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Patient 4. A 42-year-old woman was admitted with sepsis related to her central dialysis line, with a background of liver transplant, chronic graft rejection, and hepatorenal syndrome. Her immunosuppressant regimen included tacrolimus and cyclosporin. Her condition deteriorated with respiratory failure, hypotension, seizures, and a drop in the GCS score. Her plasma ammonium level was 55 mol/L. FLAIR image ( A ) and DWI ( B ) show abnormal signal intensity in the cortex involving the bilateral insular and cingulate and left posterior temporal lobes ( arrows ). The patient made an excellent recovery without significant neurologic deficit with supportive therapeutic measures.
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Acute hyperammonemic encephalopathy has significant morbidity and mortality unless promptly treated. We describe the MR imaging findings of acute hyperammonemic encephalopathy, which are not well-recognized in adult patients.
We retrospectively reviewed the clinical and imaging data and outcome of consecutive patients with documented hyperammonemic...
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Context 1
... with acute hyperammonemic encephalopathy present with progressive drowsiness, seizures, and coma due to primary toxic effects of ammonia on the brain paren- chyma. 1 Prolonged hyperammonemia can lead to significant brain injury and long-term sequelae, such as intellectual impairment. 1,2 Prompt recognition and treatment of hyperammonemia is, therefore, essential to avoid complications such as cerebral edema and brain herniation, which can prove fatal. 2 In the pediatric population, acute hyperammonemic encephalopathy and its imaging findings have been well described as a result of inborn errors of metabolism (eg, urea cycle disorders or organic acidemias). 3,4 In adults, this condition is more commonly encountered in very ill patients being treated in the ICU. Acute hepatic dysfunction is most frequently implicated, but other etiologies include portosys- temic shunt surgery, drugs (eg, sodium valproate, asparagi- nase therapy, or chemotherapy), infections, hypothyroid- ism, multiple myeloma, and post-lung or bone marrow transplantation. 1,2,5-9 The radiologic findings of acute hyperammonemic encephalopathy are less well recognized in the adult literature, yet imaging may yield clues to the underlying diagnosis. The purpose of this study was to describe the MR imaging features of adult hyperammonemic encephalopathy. The salient demographics, clinical data, and MR imaging features of the 4 patients with hyperammonemic encephalopathy are summarized in the On-line Table. Four patients (2 women; mean, age 42 Ϯ 13 years; range, 24 –55 years), all in the ICU, were included in this study. All patients presented with seizures and reduced level of consciousness (GCS scores ranging from 3 to 8). Additionally, 1 patient had abnormal posturing. Plasma ammonium levels ranged from 55 to 168 mol/L (normal range, 0 –34 mol/L). EEG was performed in 3 cases on days 2– 4 postictus and showed nonspecific generalized encephalopathic disturbance of cerebral activity in both hemispheres (On-line Table). Patient 1 was post– heart-lung transplantation for severe pulmonary arterial dilation, pulmonary insufficiency, and mi- tral valve prolapse (Figs 1 and 2). Her postoperative course in the ICU was very protracted, complicated by cardiac failure, pulmonary edema, chest infection, sternal wound sepsis, and venous thrombosis. She was on a standard immunosuppressive regimen (methylprednisolone, azathioprine, and cyclo- sporine and mycophenolate mofetil) and had been on total parenteral nutrition. Patient 2 presented with fulminant acute hepatic failure following an overdose of acetaminophen with a background of chronic alcohol abuse (Fig 3). Liver function test findings were grossly abnormal (bilirubin, 81 mol/L; ALT, 3492 IU/L; AP, 178 IU/L; AST, 20,872 IU/L; PT, 83 seconds). Patient 3 presented with severe sepsis of unknown origin (blood cultures positive for Enterococcus species) with a background of schizophrenia, chronic hepatitis C, portal hypertension, and esophageal varices (Fig 4). Liver function test results were mildly deranged (bilirubin, 20 mol/L; ALT, 63 IU/L; ALP, 201 IU/L; AST, 271 IU/L; PT, 50 seconds). Patient 4 was admitted with severe sepsis related to her tunneled central dialysis line (Fig 5). She had undergone liver transplantation 13 years prior for nonalcoholic steatohepati- tis, chronic graft rejection, worsening liver function, and hepatorenal syndrome, for which she had been undergoing he- modialysis. Her immunosuppressant regimen included tacrolimus