REVIEW

Hyperammonemia encephalopathy: An important cause of neurologicaldeterioration following chemotherapy

LOUISE NOTT1, TIMOTHY J. PRICE1, KEN PITTMAN1, KEVIN PATTERSON1, &

JANICE FLETCHER2

1Department of Oncology, The Queen Elizabeth Hospital, Woodville 5011, Australia and 2Department of Biochemistry,

Women’s and Children’s Hospital, Adelaide 5000, Australia

(Received 6 June 2007; accepted 10 June 2007)

AbstractIdiopathic hyperammonemic encephalopathy is an uncommon but frequently fatal complication of chemotherapy. It ischaracterised by abrupt alteration in mental status with markedly elevated plasma ammonia levels in the absence of obviousliver disease or any other identifiable cause, and frequently results in intractable coma and death. It usually occurs in patientswith haematologic malignancies during the period of neutropenia following cytoreductive therapy or bone marrowtransplantation, and in solid organ malignancies treated with 5-fluorouracil. Although the aetiology of this syndrome is yet tobe determined, it appears to be multi-factorial in nature. Optimal management remains to be formally established, and thecritical step is increased awareness of the syndrome by measurement of plasma ammonium levels in patients withneurological symptoms, leading to early diagnosis and the prompt implementation of therapy.

Keywords: Hyperammonemia, encephalopathy, chemotherapy

Introduction

Ammonia, the major nitrogenous product of protein

catabolism, is a highly toxic compound, particularly

to the brain. When blood concentrations of ammonia

are sufficiently elevated, cerebral oedema, altered

mental status, seizures, coma and death can ensue.

Hyperammonemia occurs when ammonia is either

overproduced or insufficiently cleared from the

serum. Ammonia is not secreted directly by the renal

tubules; instead the urea cycle (Krebs-Henseleit urea

cycle) converts it to a non-toxic compound excre-

table in the urine. The six enzymes involved in the

detoxification of ammonia by the urea cycle are

complete only in the normal liver and include:

N-acetylglutamate synthetase (NAGS), carbamyl

phosphate synthetase (CPS 1), ornithine transcar-

bamylase (OTC), argininosuccinate synthetase

(ASS), argininosuccinate lyase (ASL), and arginase

(Figure 1). Most of the endogenous ammonia is

generated from the breakdown of luminal products

and amino acids in the large intestine. The kidneys,

small bowel, and skeletal proteins can be important

sites of ammonia synthesis as well [1].

The term hyperammonemia designates a constel-

lation of clinical aetiologies that all have an elevation

of blood ammonia concentration as a common

element (Table I). These aetiologies can be either

congenital (primary) or acquired (secondary), and

can occur across the age spectrum. Nonetheless,

when hyperammonemia supervenes, the encephalo-

pathy syndrome that ensues is common to all.

Primary causes include congenital enzymopathies in

the urea cycle, which can lead to varying degrees of

hyperammonemia depending on the enzyme affected

and on whether the genetic deficiency is hetero-

zygous or homozygous. Secondary hyperammonemia

is well documented to occur in the presence of

hepatic disorders leading to portosystemic encepha-

lopathy [2]. It can, however, occur in the absence of

liver dysfunction in disorders including Reyes syn-

drome associated with salicylate administration [3],

Correspondence: Timothy Price, Department of Oncology, The Queen Elizabeth Hospital, Woodville Road, Woodville, South Australia 5011, Australia.

E-mail: timothy.price@nwahs.sa.gov.au

Leukemia & Lymphoma, September 2007; 48(9): 1702 – 1711

ISSN 1042-8194 print/ISSN 1029-2403 online � 2007 Informa UK Ltd.

DOI: 10.1080/10428190701509822

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

uretosigmoidostomy [4], and infection in a neuro-

genic bladder [5]. Disruption of mitochondrial

pathways owing to drug toxicities from cyanide,

valproic acid, iron, and cytotoxics can also result

in secondary hyperammonemia [6 – 10]. Hyperam-

monemic encephalopathy (HE) is also a rare

complication of malignancies, with and without

chemotherapy. It has occurred with an array of

different chemotherapeutic agents including cytara-

bine, vincristine, amsacrine, etoposide, L-asparagi-

nase, cyclophosphamide, 5-fluorouracil in various

combinations. HE has complicated the course

of many malignancies including acute leukaemia,

multiple myeloma, lymphoma and solid organ

tumours [11]. It has also been observed in haema-

tological malignancies following bone marrow

transplantation and solid organ transplantation

[9,12 – 15]. Accordingly, it is of vital importance

that clinicians are aware of the clinical findings

seen in hyperammonemia as early recognition and

appropriate treatment is critical to optimum outcome.

Clinical presentation

Idiopathic HE is a diagnosis made in the presence of

an elevated serum ammonia level, normal or mildly

Figure 1. Simplified version of the urea cycle. Enzymes and reactions inside the blue ellipse occur within the mitochondrial matrix. The urea

cycle converts nitrogen, derived from dietary protein intake and the breakdown of endogenous protein (catabolism), into urea, which can be

excreted from the body. The steps of this cycle, and the six enzymes involved, are indicated in red. The dashed arrow depicts the overflow of

excess carbamoyl phosphate into pyrimidine synthesis and hence, to orotic acid, which is excreted in the urine. NAGS, N-acetylglutamate

synthetase; CPS-1, carbamylphosphate syntheatse 1; OTC, ornithine transcarbamoylase; ASS, argininosuccinate synthetase; ASL,

argininosuccinate lyase; ARG-1, arginase.

