Valproate induced hyperammonaemia superimposed upon severe neuropsychiatric lupus: a case report and review of the literature
1Estee Chan MBChB, 1, 2Fiona McQueen MD FRACP
1Dept of Rheumatology, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand.
2Dept of Molecular Medicine and Pathology, University of Auckland, Auckland New Zealand.
Corresponding author: Dr Estee Chan, Department of Rheumatology, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand. Private Bag 92024, Auckland Mail Centre, Auckland 1142, New Zealand. Email:
Keywords: systemic lupus erythematosus (SLE), anticonvulsants, sodium valproate, hyperammonaemia
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Supplementary Table Individual reported cases of valproate induced hyperammonaemia
Patient demographics / Valproic Acid Dose & Duration / Peak Valproic Acid Level (therapeutic 350 – 700 µmol/L) / Peak Ammonia Level(normal 0-50 µmol/L) / Concurrent medications / Clinical Presentation / Treatment / Outcome
30-year-old male, seizure disorder [8] / 1000mg/day for 7 days / 90.5 µg/ml
(599 µmol/L) / 369 µg/dl
(217 µmol/L) / Phenobarbital clonazepam / Nausea, emesis and drowsiness / Discontinue VPA, administer neomycin enema and lactulose / Complete recovery within 4 days
23-year-old male, seizure disorder [9] / 4000mg/day for 8 years / 88.8 µg/ml
(588 µmol/L) / 234 µmol/L / Carbamazepine / Lethargy, gait ataxia, forgetfulness, nausea / Discontinue VPA, administer carnitine and lactulose / Complete recovery within 4 days
16-year-old female, seizure disorder [10] / 600mg/day for 7 days / Not reported / 480 µmol/L / Carbamazepine / Reduced level of consciousness / Discontinue VPA, administer dialysis, sodium benzoate, sodium phenybutyrate and L-arginine / Complete recovery within 4 days
23-year-old male, demyelinating disease and seizure disorder [11] / 1000mg/day for 3 days / Not reported / 524 µmol/L / Phenytoin, Phenobarbital / Reduced level of consciousness, worsening of demyelinating disease / Discontinue VPA, administer hemodialysis and L-carnitine / Died 3 weeks later
32-year-old female, seizure disorder [12] / 1000mg/day, duration not reported / 199 µg/ml
(1317 µmol/L) / 104 µg/dl
(61 µmol/L) / Carbamazepine / Impaired memory, gait ataxia, tremor, aphasia / Discontinue VPA / Complete recovery after 5 days
41-year-old female, seizure disorder [12] / Total of two 250mg tablets, taken 24 hr apart / 33 µg/ml
(218 µmol/L) / 750 µg/dl
(440 µmol/L) / Phenytoin, primidone, acetazolamide / Vomiting, disorientation, stupor / Discontinue VPA / Complete recovery after 14 days
17-year-old male, seizure disorder [12] / 6500mg/day, duration not reported / 98 µg/ml
(649 µmol/L) / 156 µg/dl
(92 µmol/L) / Carbamazepine / Agitation, kicking, biting / Reduce dose to 4500mg/day / Complete recovery after 5 days
49-year-old female, seizure disorder [12] / 500mg/day, duration not reported / 40 µg/ml
(265 µmol/L) / 133 µg/dl
(78 µmol/L) / Acetazolamide / Indifference, delayed responses, disinhibition / Discontinue VPA / Complete recovery after 4 days
58-year-old female, seizure disorder [12] / 2000mg/day, duration not reported / 59 µg/ml
(391 µmol/L) / 116 µg/dl
(68 µmol/L) / Gabapentin, azetazolamide, clonazepam / Disorientation, ataxia, lethargy / Discontiinue VPA and all medications, administer L-carnitine / Complete recovery after 6 days
32-year-old (gender unknown), seizure disorder [13] / 1500mg/day for 6 years / 68 µg/ml