and cyclosporin. Liver function test results were mildly deranged (bilirubin, 68 mol/L; ALT, 77 IU/L; ALP, 97 IU/L; AST, 414 IU/L; PT, 46 seconds). MR imaging was performed on days 1– 4 post-onset of symp- toms. Bilateral symmetric involvement of the insular cortex and cingulate gyrus was present in all 4 patients on FLAIR and T2-weighted imaging sequences (Figs 1 and 3–5). Additional involvement of parietal, frontal, temporal, or occipital cortices was seen in all patients but was much more variable in extent and was also asymmetric (On-line Table and Figs 1 and 3–5). Most areas of signal-intensity abnormality also showed corre- sponding areas of restricted diffusion (Figs 1 and 3–5). Intra- venous contrast medium was administered in 2 cases, and no abnormal enhancement was seen in either case. MR imaging performed in patient 1 also showed increased T2 and FLAIR signal intensity with restricted diffusion in the subcortical white matter in the temporal and occipital lobes, a pattern not seen in the 3 other cases (Fig 1). MR imaging in patient 2 only showed increased T2 and FLAIR signal intensity in the basal ganglia, thalami, and midbrain bilaterally without restricted diffusion (Fig 3). MR imaging in patient 3 showed involvement of the perirolandic cortex bilaterally (Fig 4). In the clinical radiologic reports, the possibility of hyperammonemic encephalopathy was raised in 3 cases. The differ- ential diagnosis given in the clinical radiologic reports included posterior reversible encephalopathy syndrome, seizure activity, metabolic and hepatic encephalopathy, and diffuse hypoxic-ischemic injury. Treatment in the 4 patients included lactulose; dietary protein restriction; discontinuation of TPN, N -acetylcystine, propo- fol, and other supportive measures such as mannitol to reduce cerebral edema; antiseizure medications, such as phenytoin and phenobarbital; and broad-spectrum antibiotics and anti- fungal agents for superadded infection. Hemodialysis, a po- tential treatment used in severe cases, was not used in any of the 4 patients. 1 Two patients died. The condition of patient 1, who had the highest plasma ammonia level at 168 mol/L, deteriorated further clinically despite therapeutic measures and plasma ammonium levels decreasing to 110 mol/L. Repeat CT imaging showed evidence of severe cerebral edema and brain herniation (Fig 2). The condition of patient 2 deteriorated further after admission to the ICU, and he died 2 days later without repeat imaging. Of the 2 survivors, patient 4 made an excellent recovery without significant intellectual or neurologic deficit. Patient 3 was discharged from the ICU 2 weeks later with a GCS score of 11 (E3, V2, M6) and significant intellectual impairment. Repeat CT imaging showed widening of the Sylvian fissures in keeping with atrophy (Fig 4). All our 4 patients were very ill and were being treated in the ICU. In all cases, extensive cortical signal-intensity changes, with associated restricted diffusion, were seen; these features are in keeping with early changes seen in hyperammonemic encephalopathy. These early imaging findings are not well- recognized in the adult literature; for example, in their com- prehensive review of MR imaging findings in hepatic encephalopathy published in the American Journal of Neuroradiology in 2008, Rovira et al 10 only discussed MR spectroscopic find- ings and late changes such as cerebral edema and brain herniation in the setting of fulminant hepatic failure and hyperammonemia. Bilateral involvement of the insular cortex and cingulate gyrus was a strikingly common feature, seen in all our 4 patients, and these findings have also been described in several other cases, mainly in the pediatric literature. 4,11 Bindu et al 4 reported 3 cases of hyperammonemic encephalopathy in children due to various causes including infantile citrullinemia, acute hepatic encephalopathy, and proximal urea cycle disorder, with similar cortical abnormalities and involvement of the insular and cingulate cortices. Takanashi et al 11 described 3 cases of acute hyperammonemic encephalopathy arising from late-onset ornithine transcarbylamase deficiency, all with evidence of injury to the cingulate and insular cortices, and they described sparing of perirolandic and occipital cortices. Involvement of brain regions other than the insular or cingulate gyrus was clearly more variable. Unlike the cases described by Takanashi et al, 11 involvement of the occipital or perirolandic cortex was seen in 2 of our cases (patients 1 and 3, respectively). Additional sites of involvement, such as the basal ganglia, brain stem, and thalami, were seen in 1 patient only (patient 2). Brain stem ...