Chemotherapy, hyperammonemia and encephalopathy 1703

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

abnormal liver function tests, respiratory alkalosis,

neurological deterioration of no other obvious

aetiology and essentially normal plasma amino acid

levels, ruling out urea cycle disorders [13]. The

amino acid glutamine may be elevated if hyperam-

monemia has been present for some time. Other

metabolic or physical factors that may have an effect

on the conscious state, such as hyperglycaemia,

hypoglycaemia, azotemia, hepatic failure, electrolyte

imbalance, sepsis and central nervous system in-

volvement by cancers, should be excluded before the

diagnosis of HE is made. Clinical signs of hyper-

ammonemia may occur at concentrations greater

than 1.5 times the upper limit of the normal range for

the laboratory and include a spectrum of progressive

lethargy, confusion, weakness, ataxia [9], agitation,

seizure, stupor, coma and death [12]. Elevated

plasma ammonia levels may also occur, not uncom-

monly, without clinical manifestations following

cytotoxic therapies as described by Xu et al. Hyper-

ammonemia was present in 40 of the 43 patients with

acute leukaemia post-chemotherapy. Despite this,

only six of these patients developed neurological

symptoms [16].

The interval between the development of HE and

the commencement of chemotherapy is variable [9],

ranging from a few hours to several days [11,12].

Most of the patients with haematologic malignancies

died during their episode of HE despite specific drug

therapy and haemodialysis, in contrast to the

reported 5-fluorouracil related cases where recovery

from the encephalopathy within a few days of specific

therapy was more likely [11,17]. It is not clear why

this difference in outcome is seen except that fewer of

the patients receiving 5-FU chemotherapy had

concurrent neutropenic sepsis.

5-FU had been used in combination with other

agents including folinic acid, mitomycin C, cisplatin

and bleomycin when associated with HE [11]. Acute

encephalopathy attributable to both continuous

infusion and bolus 5-fluorouracil (5-FU) has been

described [11,17,18]. Yeh and Cheng reported a

relatively high incidence of 5.7% (16 of 280) of

cancer patients treated with 24-h infusion of high

dose 5-FU (2.6 g/m2 per week) and leucovorin

(300 mg/m2 per week) (HDFL) [17]. None of the

patients had hepatic or renal dysfunction, nor did

they manifest symptoms typical of dihydropyrimidine

dehydrogenase (DPD) deficiency. The complication

was most frequently seen in patients with

gastric cancer (12.1%), followed by breast cancer

(4.3%) and colorectal cancer (2.4%) in their

series. More than 80% of the patients presented

with severe stupor or coma; in two patients these

symptoms were combined with seizure. The median

time of onset of encephalopathy was 19.5 h from the

start of the HDFL infusion and median duration of

encephalopathy was 15 h. Symptoms developed at

the first exposure to the drug in half the patients.

Eight (50%) patients exhibited diffuse slow waves or

intermittent theta waves on an electroencephalogram

consistent with a toxic or metabolic encephalopathy.

Development of hyperammonemia was found to

parallel the development of encephalopathy. All

patients with HE in this series survived. Lower doses

of infusional 5-FU have also been associated with

HE [18].

HE has been described infrequently in adult

patients after either autologous or allogeneic bone

marrow transplantation (BMT) for haematological

malignancies [9,12 – 15] and in a paediatric case

following an unrelated cord blood transplant for

mucopolysaccharidosis [19]. It has also been de-

scribed in the setting of a novel high dose regimen of

trastuzumab/docetaxel/melphalan/carboplatin che-

motherapy and autologous transplantation for ad-

vanced HER2þ breast cancer [12]. Neurological

complications following BMT are quite common,

with a reported incidence of approximately 37%

[20]. Infective and vascular complications are the

most important cause of neurological deterioration in

this situation; however, metabolic causes should also

be considered. More than 50% of the reported

Table I. Differential diagnosis of hyperammonemia – Primary and

secondary aetiologies.

Primary (congenital) aetiologies

1. Inborn errors of metabolism (urea cycle defects and organic

acidemias)

Secondary (acquired) aetiologies

1. Liver disease with porto-systemic shunting of blood

2. Gastrointestinal bleeding

3. Renal disease

4. Urinary tract infection with urease-producing organism (e.g.

Proteus mirabilis)

5. Ureterosigmoidostomy

6. Parenteral nutrition

7. Reye’s Syndrome

8. Chemotherapy (examples)

. 5-Fluorouracil

. Cytarabine

. L-asparaginase, etc.

9. Bone marrow transplantation

10. Solid organ transplantation

11. Drugs (examples)

. Valproic acid

. Barbiturates

. Narcotics

. Diuretics

. Alcohol

. Corticosteroids

. Salicylate intoxication

12. Severe muscle exertion/heavy exercise

13. Septic shock or neutropenic sepsis

1704 L. Nott et al.

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

transplant-related cases of HE have been fatal.

Mitchell et al. described nine cases, eight

after intensive cytoreductive therapy and the

ninth, 2 months after allogeneic BMT [9]. Only

three of them survived. The longest series of HE

was reported by Davies et al. from a 21-year

BMT database of 3358 patients [13]. They identified

12 patients (0.5%), 10 of whom died within a median

of 3.5 days after diagnosis of this complication,

despite dialysis and ammonia-trapping therapy.

