Valproate-induced hyperammonaemia superimposed upon severe neuropsychiatric lupus: a case report and review of the literature
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- Chan, E. & McQueen, F. Clin Rheumatol (2013) 32: 403. doi:10.1007/s10067-012-2150-x
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This paper presents a case of systemic lupus erythematosus (SLE) with neuropsychiatric features, where the outcome was influenced by the development of hyperammonaemia, probably induced by sodium valproate. A case of severe SLE occurring in a 20-year-old Maori girl is described. Her disease had been characterised by neuropsychiatric features for several years, culminating in persistent seizure activity at the time of her final presentation. Her management with anticonvulsants was complicated by the development of intractable hyperammonaemia which contributed to irreversible clinical deterioration. We have reviewed the English literature for reports of valproate-related hyperammonaemia which has often been described in the setting of seizure and mood disorders. This is the first case where it has been reported, superimposed upon severe neuropsychiatric SLE (NP-SLE). The mechanism by which valproate induces hyperammonaemia remains incompletely understood but is likely to relate to the urea cycle. Under normal metabolic conditions, acyl-CoA is transported into the mitochondria via a carnitine transport system. It is then converted to acetyl-CoA via β-oxidation and eventually to N-acetyl glutamate. This pathway can be interrupted by the introduction of sodium valproate, leading to a reduction of free coenzyme A, acetyl-CoA and carnitine, and resulting in the decreased availability of cofactors necessary for the function of the urea cycle. As this is the primary means of ammonia metabolism, serious elevation in serum ammonia levels may occur in patients on this anticonvulsant medication. In this patient with active NP-SLE, the combined autoimmune and metabolic brain insult contributed to a fatal outcome.
KeywordsAnticonvulsants Hyperammonaemia Sodium valproate Systemic lupus erythematosus
A 20-year-old Maori woman with a 5-year history of systemic lupus erythematosus (SLE) was transferred to our hospital with persistent polyarthritis despite aggressive immunosuppressant therapy. She first presented to a peripheral hospital 5 years before, when a diagnosis of SLE was made based on malar rash, cutaneous vasculitis, positive antinuclear antibody titre (1:640), positive anti-Smith antibody, leukopenia and lymphopenia. She was treated with prednisone and hydroxychloroquine but 1 year later developed worsening renal function (creatinine 130 μmol/L, normal range 90–110 μmol/L), with proteinuria (190 mg/24 h). Renal biopsy confirmed diffuse proliferative glomerulonephritis (Type IV, WHO classification) . This was managed with azathioprine and high-dose prednisone. The following year, she represented with left arm weakness, ataxia and intention tremor with raised anti-double-stranded DNA antibodies of >80 IU (<25) and hypocomplementemia. Magnetic resonance imaging (MRI) brain scan revealed T2-weighted hyperintensities within the basal ganglia consistent with neuropsychiatric SLE (NP-SLE). She received pulsed intravenous (IV) methylprednisolone and IV cyclophosphamide with rapid resolution of symptoms.
The current presentation was with 6 months of persistent small and large joint polyarthritis, associated with raised inflammatory markers (C-reactive protein 145 g/L) but with normal renal function (creatinine 65 μmol/L). Multiple blood and joint fluid cultures did not reveal infection. On the assumption that polyarthritis was attributable to active SLE, she received two doses of 500 mg IV cyclophosphamide and three doses of 1 g IV methylprednisolone. However, improvement was minimal, and she was transferred to our hospital for further management. Shortly after admission, she had a witnessed neurological event with an impaired level of consciousness, incontinence of urine, forced rotation of the head to the right and eye deviation to the right, suggesting a complex partial seizure. She was transferred to the Department of Critical Care Medicine for airway management.
Drug therapy included loading doses of sodium valproate (800 mg IV stat and further 800 mg 12 h later) to suppress seizures plus rituximab (1 g with 100 mg of IV methylprednisolone), hydroxychloroquine and prednisone due to clinical suspicion of NP-SLE. A CT scan and later MRI scan of the brain did not reveal localising pathology. There was no evidence of antiphospholipid antibody (APLA) syndrome, including a negative lupus anticoagulant screen and normal anti-cardiolipin IgG. Cerebrospinal fluid assessment revealed raised protein (0.74 g/L), but there was no growth. Electroencephalography (EEG) initially identified a generalised excess of slow wave activity, indicating a moderately severe encephalopathy but no seizure activity. A repeat EEG 2 days later revealed ongoing excess slow wave activity, but there was a new finding of multiple electrographic seizures arising independently over the posterior regions of both hemispheres. Given ongoing unexplained encephalopathy, a serum ammonia level was requested. This was elevated at 405 μmol/L (normal 0–50 μmol/L) with otherwise normal hepatic function and no evidence of a gastrointestinal bleed. Peak valproic acid level was 434 μmol/L (therapeutic range 350–700 μmol/L). Her hyperammonaemia became intractable with levels rising to >1,000 μmol/L despite pharmacotherapy with sodium benzoate, arginine, sodium phenyl butyrate, N-acetyl cysteine and haemofiltration. Respiratory function deteriorated with preterminal features of adult respiratory distress syndrome and Haemophilus influenzae bronchopneumonia. She died 7 days after admission.
