A 66-year-old male business manager with past medical history of hypertension, diabetes mellitus, and intermittent sinusitis was transferred to our tertiary care center for progressive encephalopathy and concern for nonconvulsive status epilepticus.
Three weeks prior to admission, he was prescribed a 10-day course of levofloxacin for presumed sinusitis. As cough and postnasal drip did not improve, he was treated with two courses of methylprednisolone in addition to levofloxacin and subsequently clarithromycin. Two days prior to presentation, he developed headaches and sinus pressure and complained about "feeling off," epigastric pain, and dry heaving. The night prior to presentation, he awoke frequently throughout the night with progressive confusion. The patient did not have fever, chills, or sweats. His family reported a history of anxiety, panic attacks, claustrophobia, and anger outbursts, with the last notable outburst having occurred about 6 months earlier. Of note, coworkers found a collection of various over-the-counter vitamins and nutritional supplements at the patient's desk.
Given increasing confusion and agitation, the patient was taken to another hospital where he became progressively more obtunded, requiring intubation for airway protection. He was empirically started on vancomycin, ceftriaxone, and acyclovir for concern of infectious meningoencephalitis. CSF analysis revealed elevated total protein at 53 mg/dL, glucose of 160 mg/dL (serum glucose: 240 mg/dL), no pleocytosis (1 WBC/mm3), negative CSF VDRL, negative West nile virus IgM and IgG, negative cryptococcal antigen, and negative fungal and bacterial cultures. Due to development of teeth grinding and concern for subclinical seizure activity, a routine electroencephalogram (EEG) was performed that revealed no seizure activity, however findings consistent with global cerebral dysfunction. He was started on phenytoin and subsequently on levetiracetam. An MRI of the brain showed chronic mild periventricular white matter hyperintensities but no acute findings. He was transferred to our tertiary care center on hospital day 3 for concern of nonconvulsive status epilepticus.
On examination, he was intubated and mechanically ventilated, with no abnormal general physical findings. On neurological examination, he was comatose, with intact brainstem reflexes and extensor posturing in all extremities to central stimulation. Initial laboratory work was notable for normal liver function panel, serum ammonia 120 mug/dL (reference range 65-107 mug/dL), and negative hepatitis panel, as well as respiratory alkalosis. Repeat CSF analysis showed 3 WBC/mm3 (76% neutrophils), 1 RBC/mm3, lactic acid 2.6 meq/L, total protein 28.5 mg/dL, and negative herpes simplex virus PCR as well as negative enterovirus panel, and acyclovir was discontinued. Treatment with lactulose was begun, but serum ammonia rapidly rose to 494 mug/dL within a few hours of arrival to our hospital. Rifaximin and L-carnitine were added, and emergent hemodialysis was initiated.
An MRI of the brain on day of transfer showed extensive areas of restricted diffusion with associated FLAIR hyperintensity involving bilateral temporal lobes and bilateral insular, bilateral frontal, and parietal regions in cortical and subcortical areas and diffuse mild effacement of the cerebral sulci (Figure 1), without enhancing lesions. Continuous electroencephalogram (cEEG) for a duration of 96 hours showed continuous, irregular, generalized low voltage slowing (Figure 2); however, intermittently observed facial and lip twitching did not have an electrographic correlate on cEEG. The MRI findings of symmetric grey matter involvement in the abovementioned areas, and in absence of hypoxic-ischemic insult and seizure activity, were deemed most consistent with hyperammonemic encephalopathy.
The patient underwent continuous venous hemofiltration for two consecutive days followed by regular hemodialysis for two days, with sustained correction of ammonia to levels between 29 and 67 mug/dL after day 3. Liver function panel and coagulation parameters remained within normal limits. Due to poor neurological examination and concern for elevated intracranial pressure (ICP), an ICP monitor was placed, revealing three occurrences of ICP elevation to 28-30 mmHg, which were treated effectively with mannitol boluses. The patient's nutrition was modified to a low protein, high glucose formula to avoid catabolism of endogenous protein. Two days after normalization of ammonia levels, the patient opened his eyes and started to follow commands and move his extremities, and the ICP monitor was discontinued. He was extubated on hospital day 10, at which time he was alert and conversant, without focal motor deficits, yet remained confused.
A computed tomography of the abdomen with venogram did not reveal a portosystemic shunt. An amino acid panel to evaluate inborn errors of metabolism, specifically urea-cycle disorders, was sent (see Table 1). Urine orotic acid excretion was significantly elevated (>900 mmol/mol creatinine; reference range: <2), strongly indicative of a biochemical diagnosis of ornithine transcarbamylase (OTC) deficiency. Genetic testing revealed a pathogenic variant, c.118 C > T, which has been described to cause a mild form of OTC deficiency. In our patient, OTC deficiency was likely unmasked due to a combination of factors: treatment with antibiotics, intake of multiple vitamin supplements, which included red yeast rice, treatment with steroids, and potential interactions of red yeast rice with antibiotics and other herbal supplements.