The presentation in these patients was similar in all

cases, with mental changes such as confusion and

combativeness followed by features of progressive

encephalopathy.

HE has also been described following solid organ

transplantation including heart-lung and orthotopic

lung transplants [21,22]. Lichtenstein et al. retro-

spectively reviewed 145 patients who had undergone

orthotopic lung transplantation and found six had

developed hyperammonemia, all within 26 days of

transplantation [21]. The 30-day post-transplanta-

tion mortality rate was significantly higher for those

with hyperammonemia (67% vs. 17%, p¼ 0.01).

Situations causing a high nitrogen load (gastrointest-

inal complications and total parenteral nutrition),

concurrent medical stressors, primary pulmonary

hypertension and hepatic glutamine synthetase defi-

ciency were all risk factors for developing the

syndrome in this series.

Disturbances in the level of consciousness in

myeloma patients are not uncommon, but are more

often due to hypercalcemia or hyperviscosity than

HE. A few reports have documented hyperammone-

mia in patients with myeloma [23 – 27]. Hyperam-

monemia in multiple myeloma can be caused by the

following: (1) the presence of factors that induce

hyperammonemia in the patient’s plasma, (2) am-

monia production by myeloma cells, and (3) forma-

tion of portosystemic shunting resulting from plasma

cell infiltration of the liver [27]. HE in patients with

myeloma has occurred in newly diagnosed patients

or in those receiving cytotoxic therapy for their

disease. In many cases, the temporal relationship

between onset of symptoms and hyperammonemia

were close. Symptomatic improvement occurred

when serum ammonium levels declined, most

successfully achieved in the setting of chemotherapy-

sensitive disease. Martinelli et al. [23] described

three patients with rapidly progressive multiple

myeloma in whom hyperammonemia became

apparent only upon disease acceleration. They

suggested that most of the ammonia production is

due to more aggressive clones. A peculiar amino acid

metabolism has been suggested to exist in myeloma

cells, inducing hyperammonemia and serum amino

acid disturbance [24].

Pathophysiology/aetiology

The central nervous system appears to be the

principal site of life-threatening toxicity in the

syndrome [9,13,28,29 pp.1209 – 1211]. A complete

understanding of the pathophysiology that invariably

accompanies hyperammonemia has not yet been

achieved, despite determined efforts by many in-

vestigators. Raised intracranial pressure (ICP) and

cerebral oedema have been demonstrated in many of

the cases of HE described in the literature [9,13].

Post-mortem cerebral changes comprising flattened

cortical gyri, cerebellar tonsillar herniation, astrocytic

cell swelling and Alzheimer type II astrocytes have

been reported along with hepatic changes including

centrilobular microvesicular steatosis [2,22,28]. It is

suggested that the cerebral oedema may reflect the

osmotic effect of accumulated intracellular gluta-

mine, which is the primary metabolic product of

ammonia metabolism in the brain [2]. The enzyme

responsible for that metabolism, glutamine synthe-

tase (GS), is located primarily in astrocytes. Gluta-

mine has been shown to be elevated in the brain and

cerebrospinal fluid (CSF) in both clinical and

experimental disorders of hyperammonemia [29

pp.1211 – 1212,30]. It is likely that HE, like other

disorders marked by elevated plasma ammonia

concentrations, has a reversible stage of cerebral

changes followed by an irreversible stage where

severe brain damage from cerebral oedema has

already occurred. The development of irreversible

brain damage may relate to the duration as well as the

extent of elevated plasma ammonia concentrations,

emphasizing again the importance of early recogni-

tion and treatment.

The aetiology of chemotherapy induced HE also

remains obscure but does appear distinct from other

disorders associated with elevated plasma ammo-

nium levels. Plasma and urinary amino acid assays

have not suggested underlying enzymatic deficiencies

in the urea cycle as being a causal factor. In

particular, plasma arginine and citrulline levels and

urinary orotic acid levels remain normal. Deficiencies

of arginosuccinase, arginosuccinate synthetase, argi-

nase or ornithine transcarbamylase are therefore

unlikely etiologic factors in chemotherapy induced

HE cases [1]. Elevated levels of mercaptans and

short-chain fatty acids characteristic of patients with

hepatic encephalopathy have not been demonstrated

in chemotherapy induced HE [9]. Furthermore, in

most cases, post-mortem examinations have failed to

reveal ultra-structural liver changes characteristic of

Reyes syndrome.

A pharmacologic basis for the development of HE

in association with certain cytotoxic drugs has been

suggested. Asparaginase had been reported to cause

Chemotherapy, hyperammonemia and encephalopathy 1705

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

hyperammonemia in acute lymphoblastic leukaemia

by hydrolysing the amido group of asparagine and by

its glutaminase activity [8]. Ara-C undergoes deami-

nation in the liver, plasma and peripheral tissues,

thereby increasing ammonia production which may

partly explain its association with HE. 5-FU-induced

HE is thought to be related to the transient

accumulation of 5-FU catabolites in a short period

[18,31 – 33]. Koenig and Patel [31] proposed that

following high dose administration of 5-FU, a large

amount of fluoroacetate, the intermediate product,

directly inhibits the Krebs cycle (Krebs tricarboxylic

acid cycle) and in turn causes impairment in the

ATP-dependent urea cycle, resulting in transient

hyperammonemia which may lead to the spectrum of

neurological sequelae described.