The American College of Rheumatology classification criteria for SLE includes 19 neuropsychiatric syndromes . The diversity of NP manifestations suggests multiple pathogenic mechanisms. Post-mortem studies have identified a non-inflammatory vasculopathy with microinfarction as the dominant neuropathological finding, and this is entirely consistent with features described here [3, 4]. Generalized and focal seizures are reported in 6–51 % of SLE patients and may be related to the presence of anti-cardiolipin antibodies with associated microangiopathy, arterial thrombosis and cerebral infarction [5, 6]. This may occur in the absence of a formal diagnosis of APLA syndrome, and toxicity to the vascular endothelium may be pivotal. Another theory proposes the importance of anti-NR2 glutamate receptor antibodies in NP-SLE, causing excitotoxic neuronal death via N-methyl-d-aspartic acid receptors [5, 7].
Summary of reported cases of valproate-induced hyperammonaemia
Age range (years)
Valproic acid dose range and duration range
Peak valproic acid level range (therapeutic 350–700 μmol/L)
Peak ammonia level range (normal 0–50 μmol/L)
250–6,500 mg/day for 2 days to 20 years
Confusion [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28], nausea/vomiting [8, 9, 12, 17, 23],ataxia [9, 12, 13, 21, 23, 27], tremor [12, 13, 16, 18, 23, 27], dyarthria/dysphasia [12, 18, 23, 25, 27]
33 Cases: complete recovery within 3 days to 3 months [8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28], 2 cases: incomplete recovery within 1 month [14, 18], 1 case: died 3 weeks later 
750–4,000 mg/day for 2 days to 11 years
750–1,500 mg/day for 4 days to 4 years
Complete recovery within 3 days to several weeks
Post traumatic stress disorder (1 case) 
1,000 mg/day for 7 days
Complete recovery within 4 days
24 and 42
1,000–1,500 mg/day for 7 –60 days
Complete recovery within 10 days to 2 weeks
Mental retardation (1 case) 
1,500 mg/day for 18 years
Complete recovery within 2 weeks
Benzodiazepine dependence (2 cases) 
49 and 51
750 mg/day for 2–3 days
Confusion, hallucinations, ataxia
Complete recovery within 6–9 days
Hyperammonaemia is most commonly caused by liver disease or inborn errors of metabolism . Less common causes include hyperinsulinaemic hypoglycaemia, carnitine deficiency such as in strict vegetarian diets, malignancies such as leukaemias and myelomas, portosystemic shunts, urinary infections, surgeries, parenteral nutrition and medications like 5-fluorouracil, salicylate, asparaginase, acetazolamide, diuretics and valproic acid . VPA-induced hyperammonaemia has been observed both in the presence or absence of clinical symptoms and even in the context of VPA levels within reference ranges [29, 49]. There is also no correlation between the level of hyperammonaemia and the severity of the clinical condition . Concomitant administration of antiepileptic medications such as phenytoin, phenobarbital and topiramate may increase the risk of hyperammonaemia [14, 27, 28]. Clinical features in symptomatic cases are often variable and episodic, with the most common presenting complaints being acute mental status changes, ataxia, nausea and vomiting and coma in severe encephalopathy, as was demonstrated by our case and in Table 1 [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48]. Although most patients achieved complete recovery without lasting neurological deficits, VPA-induced hyperammonaemia can lead to death, making this an important entity to recognise.
The mechanism of VPA-induced hyperammonaemia is incompletely understood but is thought to be related to the urea cycle [14, 25]. Under normal metabolic conditions, acyl-CoA is transported into the mitochondria via a carnitine transport system. It is then converted to acetyl-CoA via β-oxidation, and eventually to N-acetyl glutamate. This pathway can be interrupted by the introduction of sodium valproate, which combines with coenzyme A, forming valproyl-CoA . This leads to a reduction of free coenzyme A, acetyl-CoA and carnitine, resulting in the decreased availability of cofactors necessary for the function of the urea cycle and an increase in ammonia production . Hyperammonaemia can then cause encephalopathy by inhibition of glutamate uptake by astrocytes [12, 49]. The raised glutamine levels increase intracellular osmolarity, with the consequent entry of water into the astrocytes, leading to cerebral oedema and increased intracranial pressure . While genetic deficiencies may increase the risk of VPA-induced hyperammonaemia, this condition may occur even in their absence . Investigations in our case did not reveal an underlying enzymatic cause.
Definitive management of VPA-induced hyperammonaemia requires discontinuation of VPA . Supportive care in the form of mechanical ventilation, hydration and high caloric/protein-free diet may be helpful . Pharmacological treatments including sodium benzoate and sodium phenylacetate have been tried, and these worked by converting ammonia to an excretable compound [10, 25]. Lactulose is most commonly employed, and it works by enhancing the conversion of ammonia (NH3) to ammonium (NH4+), thus inducing an osmotic effect in the colon . Carnitine supplementation has been used to correct carnitine deficiency states by providing the mitochondria with acyl compounds necessary to overcome the interruption caused by VPA metabolism [34, 50]. Haemodialysis is an option only in VPA overdose whereby the VPA level is supratherapeutic . However, at therapeutic doses, VPA is highly bound to plasma proteins, and there is no accessible unbound VPA for haemodialysis to remove . This may explain the failure of haemodialysis in correcting hyperammonaemia in our patient.
In summary, we present a case of fulminant NP-SLE occurring in a young woman of Maori ethnicity. Clinical seizure activity was associated with post-mortem findings of a diffuse cerebral vasculopathy. Treatment of seizures resulted in the complication of VPA-induced hyperammonaemia and encephalopathy. The combination of autoimmune and metabolic brain insult ultimately resulted in her demise.