(450 µmol/L) / 152 µmol/L / None / Vertigo, reduced concentration, gait ataxia, asterixis / Discontinue VPA / Complete recovery within 1 month
88-year-old male, seizure disorder [14] / 1000mg/day for 2 months / 48 µg/ml
(318 (µmol/L) / 836 µg/dl
(491 µmol/L) / None / Confusion, lethargy / Discontinue VPA / Near complete recovery by day 3
78-year-old female, seizure disorder [15] / 1300mg/day for 20 years / 80 µg/ml
(530 µmol/L) / 174 µmol/L / Carbamazepine / Confusion, agitation / Discontinue VPA / Complete recovery within 1 day
72-year-old female, seizure disorder [16] / 1500mg/day for 1 year / 755 µmol/L / 113 µmol/L / Pivmecillinam / Confusion, tremor, stupor / Discontinue VPA / Complete recovery within 14 days
76-year-old female, seizure disorder [17] / 2250mg/day for 10 days / >144 µg/ml
(953 µmol/L) / 211 µg/dl
(124 µmol/L) / Phenytoin, aspirin, amlodipine, atenolol, losartan, pantoprazole / Confusion, generalised weakness, nausea, vomiting / Discontinue VPA on day 24 after several dose reductions / Complete recovery within 4 days
29-year-old female, seizure disorder [18] / 3500mg/day, duration not reported / Not reported / 62 µmol/L / Topiramate, lamotrigine, clonazepam / Reduced appetite, asthenia / Reduce VPA to 2500mg/day / Complete recovery within 2 months
32-year-old male, seizure disorder [18] / 2750mg/day, duration not reported / 105 µg/ml
(695 µmol/L) / 65 µmol/L / Topiramate, bromazepam / Asthenia, impaired ideation , motor function disorder / Reduce VPA to 2250mg/day, reduce bromazepam / Complete recovery within 2 months
38-year-old male, seizure disorder [18] / 500mg/day for 8 years / 38 µg/ml
(252 µmol/L) / 72 µmol/L / Topiramate, carbamazepine, primidone, fluoxetine / Drowsiness, aphasia, aproxia, anterograde amnesia / Discontinue VPA / Improvement 1 month later but not completely resolved
41-year-old male, seizure disorder [18] / 10mg/kg bolus, followed by continuous infusion 1mg/kg/h, followed by 500mg/day, increased to 2000mg/day by day 5 / 98 µg/ml
(649 µmol/L) / 146 µmol/L / Topiramate, carbamazepine, lamotrigine, clobazam / Slow ideation, motor activity impairment, asterixis / Reduce VPA to 1500mg/day, discontinue topiramate / Complete recovery within 2 months
56-year-old female, seizure disorder [19] / 2000mg/day for 6 years, 2500mg/day for 2 months, 3000mg/day for 10 hours / 82 µg/ml
(543 µmol/L) / 921 µg/dl
(541 µmol/L) / Carbamazepine, gabapentin, Phenobarbital, phenytoin / Intermittent confusion, forgetfulness, acute coma (10 hours after dose escalation) / Discontinue VPA, adminstercarnitine and lactulose / Complete recovery within 1 week
45-year-old female, seizure disorder [20] / 1600mg/day for 1 day / 44 µg/ml
(291 µmol/L) / 817 µg/dl
(480 µmol/L) / Phenytoin, phenobarbital / Somnolence and coma / Discontinue VPA / Complete recovery within 1 month
20-year-old male, seizure disorder [21] / 750mg/day for 3 years / Reported to be ‘normal’ / 366 µmol/L / None / Drowsiness, confusion, unsteady gait, hallucinations / Discontinue VPA / Complete recovery within 4 days
16-year-old, seizure disorder [22] / Not reported / 74.5 µg/ml
(493 µmol/L) / 261 µmol/L / None / Confusion / Discontinue VPA / Complete recovery (time not specified)
19-year-old male, seizure disorder [22] / Not reported / 72.1 µg/ml
(477 µmol/L) / 69 µmol/L / None / Confusion / Discontinue VPA / Complete recovery (time not specified)
20-year-old female, seizure disorder [23] / 1000mg/day for 6 weeks / 80 µg/ml
(530 µmol/L) / 134 µg/dl
(79 µmol/L) / Carbamazapine / Disorientation, tremor, increased seizure frequency / Discontinue VPA / Complete recovery within 4 days