The administration of chemotherapy in the ab-

sence of precipitating factors, however, does not

appear to be an independent risk factor for the

development hyperammonemia and ensuing ence-

phalopathy [34]. Certain catabolic conditions have

been recognised that increase the risk in patients

receiving chemotherapy, including azotemia, hepatic

dysfunction, body fluid insufficiency, steroids, bac-

terial infections, major gastrointestinal complications

and total parenteral nutrition [9,11]. Infection may

contribute to the development of hyperammonemia

by increasing tissue catabolism and causing prerenal

azotemia leading to an increased nitrogen load and

increased ammonia production. Our review of the

literature did not reveal any consistent pattern of

colonisation or infection. Of the seven patients who

developed HE post-HDFL chemotherapy reported

by Liaw et al., five had infections at that time [11].

These patients developed higher ammonia levels and

more rapid neurological symptoms compared to

those without concurrent infections.

There is some evidence to suggest that an acquired

reduction in hepatic glutamine synthetase activity

may also play a role in the pathogenesis of

hyperammonemic coma [35]. Most of the ammonia

that escapes the urea cycle is incorporated into

glutamine by glutamine synthetase (GS), which is

located in pericentral hepatocytes [36,37]. Gluta-

mine levels are elevated in infants and children with

hyperammonemia secondary to congenital urea cycle

enzyme defects and would be expected to be elevated

in other causes of hyperammonemia. However, in

many of the reported cases of HE in the setting of

chemotherapy or transplantation, glutamine levels

were either inappropriately normal or only slightly

elevated [9]. A marked reduction in hepatic GS

activity and levels of GS protein were detected in two

patients with HE post-lung transplantation [38].

This reduction suggested that a secondary acquired

hepatic GS deficiency may play a role in the

pathogenesis of HE perhaps by allowing more waste

nitrogen to circulate as ammonia rather than as

glutamine [35]. However, these patients may still

accumulate glutamine in the brain as evidenced by

the high levels of glutamine in the CSF of some

patients with HE [9,39]. It is thought that some

persons may be predisposed to GS protein denatura-

tion or degeneration of pericentral hepatocytes as the

toxic result of drugs given post-transplant or as a

result of unrecognised humoral or immune factors

[35].

Genetic mutations of enzymes involved in the urea

cycle (i.e. incomplete form of urea cycle enzyme

deficiencies, such as ornithine transcarbamylase

deficiency) superimposed on a stress situation, such

as that induced by cytotoxics may predispose some

individuals to the development of HE. Urea cycle

defects are being increasingly documented in pre-

viously well and intellectually accomplished teen-

agers and adults [38,40 – 42]. Several recent reports

suggest that delayed onset may correlate with allelic

variations in the gene mutation. Death during an

initial episode is frequent in patients with late-onset

urea cycle disorders, as lack of familiarity with the

disorder in the adult setting delays diagnosis and

appropriate treatment [38,43,44]. It is therefore

important that patients undergo assessment of

plasma amino acids (glutamine, arginine, etc.) and

the intermediates of urea cycle (ornithine, citrulline,

argininosuccinate, etc. as well as urine orotic acid

determination) to help clarify the pathogenetic

mechanisms involved [34]. There are genetic im-

plications associated with the diagnosis of a late onset

urea cycle disorder and cascade testing of family

members is recommended [42].

Diagnosis

A progressive increase in blood ammonia concentra-

tion, irrespective of cause, will result in onset of

cerebral oedema, coma and eventual death. Accord-

ingly, it is imperative for all clinicians to know the

presenting signs and symptoms associated with

hyperammonemia and measure blood ammonia

levels in a timely fashion as no other laboratory tests

are helpful for diagnosis of hyperammonemia. A

blood sample to measure ammonia concentration

should be taken from an artery or vein, preferably

without using a tourniquet, placed on ice for

transport to the laboratory, and analysed immedi-

ately. Ammonia levels can be elevated falsely by

haemolysis, delayed processing, and exposure to

room temperature and collection of capillary samples

by smokers. Ammonia concentrations associated

with neurological symptoms can vary between

individuals [29 p.1211]. Levels at the time of initial

1706 L. Nott et al.

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

measurement ranged from 81 to 3680 mmol/l (med-

ian 320 mmol/l), with peak levels of 215 to

3680 mmol/l (median 750 mmol/l) in one of the

largest series of chemotherapy-induced HE reported

by Davies et al. [13]. The authors of this retro-

spective series made the diagnosis of hyperammone-

mia if plasma ammonia concentration was greater

than twice normal and exceeded 200 mmol/l on at

least one occasion.

Once hyperammonenia is confirmed, additional

laboratory tests (Table II) are useful to determine

the specific cause: complete blood count with

differential, arterial blood gas; blood glucose;

electrolytes; blood urea nitrogen (BUN); creatinine;

uric acid; liver function tests: aminotransferases,

bilirubin, prothrombin time; and examination of the

urine, including color, odor, dipstick, and presence

of ketones [45,46]. If possible, at the time of the

initial evaluation, samples also should be obtained

for specialized tests, which may be necessary

depending on the results of the initial evaluation

including quantitative plasma amino acids, acy-

lcarnitine profile, lactate and qualitative urine

organic acids [47,48]. A search for precipitating

events such as hypovolemia, gastrointestinal bleed,

offending drugs or infection should be undertaken

simultaneously.