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Citations
... When ammonia, produced by the digestion of proteins and metabolism of bacteria in the gut, fails to be eliminated by the liver, it is metabolized by astrocytes into glutamine. In excess, this important precursor of the neurotransmitters glutamate and GABA can produce symmetric abnormalities of the insula, cingulate cortex, and in more severe cases, the subcortical white matter, basal ganglia, thalami, and brainstem [17]. In the case of renal failure, uremic toxins and metabolic acidosis cause disruptions in the normal excitatory-inhibitory amino acid balance and metabolic acidosis. ...
Consciousness is believed to arise from two inter-related brain functional states: wakefulness , reflecting an individual’s level of arousal and response to external stimuli, and awareness , representing the content of one’s conscious experience and the ability to interact with the external environment. Disruption to either or both states may result in a patient being “found down.” The inability to take an accurate medical history, the limitations of physical examination in the obtunded patient, and the need to rapidly make treatment decisions position imaging centrally within the evaluation of most of these patients. Radiologists should be prepared to help decide on an appropriate imaging strategy, suggest a limited differential diagnosis as to root causes for the patient’s condition, identify problems that mandate emergent medical or surgical intervention and, in some cases, assist in defining short- and long-term prognosis.
... Hyperammonemic encephalopathy affects regions, including the insular cortex, cingulate gyrus, and thalamus, exhibiting high signal intensity on DWI and low signal intensity on ADC, which signifies an acute injury. 1 In one study, high signal intensity in the insula cortex and cingulate gyrus was observed in all the patients. 2 Another study 3 reported that hyperintense areas in these regions were characteristic of hyperammonemic encephalopathy and that the occipital lobe and perirolandic cortex were more likely to appear normal. This is consistent with the findings in our patient. ...
... Uremic encephalopathy is a metabolic condition linked to renal failure with specific MRI patterns including the posterior reversible encephalopathy syndrome or cytotoxic oedema of basal ganglia [8] . Hyperammonemic encephalopathy shows particular MRI characteristics with bi-lateral symmetrical hyperintensities on both DWI and FLAIR interesting the dorsomedial thalamus and the cingulate and insular cortices [9] . Thiamine deficiency usually occurs with symmetrical T2/FLAIR hyperintensity in the regions around the third ventricle [10] . ...
Hypoglycemia is known as a sudden diminution in blood glucose level <50 mg/dL. Hypoglycemic encephalopathy is a metabolic encephalopathy that is usually observed in patients treated for diabetes or chronic alcoholism. Neurological manifestations may range from transient deficits to prolonged coma, depending on the duration and severity of hypoglycemia. Neuroradiological features of hypoglycemia are variable involving the cerebral white and gray matter regions. Acquired metabolic or toxic conditions can cause hypoglycemia-like damage to the cerebral white matter and basal ganglia. Widespread lesions in the brain parenchyma or basal ganglia have a poor prognosis. In this report, we present a patient with widespread brain damage secondary to profound and prolonged hypoglycemia.
... This soft-tissue infection has a high mortality rate when primarily involving the superficial fascia, subcutaneous fat, and deep fascia. 1 Staphylococcus aureus is one of the causative organisms of necrotizing fasciitis; however, infections are rare. Prolonged hyperammonemia is a fatal condition associated with brain injury, but is uncommon in necrotizing fasciitis patients. ...
... Hyperammonemia is frequently related to the liver's ammonia metabolism failure. 1,2 In nonhepatic etiology, massive muscle damage provides the nitrogen source and increases urea formation. 2 S. aureus is urease positive and catalyzes urea to ammonia. ...
This study described a rare case of necrotizing fasciitis presenting as neural dysfunction. The patient's serum ammonia level was significantly elevated; however, no liver function impairment was observed. Hyperammonemia is frequently related to the liver's ammonia metabolism failure. In literature reviews, infections also induce critical complications in specific circumstances. Herein, a rare case of Staphylococcus aureus necrotizing fasciitis with a hyperammonemic encephalopathy presentation was offered.
... Only our third patient underwent MRI, which showed extensive diffuse cortical restricted diffusion and FLAIR hyperintensities (Figure 1). This cortical injury has been shown to be potentially reversible 12 . Sadly, all three of our patients had poor outcomes. ...