23-year-old female, seizure disorder [23] / 500mg/day for 8 weeks / 52 µg/ml
(344 µmol/L) / 132 µg/dl
(78 µmol/L) / None / Unusual behavior, disorientation, ataxia / Discontinue VPA / Complete recovery within 6 days
28-year-old male, seizure disorder [23] / 1000mg/day for 2 weeks / 86 µg/ml
(569 µmol/L) / 130 µg/dl
(76 µmol/L) / Carbamazepine, clonazepam / Lethargy, ataxia, dysarthria / Discontinue VPA / Complete recovery within 5 days
56-year-old male, seizure disorder [23] / 1500mg/day for 12 weeks / 76 µg/ml
(503 µmol/L) / 115 µg/dl
(68 µmol/L) / None / Impaired memory, behavioral changes, urinary incontinence, increased appetite / Discontinue VPA / Complete recovery within 10 days
55-year-old female, seizure disorder [23] / 500mg/day for 3 days / 42 µg/ml
(278 µmol/L) / 124 µg/dl
(73 µmol/L) / None / Disorientation, vomiting, lethargy / Discontinue VPA / Complete recovery within 5 days
64-year-old female, seizure disorder [23] / 1000mg/day for 18 months / 94 µg/ml
(622 µmol/L) / 142 µg/dl
(83 µmol/L) / None / Agitation, impaired concentration / Discontinue VPA / Complete recovery within 7 days
39-year-old male, seizure disorder [23] / 1500mg/day for 3 years / 55 µg/ml
(364 µmol/L) / 122 µg/dl
(72 µmol/L) / Lamotrigine, levetiracetam / Ataxia, dysarthria, nystagmus / Discontinue VPA / Complete recovery within 6 days
19-year-old male, seizure disorder, mental retardation [24] / 1600mg/day, duration not reported / 950 µg/ml
(6289 µmol/L) / 65 µmol/L / Trifluoperazine, diazepam / Restlessness / Discontinue VPA, administer activated charcoal and L-carnitine / Complete recovery within 7 days
62-year-old female, seizure disorder [25] / 750mg/day, duration not reported / 75 µg/ml
(497 µmol/L) / 99 µmol/L / None / Confusion, mumbling speech, dizziness, lethargy, weakness / Discontinue VPA / Complete recovery within 3 days
43-year-old male, seizure disorder and alcohol dependence [26] / Dose not reported for 13 years / 1400 µg/ml
(9268 µmol/L) / >286 µmol/L / None / Reduced level of consciousness / Discontinue VPA, administer naloxone, N-acetylcysteine, L-carnitine and haemodiaylsis / Complete recovery within 32 days
49-year-old female, seizure disorder [27] / 1500mg/day for 8 years / 59.9 µg/ml
(397 µmol/L) / 195 µg/dl
(115 µmol/L) / Topiramate, phenobarbital / Myoclonic jerks, disorientation, aphasia, unsteady gait / Discontinue VPA / Complete recovery within 3 months
57-year-old male, seizure disorder and alcohol dependence [28] / 4500mg/day, duration not reported / 168 µg/ml
(1112 µmol/L) / 132 µmol/L / Carbamazepine / Reduced level of consciousness / Discontinue VPA, administer thiamine and lactulose / Complete recovery within 1 day
65-year-old male, cerebral infarction [22] / Not reported / 84.6 µg/ml
(560 µmol/L) / 150 µmol/L / None / Confusion / Discontinue VPA / Complete recovery (time not specified)
72-year-old female, cerebral infarction [22] / Not reported / Not reported / 64 µmol/L / None / Confusion / Discontinue VPA / Complete recovery (time not specified)
63-year-old male, intracranial haemorrhage [29] / Dose not reported for 4 months / 105 µg/ml
(695 µmol/L) / 362 µmol/L / Levetiracetam / Disorientation, unsteady gait, incontinence, obtundation / Reduce VPA to 1000mg/day, administer lacutlose / Complete recovery within 4 days
69-year-old female, bipolar disorder [30] / 750mg/day for 4 days / 107 µg/ml