The determination of acid – base status is im-

portant. A respiratory alkalosis usually accompanies

chemotherapy-induced HE and urea cycle disor-

ders, unless shock or secondary infection is present

[1]. This is secondary to hyperpnoea induced by the

elevated ammonia level. Hyperammonemia, along

with acidosis, ketosis and a low bicarbonate level is

suggestive of an organic acidemia, in which case

plasma and urinary organic acid tests would be

necessary to confirm the diagnosis. Urinary ketones

will also be present in this situation. Hyperammo-

nemia with metabolic acidosis, ketosis, markedly

elevated hepatic transaminases and hyperbilirubine-

mia suggests liver disease and hepatotoxicity as the

cause. This is in contrast to HE wherein only mild

abnormalities of liver function tests would be

expected. Cases of chemotherapy-induced HE

reported in the literature tended to have mild-to-

moderate elevations of hepatocellular enzymes

(ALT or AST less than two times normal) with

preserved synthetic liver function tests [13]. A

complete blood count may provide a clue to the

presence of sepsis which triggers the metabolic

crisis.

Quantitative plasma or serum amino acid analysis

is helpful to exclude occult urea cycle disorders or

other disorders of amino acid metabolism (Figures

2 and 3). Most amino acids (except argininosucci-

nic acid and alloisoleucine) are present in the

plasma within a normal range and mild elevations

of 5 – 10% above normal usually are not significant

[46]. Normal or only mildly elevated levels of serum

amino acids are characteristic of chemotherapy

induced HE. Mildly elevated serum glutamine levels

and high cerebrospinal fluid glutamine levels have

been reported in chemotherapy induced HE [35].

Glutamine and alanine levels are increased in all

urea cycle defects except for arginase deficiency.

Citrulline and arginine levels help to localise the

defect within the urea cycle. Urinary orotic acid

levels are also important to exclude underlying urea

cycle defects, particularly OTC deficiency charac-

terised by a markedly elevated urinary orotic

acid [1].

Brain imaging in patients with chemotherapy-

induced HE can be unremarkable but often does

reveal some abnormalities. Imaging is also important

to exclude other acute cerebral pathologies

(e.g. metastasis or stroke) requiring specific manage-

ment. Brain magnetic resonance imaging (MRI) on

diffusion-weighted image (DWI) and CT scans have

shown cerebral oedema, bilateral enhancing cerebral

white matter changes and atrophic changes in

patients with chemotherapy induced HE [49 – 51].

Some of these findings may improve over time after

cessation of the offending drug [49].

In severe cases of drug-induced HE electroence-

phalography (EEG) characterised by signs of severe

encephalopathy with continuous generalised slowing,

a predominance of theta and delta activity, occasional

bursts of frontal intermittent rhythmic delta activity,

and triphasic waves [52].

Table II. Diagnostic investigations for hyperammonemic

encephalopathy.

1. Initial evaluation

. Ammonia level

. CBC with differential

. Blood glucose

. Electrolytes, BUN, creatinine, uric acid

. Arterial blood gas

. AST, ALT, bilirubin, PT

. LDH and lactate

. Urinalysis

. Septic screen

2. Specialized tests

. Quantitative plasma amino acids

. Brain imaging – CT or MRI

. EEG

. Qualitative urine organic acids

CBC, complete blood count; ALT, alanine amoinotransferase;

BUN, blood urea nitrogen; PT, prothrombin time; AST, aspartate

aminotransferase; LDH, lactate dehydrogenase; CT, computerised

tomography; MRI, magnetic resonance imaging; EEG, electro-

encephalogram.

Chemotherapy, hyperammonemia and encephalopathy 1707

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

Treatment

Neurological abnormalities and impaired cognitive

function have significant correlation with the dura-

tion of hyperammonemia and encephalopathy

[23,53]. Treatment, therefore, should be initiated

as soon as HE is suspected and should proceed

concurrently with diagnostic evaluation. Specific

therapies for HE have been derived from those

used in the management of patients with inborn

errors of urea synthesis and focus on ameliorating

catabolism and removing nitrogen. The efficacy of

specific therapies for HE is difficult to evaluate as

many of the cases were diagnosed at a late stage and

treatments have varied. Reduction of exogenous

nitrogen load by withholding intravenous nutrition

and minimizing gastrointestinal bleeding, enhancing

nitrogen excretion by haemodialysis and ammonia-

trapping therapy with sodium benzoate and pheny-

lacetate are the cornerstones of therapy [54].

Non-protein calories are provided from 10 – 15%

glucose and intravenous fat emulsions may be added

to minimise endogenous proteolysis [29 pp.1211 –

1212]. Lactulose (b-galactosidofructose) and neo-

mycin may be administered to reduce intestinal

sources of ammonium [11].

Attention to the patient’s volume status is im-

portant as reduced tissue perfusion can further

increase protein catabolism, nitrogen load and

increased ammonium concentrations. In addition,

pharmacologic treatment of HE requires good renal

function. However, fluid infusion rates must be

adjusted carefully to avoid over-hydration and

exacerbation of cerebral oedema. Saline infusion

should be minimised because of the high saline

content of ammonia-trapping drugs and subsequent

risk of hypernatremia. Conversely, hypokalemia can

ensue because of urinary potassium losses enhanced

by ammonium-trapping drug metabolites, necessitat-

ing addition of potassium to the intravenous fluids

[54].