The patient was maintained on low protein diet and discharged to rehabilitation on hospital day 20 and to home 6 days later, with persistent mild cognitive impairment especially in fluency and memory. A repeat MRI of the brain was obtained 3 weeks after the initial MRI and showed interval decrease in diffusion restriction and FLAIR hyperintensities and resolution of the diffuse mild effacement of the cerebral sulci. He continued to improve clinically and returned to work full time 10 weeks after his initial presentation. At a 3-month follow-up visit, he had returned to his premorbid baseline functional status. At a 6-month follow-up visit, he continued to do well with maintenance of low normal ammonia levels through low protein diet.
Main sources of ammonia are colon (through bacterial metabolism of proteins and urea) and small intestine (through bacterial degradation of glutamine). In a healthy human, the main metabolic route is uptake of ammonia by periportal hepatocytes followed by urea synthesis via the urea cycle. Ammonia that escapes this pathway is converted to glutamine in perivenous hepatocytes. Hepatic transformation of ammonia into urea and subsequent excretion of urea via colon or kidneys prevent entrance of ammonia into the systemic circulation. If the hepatic metabolic capacity is exceeded, or if ammonia bypasses the liver by shunting of blood, circulating ammonia levels increase and elimination of ammonia is shifted to kidneys, brain, and skeletal muscle. Ammonia that reaches the brain can be metabolized by forming glutamine from glutamate, mostly in astrocytes with subsequent transfer of glutamine to neurons, and deamination of glutamine resulting in formation of the neurotransmitter glutamate. Muscle adds to the detoxification process by ammonia uptake and synthesis of glutamine. Ammonia excretion through the kidneys, usually accounting for excretion of 30% of ammonia, can be upregulated to 70%.
Ammonia penetrates the blood-brain barrier through either passive diffusion or mediated transport. While the exact pathogenesis of neurotoxicity is still elusive, ammonia is believed to play a major role by affecting neuronal function as well as creation of brain edema, each of which can contribute to the development of encephalopathy. Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials. Increased cerebral uptake of neutral amino acids, resulting from increased amino acid transport in setting of hyperammonemia, can disturb synthesis of the neurotransmitters dopamine, norepinephrine, and serotonin. Enhanced ammonia metabolism in astrocytes leads to an increase in their production of reactive nitrogen or oxygen species and increased intracellular osmolarity, eventually resulting in brain edema. Furthermore, elevated extracellular glutamate levels, a result of ammonia-induced glutamate release and impaired glutamate clearance, may cause overstimulation of N-methyl-D-aspartate (NMDA) receptors. NMDA receptor activation then triggers nitric oxide synthetase which leads to increased synthesis of the vasodilator nitric oxide. Subsequent resultant intracerebral vasodilatation may contribute to the increase in intracranial pressure. Additionally, astrocyte swelling triggers inflammatory cascades, apoptosis, and metabolic pathways that lead to elevated lactate, cerebral edema, and loss of cerebral autoregulation.
The differential diagnosis of hyperammonemia that is not associated with severe liver disease largely falls into one of two categories: increased ammonia production or decreased ammonia elimination.
Increased ammonia production has been observed in hematooncological disorders, organ transplantation, infections, or states of increased catabolism or protein load. The exact mechanism for hyperammonemia in patients with hematooncological disorders is unknown. Myeloma cells have been shown to produce excess ammonia due to increased amino acid metabolism, and plasma cell infiltration of the liver can lead to a portosystemic shunt. In leukemia patients, occurrence of idiopathic hyperammonemia has been described hours to days after initiation of intensive chemotherapy, often followed by progression to coma and death. Similarly, severe hyperammonemia with frequent lethal course has been described in patients with hematological malignancies treated with bone marrow transplantation. Hyperammonemia has also been described in rare cases after heart-lung or lung transplantation. Pathogenesis of hyperammonemia in these situations is believed to be multifactorial involving increased protein catabolism, parenteral nutrition, gastrointestinal hemorrhage, sepsis or mucositis, and transient acquired enzyme reductions affecting urea synthesis, as well as drug effects from chemotherapy agents.
