An Interesting Case of Encephalopathy

Dr. Kishore Chandki

Registrar, PICU & SCBU
March 25, 2006, C.N.B.C.; Indore

An Interesting Case of Encephalopathy

A 10 yr old female child r/o Indore admitted with c/o Cough & Cold Fever mild Reduced appetite X 5 days X 5 days X 4 days

Pain in abd. & loose motions 4-6/day

Reduced consciousness

X 2 days
X 1 day

H/O similar illness : cough, cold, reduced oral acceptance & reduced consciousness a year back!

An Interesting Case of Encephalopathy

O/E : Weight 21 kg, Obtunded, responding to voice commands Temp. 100F, Pulse 110/min, RR 34/min, BP 110/80 mmHg Pharyngeal mucosa : congested, Skin turgor : reduced No signs of meningism or CN palsy, DTR not elicitable Rest of systemic examination was unrewarding! Child was a k/c/o CP Epilepsy with mild-moderate MR & was receiving Valproate (@20mg/kg/d) & Clobazam for last 3 yrs. No h/o drug default, or epilepsy in family. ?Seizure free for past 2 yrs.

An Interesting Case of Encephalopathy

MRI brain 7 months back revealed no significant abnormality & EEG showed generalized activity (?drug induced / anxiety related) Child receiving syr. Enhancin DS & Ibugesic plus prior to hospitalization Workup a day before hospitalization : Hb : 10.3 gm/dL TLC : 7900, P70L26E1M3

SGPT : 19.7 U/L

RBS : 73.9 m/dL CXR : Normal

An Interesting Case of Encephalopathy

IV cannula was put, samples taken, maintenance fluid (Electrolyte P with D10W) & antibiotic (IV Augmentin) started. Child had deteriorating sensorium, falling BP within an hour of hospitalization.

RBS by Glucometer was HIGH (>600 mg/dL)

Child received fluid resuscitation, after which BP was 90/64

DDx : 1. DKA : Clues from Hx

2. Hyperosmolar state 3. ?

An Interesting Case of Encephalopathy

Repeat RBS was 452 mg/dL, ABG revealed pH 7.416, pO2 68, pCO2 47, HCO3- 30. Urine showed sugar 1+, ketones traces. Fundus WNL Serum electrolytes & calcium were within normal limits Repeat RBS was 236 mg/dL, BP 105/73

TLC: 9300, P57L40,E1,M2, MP by QBC negative

Subsequent RBS was 86 mg/dL, BP normal, off O2 Child hemodynamically stable wihin hours, afebrile, remaining dull & sleepy all the time! HbA1c was 7.9% (Normal Value <6.9%)

An Interesting Case of Encephalopathy

A 10 yrs old underweight female k/c/o CP epilepsy with mild to moderate mental retardation, on valproate & clobazam, ?well controlled seizures, who presented with altered sensorium, falling BP, revived on fluid resuscitation. Had normal subsequent RBS & ABG, raised HbA1c. Remaining dull & sleepy all the time. Serum electrolytes, calcium, SGPT normal, no obvious reason!

An Interesting Case of Encephalopathy

Serum ammonia after 48 hrs of hospitalization was 125 g/dL (reference range: 3086 g/dL) In view of this, a Dx of Valproate induced hyperammonemia with ?Glucose intolerance was made Valproate discontinued, Inj. Carnitine & Lactulose was started Child showed dramatic improvement, shifted to ward after 24 hrs & discharged next day with advice of GTT & workup for IEM on follow up!

An Interesting Case of Encephalopathy

Final Diagnosis : Metabolic encephalopathy : Hyperammonemic Encephalopathy ? Valproate Induced (VHE) ?? Mitochondrial disorder/ Other metabolic disorder e.g. OTC deficiency Precipitating illness : ARI

Valproate Induced Hyperammonemia

Extremely rare complication May occur at therapeutic levels

Also in a prior history of good response to drug

Typically seen in rare urea cycle enzyme deficiency LFTs are normal Associated with hypocarnitinemia Can result in cerebral edema & cortical blindness This case exemplifies the relationship between valproate use and liver function, ammonia levels, and cognitive status!

JCPSP 2005, Vol. 15 (9): 571-572

Valproate Induced Hyperammonemia

Malaise, lethargy, and mental slowing, which may progress to marked sedation, altered mental status, coma, and even death. Hyperammonemia may occur at NORMAL therapeutic valproate blood levels in the absence of any other laboratory abnormalities, making it less obvious to treating physicians relying on conventional serum levels or liver assays.

Neurology, Vol 31, Issue 9 1173-1174

Valproate Induced Hyperammonemia

Factors implicated :
Children < 2 yrs

Urea cycle defects, e.g. OTC def

Renal failure Hypoalbuminemia Concomitant adm of topiramate*, cimetidine & aspirin : free valproate

Concomitant adm of Phenytoin, Phenobarbitone

Neurology, August 22, 2000; 55(4): 606 - 606

Valproate Induced Hyperammonemia

Measures :
Take precaution while on polytherapy

Always rule out metabolic disorders esp. urea cycle defect when using in infants
Monitor serum ammonia if using in neonates, asymptomatic elevations Have high index of suspicion whenever a child on valproate has unexplained lethargy, vomiting or changes in mental status L-Carnitine supplementation 50-100 mg/kg/d in those at risk of hepatotoxicity or significant in serum free carnitine levels measured periodically Neurology India 53:2,226-228 2005

Valproate Induced Hyperammonemia

Measures :
Patient Info.:

Notify physician if nausea, vomiting, unexplained lethargy, change in mental status, general feeling of weakness, loss of appetite, abdominal pain! Increased seizure frequency previously well controlled with same dose of valproate

Nephrol Dial Transplant (2002) 17: 1351-1353

Valproate Induced Hyperammonemia

Management : Reduce the dose or stop valproate

Reduce protein intake, glucose & lipids to ameliorate catabolism

L-Carnitine supplmentation

IV Sodium benzoate, sodium phenylacetate & Larginine

Little role of lactulose

Hemodialysis

Am J Psychiatry 154:8, August 1997

Valproate Induced Hyperammonemia

Drugs causing Hyperammonemia :
Valproate alone or with other AEDs

Haloperidol
Salicylate intoxication (~Reye syndrome, NH3 & respiratory alkalosis)

High dose chemotherapy e.g. 5 - Fluorouracil

Am J Psychiatry 154:8, August 1997

Valproate Induced Hyperammonemia

Conclusion
Reliance on conventional assays may produce a false sense of security, because Valproate has been linked to Hyperammonemia and altered mental status in the context of normal LFTs. The importance of this life threatening condition should be well emphasized!

Thanks

Courtesy : Dr. Umesh Kataria Dr. Rachana Gupta