The ammonia-trapping agents (alternate pathway

therapy), sodium phenylacetate and sodium benzoate

for intravenous use or sodium phenylbutyrate for oral

Figure 2. Diagnostic algorithm for the primary causes of hyperammonemia. ASA, argininsuccinic acid; CPS, carbamylphosphate syntheatse;

OTC, ornithine transcarbamoylase.

1708 L. Nott et al.

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

use have been helpful in the setting of controlling

hyperammonemia as a consequence of urea cycle

defects by trapping and converting ammonia into

compounds that are excreted in the urine. Benzoate

forms hippurate with glycine, and phenylacetate

forms phenylacetyl glutamine (PAG) with glutamine,

which are then excreted in the urine without further

metabolism. Arginine can aid in the treatment of

hyperammonemia by inducing the formation of

arginosuccinate and citrulline, both of which can

function as a conduit for nitrogen excretion [10,22].

Close monitoring of the plasma ammonia levels,

electrolytes, pH and PCO2 is required during

therapy. Although there is minimal toxicity related

to ammonia-trapping drugs, they do represent a

significant osmotic load and nausea and vomiting can

occur with the initial dose often necessitating potent

anti-emetic drugs [11,54].

Figure 3. Diagnostic algorithm for the secondary causes of hyperammonemic encephalopathy.

Chemotherapy, hyperammonemia and encephalopathy 1709

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

Haemodialysis is effective in lowering ammonia

levels and should be initiated if ammonia-trapping

agents have not stabilised or lowered ammonia

levels within 4 h, or if the patient’s clinical condi-

tion worsens. Ammonia-trapping agents should be

continued during haemodialysis, because their

effects seem to be additive [22]. Haemodialysis

should be continued until the ammonia concentra-

tion has dropped below 200 mmol/l for a period of

at least 24 h as it appears to have little effect below

this level. However, plasma ammonia levels may

increase again (rebound) because of the delay before

ammonia-trapping drugs begin to work and the

ongoing catabolism that continues to produce waste

nitrogen [55]. Continuous arteriovenous or venove-

nous haemofiltration may be used if haemodialysis

is not available, although it is not as effective. This

method may be useful to clear newly produced

nitrogen after haemodialysis is withdrawn whilst

awaiting complete reversal of the catabolic process,

which may take 48 h or more. Peritoneal dialysis is

the least acceptable method of ammonia clearance

as it is very slow and detoxification may take several

days [55,56].

Respiratory status should be closely monitored as

the clinical condition can deteriorate rapidly. Patients

with respiratory compromise should receive assisted

ventilation because increased work of breathing

results in higher caloric demands, leading to in-

creased catabolism and nitrogen accumulation.

Monitoring and conventional treatment of increased

intracranial pressure are also important [57]. Given

the high incidence of concurrent infection, empirical

broad spectrum antibiotics may be considered if

there is clinical suspicion of sepsis. Certain drugs,

including glucocorticoids, which increase protein

catabolism, and valproic acid, which decreases urea

cycle function and increases ammonia levels, should

be avoided if possible [57,58].

Conclusion

Because of the multi-factorial aetiology of hyperam-

monemic encephalopathy, many patients receiving

cytotoxics will be at risk, and prospective identifica-

tion of patients, for example by metabolic testing, is

not likely to be of value. Prompt diagnosis depends

on a high index of suspicion, and monitoring of

ammonia levels, particularly when neurological

deterioration, respiratory alkalosis or unexplained

seizures occur following intensive chemotherapy.

Many of the severe cases will be fatal despite therapy.

It is likely that early recognition and aggressive

treatment will provide the opportunity for a more

favourable outcome prior to the development of

irreversible brain damage.

References

1. Summar M, Tuchman M. Proceedings of a consensus

conference for the management of patients with urea cycle

disorders. J Pediatr 2001;138(1 Suppl):S6 – S10.

2. Brusilow SW. Hyperammonemic encephalopathy. Medicine

(Baltimore) 2002;81:240 – 249.

3. Flannery DB, Hsia YE, Wolf B. Current status of hyper-

ammonemic syndromes. Hepatology 1982;2:495 – 506.

4. Kaufman JJ. Ammoniagenic coma following ureterosigmoi-

dostomy. J Urol 1984;131:743 – 745.

5. Drayna CJ, Titcomb CP, Varma RR, Soergel KH.

Hyperammonemic encephalopathy caused by infection in a

neurogenic bladder. N Engl J Med 1981;304:766 – 768.

6. Duarte J, Macias S, Coria F, Fernandez E, Claveria LE.

Valproate-induced coma: case report and literature review.

Ann Pharmacother 1993;27:582 – 583.

7. Cuturic M, Abramson RK. Acute hyperammonemic coma

with chronic valproic acid therapy. Ann Pharmacother

2005;39:2119 – 2123.

8. Leonard JV, Kay JD. Acute encephalopathy and hyperammo-

naemia complicating treatment of acute lymphoblastic leukae-

mia with asparaginase. Lancet 1986;1:162 – 163.

9. Mitchell RB, Wagner JE, Karp JE, Watson AJ, Brusilow SW,

Przepiorka D, et al. Syndrome of idiopathic hyperammonemia

after high-dose chemotherapy: review of nine cases. Am J Med

1988;85:662 – 667.