(710 µmol/L) / 143 µmol/L / Sertraline, alprazolam, trimipramine, meclizine hydrochloride, trazadone, clonidine / Lethargy, coma / Discontinue VPA and all psychiatric medications, administer naloxone and lactulose / Complete recovery within 5 days
41-year-old male, bipolar disorder [31] / Dose not reported for 3 years / 73.5 µg/ml
(487 µmol/L) / 377 µmol/L / Acebutolol, hydrochlorothiazide, ibuprofen, haloperidol, benztropine, gemfibrozil, lorazepam, multivitamins / Inappropriate behavior, increased somnolence, emesis / Discontinue VPA, administer activated charcoal with sorbitol, L-carnitine and lactulose / Complete recovery within 4 days
53-year-old male, bipolar disorder [21] / Unknown dose for unknown duration (dose increased to 1000mg/day 2 days prior ) / Reported to be ‘normal’ / 95 µmol/L / None / Ataxia, confusion, disturbed sleep / Discontinue VPA / Complete recovery after 3 days
60-year-old male, bipolar disorder [21] / 1000mg/day for 1 month / Reported to be ‘normal’ / 150 µmol/L / None / Vomiting, generalized weakness, disorientation / Discontinue VPA / Complete recovery within 3 days
76-year-old male, bipolar disorder [32] / 3000mg/day for 11 years / 73 µg/ml
(483 µmol/L) / 214 µmol/L / Quetiapine, primidone, metoprolol, atorvastatin, lisinopril, levothyroxine, aspirin / Confusion, lethargy / Discontinue VPA and primidone, administer lactulose / Complete recovery within 3 days
29-year-old female, bipolar disorder [33] / 1000mg/day for 5 months, increased to 1500mg/day 17 days prior / 113 µg/ml
(748 µmol/L) / 182 µmol/L / Fluvoxamine, clonazepam / Slurred speech, ataxia, confusion / Discontinue VPA / Complete recovery within 3 days
38-year-old female, bipolar disorder [34] / 1000mg/day for 6 months / 73 µg/ml
(483 µmol/L) / 101 µmol/L / Venlafaxine, L-thyroxine, lithium / Cognitive slowing, lethargy / Administer carnitine / Complete recovery after 2 weeks
53-year-old female, bipolar disorder and alcohol dependence [35] / 1500mg/day for 5 days then 1750mg/day for 7 days / 107 µg/ml
(708 µmol/L) / 79 µmol/L / Haloperidol, benztropine / Confusion, lethargy / Reduce VPA to 750mg/day / Complete recovery within 2 weeks
35-year-old male, bipolar disorder and alcohol dependence [36] / 1500mg/day for 5 years / 100 µg/ml
(662 µmol/L) / 83 µmol/L / Temazepam, lorazepam / Loss of consciousness / Discontinue VPA / Complete recovery after 3 days
33-year-old female, bipolar disorder [37] / 1500mg/day for 2 days / 120 µg/ml
(794 µmol/L) / 283 µmol/L / Clonazepam, venlafaxine, mirtazapine, bupropion, hydroxyzine / Lethargy, reduced level of consciousness / Discontinue VPA and all medications, administer carnitine and lactulose / Complete recovery within 4 days
47-year-old female, bipolar disorder [38] / 2000mg/day for 5 years, 2500mg/day for 7 months / 83.5 µg/ml
(553 µmol/L) / 48 µmol/L / None / Confusion, memory loss, apathy, parkinsonism / Discontinue VPA / Complete recovery within 1 week
49-year-old female, bipolar disorder [39] / 1000mg/day for 7 days / 84 µg/ml
(556 µmol/L) / 59 µmol/L / Zotepine / Unsteady gait, sleepiness / Reduce VPA to 500mg/day, then discontinue, administer lactulose / Complete recovery within 7 days
29-year-old male, bipolar disorder [40] / Intentional overdose of 4000mg VPA / 5469 µmol/L / 348 µmol/L / Diazepam / Reduced level of consciousness, agitation, unsteadiness, vomiting / Discontinue VPA, administer mannitol / Incomplete recovery after 150 days
57-year-old female, bipolar disorder [41] / Not reported / 67 µg/ml
