Neurology -- Correspondence for Limdi et al., 64 (2) 353-355

Correspondence published:

Efficacy of rapid IV administration of valproic acid for status epilepticus: Andrea O. Rossetti, Edward B. Bromfield (15 March 2005)

Reply to Rossetti et al: Nita A Limdi, Faught Edward, Burneo Jorge (15 March 2005)

Efficacy of rapid IV administration of valproic acid for status epilepticus 15 March 2005

Andrea O. Rossetti,
Division of Epilepsy, Department of Neurology
Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115,
Edward B. Bromfield
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Re: Efficacy of rapid IV administration of valproic acid for status epilepticus

arossetti{at}partners.org Andrea O. Rossetti, et al.

We read the paper by Limdi et al with interest.[1] It confirms that intravenous valproic acid (VPA) is efficacious in status epilepticus (SE), and well tolerated with respect to the cardiovascular system. As noted by the authors, similar safety was previously reported by others. Intravenous VPA has been used safely in critically ill hypotensive patients [2] and pediatric subjects. [3] It is also efficacious in various SE forms including generalized convulsive [2,3], complex-partial [3], and myoclonic [4]. Limdi et al interestingly report very high VPA dosages (up to 78 mg/kg), used not only safely but “successfully” as defined by cessation of SE. However, a critical parameter in the evaluation of SE treatment is the final outcome of the patients (i.e., mortality). Although many factors can contribute to a fatal outocme in this setting, it would be of interest to see how mortality in this fairly large series compares to studies using other antiepileptic drugs.
Another important issue is the possibility of inducing a VPA- hyperammonemic encephalopathy after rapid intravenous VPA loading. This may be important in clinical practice because this condition can be extremely difficult to differentiate from a prolonged postictal state or ongoing nonconvulsive SE. [5]
One of us recently observed two episodes of encephalopathy within 24 to 48 hours after intravenous VPA treatment of complex partial SE, despite VPA blood levels within the usual therapeutic range. The diagnosis was made by EEG analysis, showing monotonous background delta-theta slowing and determination of serum ammonia, which was elevated up to twice the normal limit in both patients. The condition reversed after the VPA dosage was lowered. Interestingly, both patients had widespread structural brain damage (stroke, abscess). This entity may be unrecognized if one solely relies on clinical response to pharmacologic treatment, as may have been the case for some of the patients of Limdi et al. [1]
We suggest that the risk of VPA-encephalopathy should be considered when high doses of valproate are used. We believe that there is a need to routinely assess post-treatment EEG and ammonia levels in clinical studies focusing on intravenous VPA treatment of SE. Furthermore, platelets monitoring may also be of interest.
References
1. Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;64:353-355.
2. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722-724.
3. Yu KT, Mills S, Thompson N, Cunan C. Safety and efiicacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003;44:724-726.
4. Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000;54:1201.
5. Vossler DG, Wilensky AJ, Cawthon DF, et al. Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy. Epilepsia 2002;43:154-159.
The authors report no conflicts of interest.

Reply to Rossetti et al 15 March 2005

Nita A Limdi,
University of Alabama at Birmingham
1719 6 th Avenue South, Birmingham AL 35294-0021,
Faught Edward, Burneo Jorge
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Re: Reply to Rossetti et al

nlimdi{at}uab.edu Nita A Limdi, et al.

We appreciate the comments of Rossetti et al. In addressing the issue of mortality, we do not recommend comparing survival across studies using other AEDs since no head-to-head comparisons are available and no control group was used in our study. However, survival in our cohort was 65% (n=41). Mortality (n=22) was unrelated to AED use but actually due to the underlying morbidity (cardiopulmonary arrest: n=8, subdural hematoma: n=1, ischemic stroke: n=4, ICH w herniation: n=1, respiratory failure: n=2, AMI: n=1, sepsis: n=5). [1]
In this retrospective cohort, ammonia levels were not measured systematically in all patients. Although physicians discontinued valproate (VPA) therapy in two cases because of high ammonia levels, these two patients were not clinically encephalopathic. [1] We did not observe any case of hyperammonemic encephalopathy among our patients but acknowledge that this can occur with valproate. We do not agree with Rossetti et al that clinical studies focusing on IV VPA for the treatment of SE should routinely involve post-treatment EEG in all patients to diagnose VPA encephalopathy. EEG monitoring should be reserved for confirmation of efficacy and to rule out encephalopathy or continued seizures in patients who become or remain unresponsive.
It should be noted that VPA could also produce an encephalopathy in the presence of normal ammonia levels. [2] Routine monitoring of ammonia levels after VPA infusion in clinical practice is not necessary unless the patient becomes or remains encephalopathic. Furthermore, in an encephalopathic patient, although one can consider high ammonia level a causative factor, it may be irrelevant. Other possible causes including concurrent drug therapy, comorbidity and diet should also be considered. [3-7]
Monitoring of ammonia levels in clinical studies of VPA to ensure that the increase (if any) is transient is recommended. Unpublished data from an ongoing prospective study (n=36) with rapid infusion of VPA (20 or 30 mg/kg) indicate that hyperammonemia is common but transient. Ammonia levels rise at 60 minutes post infusion and decline towards baseline at 24 hours. None of the patients receiving IV VPA had a decline in level of consciousness (LOC) at 60 minutes or 24 hours (as measured by the NIH stroke scale LOC tool). Although platelet counts were unchanged over 24 hours, monitoring platelets could help detect a dose-dependent adverse effect of VPA, which is usually reversed with dose reduction.
References
1. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo JG. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005;64:353-355.
2. Vossler DG. Wilensky AJ. Cawthon DF. Kraemer DL. Ojemann LM. Caylor LM. Morgan JD. Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy. Epilepsia. 43:154-9, 2002 Feb.
3. Burneo JG. Limdi N. Kuzniecky RI. Knowlton RC. Mendez M. Lawn N. Faught E. Welty TE. Prasad A. Neurotoxicity following addition of intravenous valproate to lamotrigine therapy. 60:1991-2, 2003 Jun 24.
4. Solomon GE. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology. 55:606, 2000 Aug 22
5. Hamer HM. Knake S. Schomburg U. Rosenow F. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology. 54:230-2, 2000 Jan 11.
6. Oechsner M. Steen C. Sturenburg HJ. Kohlschutter A. Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. Journal of Neurology, Neurosurgery & Psychiatry. 64:680-2, 1998 May
7. Gidal BE. Inglese CM. Meyer JF. Pitterle ME. Antonopolous J. Rust RS. Diet- and valproate-induced transient hyperammonemia: effect of L- carnitine. Pediatric Neurology. 16:301-5, 1997 May.