10. Winter SS, Rose E, Katz R. Hyperammonemia after

chemotherapy in an adolescent with hepatocellular carcinoma.

J Pediatr Gastroenterol Nutr 1997;25:537 – 540.

11. Liaw CC, Wang HM, Wang CH, Yang TS, Chen JS, Chang

HK, et al. Risk of transient hyperammonemic encephalopathy

in cancer patients who received continuous infusion 5-

fluorouracil with the complication of dehydration and infec-

tion. Anticancer Drugs 1999;10:275 – 281.

12. Espinos J, Rifon J, Perez-Calvo J, Nieto Y. Idiopathic

hyperammonemia following high-dose chemotherapy. Bone

Marrow Transplant 2006;37:899. Comment: Am J Med 1988;

85:662 – 667.

13. Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ.

Idiopathic hyperammonemia: a frequently lethal complication

of bone marrow transplantation. Bone Marrow Transplant

1996;17:1119 – 1125.

14. Ho AY, Mijovic A, Pagliuca A, Mufti GJ. Idiopathic

hyperammonemia syndrome following allogeneic peripheral

blood progenitor cell transplantation (allo-PBPCT). Bone

Marrow Transplant 1997;20:1007 – 1008.

15. Tse N, Cederbaum S, Glaspy JA. Hyperammonemia follow-

ing allogeneic bone marrow transplantation. Am J Hematol

1991;38:140 – 141.

16. Xu SR, Yao EG, Dong ZR, Liu RS, Pan L, Lin FR, et al.

Plasma ammonia in patients with acute leukaemia. Chin Med

J (Engl) 1992;105:713 – 716.

17. Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional

therapy is associated with hyperammonemia, lactic acidosis

and encephalopathy. Br J Cancer 1997;75:464 – 465.

18. Kim YA, Chung HC, Choi HJ, Rha SY, Seong JS, Jeung HC.

Intermediate dose 5-fluorouracil-induced encephalopathy.

Jpn J Clin Oncol 2006;36:55 – 59.

19. Snyder MJ, Bradford WD, Kishnani PS, Hale LP. Idiopathic

hyperammonemia following an unrelated cord blood trans-

plant for mucopolysaccharidosis I. Pediatr Dev Pathol

2003;6:78 – 83.

20. Gallardo D, Ferra C, Berlanga JJ, Banda ED, Ponce C, Salar

A, et al. Neurologic complications after allogeneic bone

marrow transplantation. Bone Marrow Transplant 1996;

18:1135 – 1139.

1710 L. Nott et al.

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.

21. Lichtenstein GR, Yang YX, Nunes FA, Lewis JD, Tuchman

M, Tino G, et al. Fatal hyperammonemia after orthotopic lung

transplantation. Ann Intern Med 2000;132:283 – 287.

22. Berry GT, Bridges ND, Nathanson KL, Kaplan P, Clancy

RR, Lichtenstein GR, et al. Successful use of alternate waste

nitrogen agents and hemodialysis in a patient with hyper-

ammonemic coma after heart-lung transplantation. Arch

Neurol 1999;56:481 – 484.

23. Martinelli G, Peccatori F, Ullrich B, Ghielmini M, Roggero E,

Goldhirsch A. Clinical manifestation of severe hyperammo-

nemia in patients with multiple myeloma. Ann Oncol

1997;8:811.

24. Kwan L, Wang C, Levitt L. Hyperammonemic encephalo-

pathy in multiple myeloma. N Engl J Med 2002;346:1674 –

1675.

25. Matsuzaki H, Uchiba M, Yoshimura K, Yoshida M, Akahoshi

Y, Okazaki K, et al. Hyperammonemia in multiple myeloma.

Acta Haematol 1990;84:130 – 134.

26. Matsuzaki H, Hata H, Sonoki T, Matsuno F, Kuribayashi N,

Yoshida M, et al. Serum amino acid disturbance in multiple

myeloma with hyperammonemia. Int J Hematol 1995;61:

131 – 137.

27. Takimoto Y, Imanaka F, Hayashi Y, Morioka S. A patient

with ammonia-producing multiple myeloma showing hyper-

ammonemic encephalopathy. Leukemia 1996;10:918 – 919.

28. Voorhies TM, Ehrlich ME, Duffy TE, Petito CK, Plum F.

Acute hyperammonemia in the young primate: physiologic

and neuropathologic correlates. Pediatr Res 1983;17:970 –

975.

29. Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The

Metabolic and Molecular Bases of Inherited Disease, 7th ed.

New York: McGraw-Hill; 1995.

30. Hourani BT, Hamlin EM, Reynolds TB. Cerebrospinal fluid

glutamine as a measure of hepatic encephalopathy. Arch

Intern Med 1971;127:1033 – 1036.

31. Koenig H, Patel A. Biochemical basis for fluorouracil

neurotoxicity. The role of Krebs cycle inhibition by fluor-

oacetate. Arch Neurol 1970;23:155 – 160.

32. Ardalan B, Glazer R. An update on the biochemistry of 5-

fluorouracil. Cancer Treat Rev 1981;8:157 – 167.

33. Pinedo HM, Peters GF. Fluorouracil: biochemistry and

pharmacology. J Clin Oncol 1988;6:1653 – 1664.

34. Valik D. Encephalopathy, lactic acidosis, hyperammonemia

and 5-fluorouracil toxicity. Br J Cancer 1998;77:1710 – 1712.

