fosphenytoin (only if the level is not high) or IV levetiracetam.
• Hold olanzapine while he is drowsy, and reintroduce it later.
• Management if ammonia is raised (typical regimens; check doses locally):
  • Stop valproate and bridge with levetiracetam or another non-hepatically-cleared drug. Prognosis is generally excellent, with recovery within days of stopping valproate.
  • Give IV L-carnitine, commonly about 100 mg/kg load then 50 mg/kg every 8 hours.
  • Give lactulose, with or without rifaximin.
  • Consider hemodialysis or CRRT if ammonia is very high, consciousness is deteriorating, or there is cerebral edema.
• If phenytoin is toxic, hold it and give supportive care. Re-check levels in 2-3 days before restarting (Tintinalli's).

Why this should not wait

Working diagnosis

• He has taken valproate for decades, together with phenytoin, an enzyme inducer that raises the risk.
• The picture is acute vomiting with falling alertness and no other obvious cause.
• Valproate raises ammonia even when liver tests and drug levels are normal.

• Blood ammonia above about 80 μg/dL (35 μmol/L), sent on ice.
• Valproate level and liver tests that are often near normal.
• Phenytoin free level, glucose, electrolytes, lactate, and urine and blood cultures, to exclude the mimics.
• CT head and EEG if drowsiness is unexplained or persists after ammonia is treated.

Treatment

• Admit to a monitored or high-dependency bed. Keep him nil by mouth, with aspiration precautions.
• Check bedside glucose. Correct hypoglycemia, giving thiamine before dextrose.
• Give IV isotonic fluids, and correct electrolytes.
• Take blood and urine cultures. If sepsis is possible, start empirical IV antibiotics within the first hour.
  • Avoid carbapenems. They sharply lower valproate levels and can cause seizures.
• Use ondansetron for vomiting after checking the QT interval. Avoid metoclopramide, prochlorperazine and haloperidol.

• Stop valproate. This is the main treatment, and recovery is usually complete within days.
• Do not leave him without seizure cover. Bridge with IV levetiracetam, and continue phenytoin only if its free level is not high.
• Give IV L-carnitine, commonly 100 mg/kg load (maximum 6 g), then 50 mg/kg every 8 hours. Check the dose locally.
• Give lactulose (or add rifaximin) to lower ammonia.
• If ammonia is very high, consciousness is worsening or there is cerebral edema, consider hemodialysis or CRRT, and involve ICU and nephrology.
• When he recovers, choose a long-term antiepileptic that is not valproate. Do not restart valproate without specialist advice.

• Hold phenytoin and give supportive care. Check the free level, because valproate raises the free fraction.
• Repeat levels in 2-3 days and restart at a lower dose.
• Review any recent antibiotic or antifungal that may have raised the level.

• Treat with culture-directed IV antibiotics, fluids and source control. Check for obstruction with a renal ultrasound.
• Pick antibiotics that do not interact with his antiepileptics.

• Hold olanzapine while he is drowsy.
• Check for olanzapine-related DKA, constipation or ileus, and neuroleptic malignant syndrome.
• Watch for clobazam accumulation. Do not stop it abruptly.

When to escalate