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Single voxel MR spectroscopy (MRS) (TR/TE msec, 1500/35). Initial exam (a; left basal ganglia voxel) shows an elevated glutamine and glutamate peak complex at 2-2.5 ppm and 3.8 ppm (Glx) and reduction of myoinositol (MI). 19 days later, similar changes were present in the same area (b), though subtle differences cannot be discerned due to ferromagnetic artifact on the first study. On the pentultimate MRS performed 3 months later, no significant glutamine or glutamate elevation was present in the left parietal white matter; however, myoinositol was mildly depressed. On the final MRS performed at 6-month follow-up over the left basal ganglia, similar changes are noted; glutamine remains well-controlled and myoinositol and choline (Cho) were mildly depressed.
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Background:
Urea cycle-related brain disease may take on variable neuroimaging manifestations, ranging from normal to abnormal with or without a signature appearance. In the past, we have described the usefulness of multimodal imaging in identifying biomarkers of neuronal injury in UCD patients. In this study, we report unique findings in an adole...
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Citations
... 8,9 In one of the studies reporting ASL findings in hyperammonemic encephalopathy due to urea cycle disorders, initial hypoperfusion was followed by hyperperfusion. 10 In the index case, profound increase in CBF was noted on ASL in the acute phase. These findings are in correspondence with the presence of cytotoxic cerebral edema. ...
We describe a very rare case of acute fulminant hepatic failure as a complication of acute viral hepatitis caused by hepatitis A virus, complicated by hyperammonemic encephalopathy. The brain magnetic resonance imaging (MRI) findings were suggestive of cytotoxic edema involving bilateral cerebral hemispheres. The novel findings of hyperperfusion on arterial spin labeling perfusion MRI and hyperemic hypoxia on susceptibility weighted imaging are discussed. The patient had a rapid progression of cerebral edema and succumbed to the illness despite supportive care. Characteristic neuroimaging findings may help in the diagnosis of acute hyperammonemic encephalopathy of brain MRI, which may be useful in leading to appropriate clinical workup and diagnosis of the underlying cause of hyperammonemia. In our case, hyperammonemic encephalopathy was precipitated by fulminant hepatic failure caused by hepatitis A virus, which is a rare occurrence.
... 8,9 In one of the studies reporting ASL findings in hyperammonemic encephalopathy due to urea cycle disorders, initial hypoperfusion was followed by hyperperfusion. 10 In the index case, profound increase in CBF was noted on ASL in the acute phase. These findings are in correspondence with the presence of cytotoxic cerebral edema. ...
... Hyperammonemia-induced brain injury is the principal mechanism responsible for MRI and spectroscopic abnormalities in UCD. Ammonia causes perfusion dysautoregulation and upregulates glutamine synthetase, increasing brain glutamine (in excess, impairs osmoregulation) and glutamate (in excess, causes excitotoxicity) [6,[24][25][26][27]. White matter and/or deep gray nuclei can be interrogated by MRS; however, frontal white matter may yield the most reliable results [24]. ...
... Glutamine and glutamate concentration on MRS correlates more with clinical status than plasma glx and ammonia levels. Therefore, MRS is well suited to track the metabolic recovery of the brain demonstrating resolution of lactate and improved glutamine and myoinositol levels [6,[24][25][26][27]. ...
... The most characteristic form of brain involvement in UCD is the central pattern with mixed cytotoxic and vasogenic edema most severely affecting the perirolandic, periinsular, and basal ganglia regions [6,[27][28][29]. Thalami are typically spared. ...
Proton MRS of the brain provides the ability to gather direct information regarding the metabolic status of the brain at the time of MRI. Although selective vulnerability of brain tissue may yield distinct imaging patterns in neurometabolic disorders, it is not uncommon for the brain MRI to be normal, nonspecific, or show ambiguous abnormalities among several possible diagnoses, metabolic, or otherwise. This review highlights childhood neurometabolic diseases in which 1H MRS may show diagnostic or suggestive metabolic profiles without complicated acquisition or postprocessing techniques.
... MRS samples brain tissue directly and often outperforms surrogate markers (blood and CSF analyses) in evaluation of brain tissue [1][2][3][4][5][6][7][8]. Further, CSF attainment via lumbar puncture can be difficult and risky in acutely ill patients, with the procedure often being avoided or delayed. ...
Despite its vigorous ability to detect and measure metabolic disturbances, ¹H MRS remains underutilized in clinical practice. MRS increases diagnostic yield and provides therapeutic measures. Because many inborn metabolic errors are now treatable, early diagnosis is crucial to prevent or curb permanent brain injury. Therefore, patients with known or suspected inborn metabolic errors stand to benefit from the addition of MRS. With education and practice, all neuroradiologists can perform and interpret MRS notwithstanding their training and prior experience. In this two-part review, we cover the requisite concepts for clinical MRS interpretation including technical considerations and normal brain spectral patterns based on age, location, and methodology.
... 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]. In contrast, MRS in our patient showed normal level of Glx compared to controls together with borderline low plasma glutamine level. ...
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.
... Brain disorders related to UCDs may be evidenced by neuroimaging with manifestations ranging from normal to abnormal with or without a signature appearance. In recent years, it has been demonstrated that multimodal brain MRI using T1 weighted image, T2 weighted image, T2 fluid-attenuated inversion recovery, diffusionweighted image, functional MRI, or/and 1 H/ 13 C magnetic resonance spectroscopy (MRS) is effective for the identification and evaluation of pathogenic neurologic conditions in patients with UCDs [37]. In patients with OTCD, even a partial or asymptomatic OTCD, 1 H MRS could detect increased glutamine levels, reduced myoinositol and choline levels in the brain, including frontal and parietal white matter, frontal gray matter, posterior cingulate gray matter, and thalamus [38]. ...
Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.
... Other MRI findings may include signal intensity increase in the regions of frontal lobes, cingulate gyri, temporal lobes, as well as the insular regions (60). Many patients may have a normal MRI with changes that appear after an acute hyperammonemic episode (61). ...
... Although there are several reports of multimodal MRI at baseline or during acute HA, less is known about the recovery of HA with regard to changes in time and space. A prospective multimodal sequence of an OTCD patient with MRI/MRS exams performed during (5 over 1 month) and after (3 and 5 months) a hyperammonemic episode demonstrated abnormal signal changes in the posterolateral putamen, and supplemental motor strip (SMA), pre-motor cortex, and post-central gyrus (61). This occurred with cerebral hypoperfusion evolving to hyperperfusion. ...
... This is not surprising since many patients report residual neurocognitive slowing following HA recovery. This study demonstrated the long-term effects and altered structural and metabolic sequence despite resolution of plasma markers of altered metabolism (61). ...
The urea cycle disorders (UCD) are rare genetic disorder due to a deficiency of one of six enzymes or two transport proteins that act to remove waste nitrogen in form of ammonia from the body. In this review, we focus on neuroimaging studies in OTCD and Arginase deficiency, two of the UCD we have extensively studied. Ornithine transcarbamylase deficiency (OTCD) is the most common of these, and X-linked. Hyperammonemia (HA) in OTCD is due to deficient protein handling. Cognitive impairments and neurobehavioral disorders have emerged as the major sequelae in Arginase deficiency and OTCD, especially in relation to executive function and working memory, impacting pre-frontal cortex (PFC). Clinical management focuses on neuroprotection from HA, as well as neurotoxicity from other known and yet unclassified metabolites. Prevention and mitigation of neurological injury is a major challenge and research focus. Given the impact of HA on neurocognitive function of UCD, neuroimaging modalities, especially multi-modality imaging platforms, can bring a wealth of information to understand the neurocognitive function and biomarkers. Such information can further improve clinical decision making, and result in better therapeutic interventions. In vivo investigations of the affected brain using multimodal neuroimaging combined with clinical and behavioral phenotyping hold promise. MR Spectroscopy has already proven as a tool to study biochemical aberrations such as elevated glutamine surrounding HA as well as to diagnose partial UCD. Functional Near Infrared Spectroscopy (fNIRS), which assesses local changes in cerebral hemodynamic levels of cortical regions, is emerging as a non-invasive technique and will serve as a surrogate to fMRI with better portability. Here we review two decades of our research using non-invasive imaging and how it has contributed to an understanding of the cognitive effects of this group of genetic conditions.
... 11 Irreversibility mainly occurs in case of prolonged hyperammonemic crises and/or when blood ammonia reaches levels between 200 and 500 mM, during the 2 first years of life. [12][13][14][15][16][17] It has previously shown that neonates with UCDs may present with seizures during HA. 7,18 However, most of the seizures are subclinical, and therefore only identified with prolonged continuous EEG. ...
Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy.
... Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error of metabolism and the most common of the urea cycle disorders (1). Deficient protein metabolism in OTCD results in hyperammonemia (HA) that, in turn, disrupts the neurocognitive function in domains of working memory and executive function in several brain regions, including prefrontal cortex (PFC) (2)(3)(4). Investigation of neurocognitive function in working memory domain can become critical to understand the underlying effects of hyperammonemia in patients with OTCD. ...
Ornithine transcarbamylase deficiency (OTCD) is the most common form of urea cycle disorder characterized by the presence of hyperammonemia (HA). In patients with OTCD, HA is known to cause impairments in domains of executive function and working memory. Monitoring OTCD progression and investigating neurocognitive biomarkers can, therefore, become critical in understanding the underlying brain function in a population with OTCD. We used functional near infrared spectroscopy (fNIRS) to examine the hemodynamics of prefrontal cortex (PFC) in a fraternal twin with and without OTCD. fNIRS is a non-invasive and wearable optical technology that can be used to assess cortical hemodynamics in a realistic clinical setting. We quantified the hemodynamic variations in total-hemoglobin as assessed by fNIRS while subjects performed the N-back working memory (WM) task. Our preliminary results showed that the sibling with OTCD had higher variation in a very low frequency band (<0.03 Hz, related to mechanism of cerebral autoregulation) compared to the control sibling. The difference between these variations was not as prominent in the higher frequency band, indicating the possible role of impaired autoregulation and cognitive function due to presence of HA. We further examined the functional connectivity in PFC, where the OTCD sibling showed lower interhemispheric functional connectivity as the task load increased. Our pilot results are the first to show the utility of fNIRS in monitoring OTCD cortical hemodynamics, indicating the possibility of inefficient neurocognitive function. This study provides a novel insight into the monitoring of OTCD focusing on the contribution of physiological process and neurocognitive function in this population.
Magnetic resonance spectroscopy (MRS) is a valuable adjunct to structural brain imaging. State-of-the-art MRS has benefited greatly from recent technical advancements. Neurometabolic alterations in pediatric brain diseases have implications for diagnosis, prognosis, and therapy. Herein, the authors discuss MRS technical considerations and applications in the setting of various pediatric disease processes including tumors, metabolic diseases, hypoxic/ischemic encephalopathy/stroke, epilepsy, demyelinating disease, and infection.