35. Tuchman M, Lichenstein GR, Rajagopal BS, McCann MT,

Furth EE, Bavaria J, et al. Hepatic glutamine synthetase

deficiency in fatal hyperammonemia after lung transplanta-

tion. Ann Intern Med 1997;127:446 – 449.

36. Gebhardt R, Lindros K, Lamers WH, Moorman AF.

Hepatocellular heterogeneity in ammonia metabolism: de-

monstration of limited colocalization of carbamoylphosphate

synthetase and glutamine synthetase. Eur J Cell Biol 1991;

56:464 – 467.

37. Gebhardt R. Metabolic zonation of the liver: regulation

and implications for liver function. Pharmacol Ther 1992;

53:275 – 354.

38. Finkelstein JE, Hauser ER, Leonard CO, Brusilow SW. Late-

onset ornithine transcarbamylase deficiency in male patients.

J Pediatr 1990;117:897 – 902.

39. Hourani BT, Hamlin EM, Reynolds TB. Cerebrospinal fluid

glutamine as a measure of hepatic encephalopathy. Arch

Intern Med 1971;127:1033 – 1036.

40. Drogari E, Leonard JV. Late onset ornithine carbamoyl

transferase deficiency in males. Arch Dis Child 1988;

63:1363 – 1367.

41. Cohn RM, Roth KS. Hyperammonemia, bane of the brain.

Clin Pediatr (Phila) 2004;43:683 – 689.

42. Chiong MA, Bennetts BH, Strasser SI, Wilcken B. Fatal late-

onset ornithine transcarbamylase deficiency after coronary

artery bypass surgery. Med J Aust 2007;186:418 – 419.

43. Thakur V, Rupar CA, Ramsay DA, Singh R, Fraser DD. Fatal

cerebral edema from late-onset ornithine transcarbamylase

deficiency in a juvenile male patient receiving valproic acid.

Pediatr Crit Care Med 2006;7:273 – 276.

44. Rohininath T, Costello DJ, Lynch T, Monavari A, Tuchman

M, Treacy EP. Fatal presentation of ornithine transcarbamy-

lase deficiency in a 62-year-old man and family studies.

J Inherit Metab Dis 2004;27:285 – 288.

45. Saudubray JM, Chappentier C. Clinical phenotypes:

diagnosis/algorithms. In: Scriver CR, Beaudet AL, Sly WS,

Valle D, editors. Metabolic and Molecular Bases of Inherited

Disease, 8th ed. New York: McGraw-Hill; 2001. p 1327.

46. Burton, BK. Inborn errors of metabolism in infancy: a guide

to diagnosis. Pediatrics 1998;102:e69.

47. Calvo M, Artuch R, Macia E, Luaces C, Vilaseca MA, Pou J,

et al. Diagnostic approach to inborn errors of metabolism in

an emergency unit. Pediatr Emerg Care 2000;16:405 – 408.

48. Weiner, DL. Metabolic emergencies. In: Fleisher GR, Ludwig

S, Henretig FM, editors. Textbook of Pediatric Emergency

Medicine, 5th ed. Lippincott: Philadelphia; 2006. p 1193.

49. Ishibashi S, Nishimura H, Mizusawa H. 5-FU-induced acute

leukoencephalopathy. Intern Med 2004;43:1009 – 1010.

50. Hantson P, Grandin C, Duprez T, Nassogne MC, Guerit JM.

Comparison of clinical, magnetic resonance and evoked

potentials data in a case of valproic-acid-related hyperammo-

nemic coma. Eur Radiol 2005;15:59 – 64.

51. Ziyeh S, Thiel T, Spreer J, Klisch J, Schumacher M.

Valproate-induced encephalopathy: assessment with MR

imaging and 1H MR spectroscopy. Epilepsia 2002;43:1101 –

1105.

52. Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J.

Valproate-induced hyperammonemic encephalopathy. Acta

Neurol Scand 2006;114:1 – 7.

53. Maestri NE, Clissold D, Brusilow SW. Neonatal onset

ornithine transcarbamylase deficiency: a retrospective analysis.

J Pediatr 1999;134:268 – 272.

54. Batshaw ML, MacArthur RB, Tuchman M. Alternative

pathway therapy for urea cycle disorders: twenty years later.

J Pediatr 2001;138(1 Suppl):S46 – S54, discussion S54 – S55.

55. Wong KY, Wong SN, Lam SY, Tam S, Tsoi NS. Ammonia

clearance by peritoneal dialysis and continuous arteriovenous

hemodiafiltration. Pediatr Nephrol 1998;12:589 – 591.

56. Summar M. Current strategies for the management of

neonatal urea cycle disorders. J Pediatr 2001;138(1 Suppl):

S30 – S39.

57. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver

CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic

and Molecular Bases of Inherited Disease, 7th ed. New York:

McGraw-Hill; 1995. pp 1214 – 1215.

58. Berry GT, Kaplan PB, Lichtenstein GR. Hyperammonia

possibly due to corticosteroids. Arch Neurol 2000;57:1085 –

10856.

Chemotherapy, hyperammonemia and encephalopathy 1711

Leu

k L

ymph

oma

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itaet

s- u

nd L

ande

sbib

lioth

ek D

uess

eldo

rf o

n 11

/07/

13Fo

r pe

rson

al u

se o

nly.