(444 µmol/L) / 79 µmol/L / Clonazepam / Slurred speech, ataxia, coma / Discontinue VPA / Complete recovery within 5 days
50-year-old female, schizoaffective disorder [42] / 1250mg/day for 4 years / 101 µg/ml
(669 µmol/L) / 242 µg/dl
(142 µmol/L) / Lamotrigine, quetiapine, lorazepam / Loss of consciousness, incontinence, tremor / Discontinue VPA, administer lactulose / Complete recovery within 3 days
45-year-old female, schizoaffective disorder [43] / 1000mg/day for 3 weeks / 114 µg/ml
(755 µmol/L) / 445 µg/dl
(261 µmol/L) / Carbamazepine, risperidone, fluphenazine, quetiapine, furosemide / Confusion, agitation, reduced level of consciousness, seizure / Discontinue VPA, administer lactulose / Complete recovery within 4 days
23-year-old male, schizoaffective disorder and substance abuse [35] / 1500mg/day for 2 weeks / 70 - 80 µg/ml
(463 – 530 µmol/L) / 193 µmol/L / Olanzapine / Lethargy, bizarre speech, confusion / Discontinue VPA and administer lactulose / Complete recovery after several weeks
21-year-old female, schizoaffective disorder [44] / 500mg/day titrated up to 750mg/day within 4 days / 108 µg/ml
(715 µmol/L) / 228 µg/dl
(134 µmol/L) / Amisulpride / Nausea, vomiting, drowisness, disorientation, ataxia / Discontinue VPA, administer lactulose / Complete recovery within 1 week
51-year-old female, post traumatic stress disorder [33] / 1000mg/day for 7 days / 145 µg/ml
(960 µmol/L) / 232 µmol/L / Topiramate, quetiapine / Reduced level of consciousness / Discontinue VPA, administer L-carnitine / Complete recovery after 4 days
24-year-old female, borderline personality disorder and depression [34] / 1000mg/day for 60 days / Not reported / 102 µmol/L / Sertraline, tranylcypramine, liothyronine, thioridazine, clonazepam / Fatigue, lethargy, nausea / Discontinue VPA, administer carnitine / Complete recovery after 10 days
42-year-old male, psychotic depression [45] / Day 1 500mg/day, day 2 1000mg/day, day 3-7 1500mg/day / 102 µg/ml
(675 µmol/L) / 96 µg/dl
(57 µmol/L) / Amitriptyline, flupentixol, mirtazapine, lithium, risperidone, clomipramine / Sedation, tremor, myoclonus / Discontinue VPA / Complete recovery within 2 weeks
79-year-old male, paranoid schizophrenia and seizure disorder [46] / 2250mg/day for 2 days / 48.5 µg/ml
(321 µmol/L) / 89 µmol/L / Olanzapine, phenytoin, amlodipine, finasteride, risderonate, aspirin / Lethargy, confusion, disorientation / Discontinue VPA, administer lactulose / Complete recovery after 2 days
41-year-old male, schizophrenia [39] / 1500mg/day for 21 days / 125 µg/ml
(828 µmol/L) / 182 µmol/L / Zotepine / Loss of consciousness / Discontinue VPA and all medications / Complete recovery within 2 days
38-year-old female, mental retardation and aggression [47] / 1500mg/day for 18 years / 91 µg/ml
(602 µmol/L) / 130 µmol/L / Quetiapine, fluoxetine, fluphenazine / Unsteady gait, sedation / Reduce VPA to 1000mg/day / Complete recovery within 2 weeks
51-year-old female, benzodiazepine and heroin dependence [48] / 750mg/day for 3 days / Not reported / 65 µmol/L / Alprazolam, methylphenidate, fluoxetine, buproprion, levothyroxine, atenolol, haloperidol / Hallucinations, dizziness / Discontinue VPA, administer lactulose / Complete recovery after 6 days
49-year-old female, benzodiazepine and alcohol dependence [48] / 750mg/day for 2 days / Not reported / 50 µmol/L / Citalopram, lorazepam / Confusion, hallucinations, unsteady gait, agitation, delusional / Discontinue VPA, administer lactulose / Complete recovery after 9 days
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