Infections with urea-producing bacteria (Proteus mirabilis, Escherichia coli, Klebsiella species, Providencia rettgeri, Morganella morganii, and diphtheroids) can lead to noncirrhotic hyperammonemic encephalopathy, mostly reported in children with congenital urinary tract abnormalities and urinary stasis. However, cases have been reported in adults with urinary retention and neurogenic bladder, or even in absence of urinary tract abnormalities. Ammonia production in the setting of urinary tract infection alkalinizes the urine with subsequent increase of the fraction of ammonium ions. The ammonium ion is less permeable than neutral ammonia and cannot diffuse back into urine and hence escapes detoxification in the liver by uptake into the systemic circulation via venous drainage from the bladder. Furthermore, systemic mycobacterium or mycoplasma infections in organ recipients as well as herpes simplex virus infection in neonates have been described to lead to hyperammonemia.
Increased ammonia production also occurs during increased muscle catabolism, such as with seizures, starvation, or trauma. However, symptomatic hyperammonemia usually only occurs in patients with underlying urea-cycle disorders. Similarly, total parenteral nutrition (TPN), which contains a high protein load, has been reported to unmask a long-term asymptomatic urea-cycle disorder or occur with TPN containing only essential amino acids with subsequently impaired ammonia detoxification due to absence of ornithine.
Inborn errors of metabolism (IEMs) that can cause hyperammonemia include urea-cycle disorders, organic acidurias, carnitine deficiency from defects in fatty acid oxidation, dibasic aminoaciduria, and defects in pyruvate metabolism. While most IEMs present during the neonatal period or early childhood, some, especially urea-cycle disorders, can present in adults. Every enzyme in the urea cycle, carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase, argininosuccinate synthetase (ASS), argininosuccinic acid lyase, and arginase, can be affected by an inherited deficiency. OTC deficiency, which is inherited in an X-linked recessive manner, is the most common one, with an estimated prevalence of 1 : 14.000. Late presentations and phenotypic variance are widely known for OTC deficiency. Mild OTC deficiency can remain largely asymptomatic until an inciting event unmasks the deficiency and leads to symptomatic hyperammonemia. CPS deficiency, N-acetyl glutamine synthetase, and type II citrullinemia also can be present in adulthood. Precipitating factors for clinical manifestation of these deficiencies include infections, TPN, gastrointestinal hemorrhage, or valproate intake.
Ammonia elimination can be significantly decreased in presence of a portosystemic shunt. Congenital portosystemic shunts are a rare cause of noncirrhotic hyperammonemia, and shunt volume determines time of manifestation, with increased prevalence in patients above the age of 60. An acquired form of noncirrhotic portosystemic shunt that can lead to hyperammonemic encephalopathy is portal vein thrombosis.
Ureterosigmoidostomy is another anatomic situation that can lead to hyperammonemia, due to increased ammonia formation by bacterial degradation after urine excretion directly into the sigmoid colon. While this can occur in liver-healthy individuals, for example, due to coprostasis or infection with urea-splitting bacteria, most cases occur in the setting of hepatic failure.
Drug-induced hyperammonemia can result from interference with the urea cycle or enhancement of renal release of ammonia into the systemic circulation. Valproic acid is the most well known, but others include carbamazepine, sulfadiazine, ribavirin, salicylates, and glycine.
The exact pathogenesis of hyperammonemia due to valproic acid is unclear, but it has been suggested that the mechanism is through inhibition of glutamate uptake by astrocytes. The reported prevalence of valproic acid induced hyperammonemia is as high as 35-45% and seems to be higher in patients with carnitine deficiency or with congenital urea-cycle enzymatic defects. Symptoms can present as early as 2 weeks into therapy or as late as several years later. Patients can be asymptomatic with mildly elevated liver enzymes or present with cognitive dysfunction, coma, or severe hepatotoxicity. Serum valproic acid levels can be normal and do not correlate with the level of hyperammonemia or symptoms. Furthermore, ammonia levels do not correlate with the severity of encephalopathy.
Symptoms can range from mild, such as irritability, headache, and vomiting, to severe with encephalopathy, seizures, ataxia, and coma. Depending on the underlying etiology, the symptoms can fluctuate and episodically occur, often precipitated by increased protein intake, drugs, or infections. Psychiatric manifestations, such as manic episodes or psychosis, may be seen in chronic manifestations of late-onset presentations of inborn errors of metabolism. Seizures, cerebral edema, and herniation are manifestations of acute hyperammonemia and usually occur with ammonia levels exceeding 200 mumol/L. The difference between acute and chronic hyperammonemia is believed to lie in the effect of glutamine on the brain. In patients with acute liver failure, a strong association of arterial ammonia levels higher than 200 mug/dL with cerebral herniation has been shown.