Non-hepatic hyperammonemia syndrome is a rare cause of neurologic dysfunction and cerebral edema and has most commonly been reported in post-transplant patients. Only recently has opportunistic infection with Ureaplasma species and Mycloplasma hominis been found to be key to the pathogenesis. We describe the cases of three immunosuppressed patients who developed hyperammonemia syndrome with new onset refractory status epilepticus and diffuse cerebral edema. PCR was positive for Mycloplasma hominis in one patient and Ureaplasma parvum in the other two. Despite of early diagnostic suspicion and aggressive management with empirical antibiotics, seizure control, hypertonic saline, and ammonia elimination, none of our patients survived this life-threatening infection. Non-hepatic hyperammonemia and new onset seizures can be presenting features of disseminated Ureaplasma species and Mycoplasma hominis infections in post-transplant patients. Immunosuppression in the absence of organ transplantation is likely sufficient to trigger this entity, as was the case in our third patient. When suspected, empiric combination antibiotics should be used due to high likelihood of resistance. The diagnostic test of choice is PCR. Patients with hyperammonemia syndrome associated with these infections typically have a poor prognosis. Early recognition and aggressive multimodal interventions may be key to ameliorating the high mortality and severe neurologic sequelae from this entity.
... 3 On neuroimaging, extensive cortical injury and a finding of bilateral and symmetrical involvement of the insular and cingulate cortices is suggestive of hyperammonaemic encephalopathy. 9 The cortical changes have been shown to be largely reversible, which is consistent with what was seen in our case (see figure 2). ...
Hyperammonaemia syndrome secondary to Ureaplasma spp. infection is well documented in the post-lung transplant population. We report a case of a man in his fifties with hyperammonaemia syndrome secondary to disseminated Ureaplasma parvum infection. This occurred in the context of immunosuppression for chronic graft versus host disease and six years following an allogeneic stem cell transplant for diffuse large B-cell lymphoma. Following treatment of U. parvum septic arthritis with ciprofloxacin and doxycycline, the patient experienced a full neurological recovery, and continues on suppressive doxycycline therapy with no recurrence of symptoms to date.
... On the other hand, chronic hyperammonemia due to cirrhosis or urease cycle enzyme defects causes hyperintensity changes in the globus pallidus, thalamus, and cortices (parietal, temporal, occipital, and frontal cortices), as observed with T2-Fluid-attenuated inversion recovery. [13] No abnormalities were observed in our patient on MRI. This may be due to the short duration of the illness, the patient's blood ammonia level, and early medical intervention on day three of the illness. ...
Opsoclonus myoclonus syndrome (OMS) is a rare autoimmune condition occurring due to Purkinje cell degeneration due to remote aetiology. Most often it occurs as a paraneoplastic syndrome. Here we report a case of opsoclonus-myoclonus-ataxia tremor syndrome in a 60-year-old woman that occurred due to hyperammonemia and she recovered completely with immunotherapy and correction of hyperammonemia. OMS is the first in literature associated with hyperammonemia.
... 21 Neuroimaging demonstrates characteristic changes of hyperammonemia encephalopathy, diffusion restriction seen with diffusion weight imaging (DWI) on MRI are predominantly in the cortex-mainly the insular cortex and cingulate gyrus and are diffuse, symmetrical, and have corresponding fluid attenuated inversion recovery (FLAIR) hyperintensities (Figures 1 and 3). [22][23][24] The biochemical abnormalities seen with OTC deficiency and CPS-1 deficiency include hyperammonemia, elevated levels of glutamine, alanine, and asparagine, which serve as storage forms of waste nitrogen, and normal or decreased levels of citrulline. To differentiate between the 2 deficiencies, urine orotic acid is measured and elevated in OTC deficiency. ...
Elevated ammonia levels lead to cerebral edema, encephalopathy, seizures, coma, and death. Hyperammonemia is primarily associated with liver disease; however, there are rare cases without liver disease. Noncirrhotic hyperammonemia is primarily due to increased production and/or decreased elimination of ammonia. We present a rare case of a 35-year-old female with severe acute noncirrhotic hyperammonemia associated with gram-negative septic shock and a suspected undiagnosed partial urea cycle enzyme deficiency. She had elevated blood and urine amino acid levels speculated to be due to an underlying urea cycle defect, which was unmasked in the setting of septic shock with urea splitting bacteria leading to severely elevated ammonia levels. Ammonia levels were rapidly corrected with hemodialysis, as other conventional treatments failed. We highlight the importance of considering noncirrhotic causes of hyperammonemia in patients with elevated ammonia levels and intact liver function. Prompt treatment should begin with reducing the catabolic state, nitrogen scavenging, replacing urea cycle substrates, decreasing intestinal absorption, and augmented removal of ammonia with renal replacement therapy.
... The brain MRI showed signal abnormalities and involvement of white matter that are reminiscent of those reported in the literature in patients with HA. Although we cannot ignore that this might be attributed to other factors such as hypoxic injury or recurrent hypoglycemia, it is plausible that the pattern in our patient may be directly related to HA [18][19][20]. Ammonia toxicity in the brain is tightly connected to glutamine metabolism [21][22][23]. This observation is supported by MRS that has shown high glutamine concentrations during HA in rat models [24,25] but also in human with UCD or hepatic encephalopathy (Table 1) [13,14,[26][27][28][29][30][31][32][33][34][35][36][37]. ...
Hyperinsulinism/hyperammonemia syndrome (HI/HA) is an autosomal dominant disorder caused by monoallelic activating mutations in the glutamate dehydrogenase 1 (GLUD1) gene. While hyperinsulinism may be explained by a reduction in the allosteric inhibition of GLUD1, the pathogenesis of HA in HI/HA remains uncertain; interestingly, HA in the HI/HA syndrome is not associated with acute hyperammonemic intoxication events. We obtained a brain magnetic resonance (MR) in a woman with HI/HA syndrome with chronic asymptomatic HA. On MR spectroscopy, choline and myoinositol were decreased as in other HA disorders. In contrast, distinct from other HA disorders, combined glutamate and glutamine levels were normal (not increased). This observation suggests that brain biochemistry in HI/HA may differ from that of other HA disorders. In HI/HA, ammonia overproduction may come to the expense of glutamate levels, and this seems to prevent the condensation of ammonia with glutamate to produce glutamine that is typical of the other HA disorders. The absence of combined glutamate and glutamine elevation might be correlated to the absence of acute cerebral ammonia toxicity.
... Pediatric patients presenting with hyperammonemia generally show urea cycle defects, organic acid disorders, or fatty acid oxidation disorders, though other causes are also possible in rare cases [7]. Adults presenting with hyperammonemia show either increased ammonia load due to infection, protein overload, gastrointestinal bleed, severe exercise, seizures, trauma, certain drugs etc. or can be due to decreased ammonia excretion like acute hepatic dysfunction, post-operative, inborn errors of urea metabolism, drugs, etc. [8,9]. ...
... Post-operative hyperammonemia is commonly linked to cases of lung transplantation [10,11], transurethral resection of prostrate [12,13], bone marrow transplantation [14], portosystemic shunt surgeries, and gastrointestinal carcinoma [15,16], though stress involved with other major surgeries can also precipitate the same. Yoshida et al. report their experience about fatal outcomes following heart-lung transplantation [17] as was 1 of the 4 patients reported by U-King-Im et al. [9]. ...
... 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 or. herniation [9]. ...
Abstract
Objective
To synthesize the evidence for incidence, pathophysiology, etiology, and protocol-based management of hyperammonemia in lung transplant patients.
Background
Elevated ammonia levels are toxic to the brain, and hyperammonemia results in a potentially fatal complication for lung transplant recipients. The hallmark of this condition is ammonia production being way out of proportion to the degree of liver derangement. While there are many hypotheses, the cause remains obscure.
Methods
A retrospective review of patients with hyperammonemia following lung transplantation was done to understand the pathophysiology, various treatment modalities, and its impact on patient mortality and morbidity. Studies in the English literature were identified through an electronic database search from PubMed/MEDLINE, Ovid Embase, Google Scholar, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Web of Science, and ClinicalTrials.gov until June 2020. No restriction of dates were used, and the search was up until June 2020.
Discussion
Mortality among patients with hyperammonemia following lung transplantation is high. Multi-modal treatment approaches include avoiding nephrotoxic drugs, use of bowel decontamination, nitrogen scavengers, branched-chain amino acids, adjustment of immunosuppression, antibiotics like fluoroquinolones or azithromycin, and renal replacement therapy. However, there remains a scarcity of preoperative screening protocol for patients at risk of hyperammonemia as well evidence-based post-operative management guidelines. Intermittent hemodialysis, compared to continuous venovenous hemodialysis, provides better patient outcomes.
Conclusion
Early detection of patients at risk by appropriate screening, along with maintaining a high degree of suspicion for hyperammonemia and multi-modal treatment approach, is the key to successful patient outcomes. Further prospective observational studies would facilitate development of protocol-based treatment of this potentially fatal condition.
