Original Article
Brief Report
Organic Osmolytes in the Brain of an Infant with Hypernatremia
N Engl J Med 1994; 331:439-442August 18, 1994
- Article
Neurologic symptoms due to electrolyte disorders are common, occurring in patients with diarrhea, diabetes mellitus, head injury, renal failure, and many other disorders, especially in infants and the elderly. The clinical syndromes of dehydration and overhydration, often first detected in measurements of plasma sodium or osmolality, are among the most frequent causes of the neurologic symptoms, which include irritability, seizures, lethargy, and coma. There are multiple hormonal and neurogenic mechanisms to maintain total body water and the concentration of solutes (osmolality) within narrow limits. Interruption of these homeostatic mechanisms leads to the retention or loss of either water or solute; the result may be overhydration (with hypo-osmolality) or dehydration (with hyperosmolality). Neurologic function may be impaired in both hypo-osmolar and hyperosmolar states. Forty to 60 percent of children with severe hypernatremia (defined as a plasma sodium concentration ≥ 160 mmol per liter) have neurologic symptoms, as do a majority of patients with hyponatremia (plasma sodium concentration <120 mmol per liter). The mortality rate in patients with severe hypernatremia is as high as 50 to 60 percent1.
Rapid cerebral dehydration can rupture the blood vessels connecting the brain to the rigid calvarium. As a protective mechanism, the brain appears to generate new intracellular solute (sometimes called “idiogenic osmoles”)2. Osmoles (or osmolytes) are volume-regulatory organic solutes that can accumulate to a high concentration within cells, without adverse effects on cellular structure or function. Intracellular osmolality is thereby increased, minimizing the loss of intracellular brain water. A corollary of this process is the clinical observation that overly rapid correction of hyperosmolar states can be fatal. As extracellular fluid is replaced, the increase in intracellular water associated with idiogenic osmoles can lead, it is presumed, to cerebral edema. The rates of accumulation or removal of the idiogenic osmoles are unknown, so that treatment of patients with hyperosmolal and hypo-osmolal states is empirical.
The concept of idiogenic osmoles has recently received support from the identification of several metabolites that are also putative organic osmoles -- myo-inositol, N-acetylaspartate, choline (including glycerophosphoryl choline), and taurine -- in the brains of laboratory animals3,4. The most important of these compounds can be quantified with proton nuclear magnetic resonance (NMR) spectroscopy in the brains of humans in vivo5. We describe here a patient with severe dehydration in whom myo-inositol and other substances accumulated and may have functioned as osmolytes, accounting for the presenting neurologic syndrome and slow recovery from hypernatremia.
Methods
Patient
An 18-month-old girl presented with severe dehydration and hypernatremia (plasma sodium concentration, 195 mmol per liter). The child had not been drinking and was lethargic but otherwise normal. During the correction of dehydration with intravenous glucose plus 0.45 percent sodium chloride, the child's plasma sodium concentration decreased progressively to 144 mmol per liter in three days. Her lethargy diminished, but she had two seizures. The rate of fluid replacement was then reduced. The child's condition improved, she had no further seizures, and she was alert at discharge after 24 days.
Magnetic resonance imaging (MRI) and proton NMR spectroscopy of the cerebral cortex were performed 4, 7, 12, 22, and 36 days after admission to the hospital. The plasma sodium concentration was 156 mmol per liter on day 4 and 140 mmol per liter on day 36.
The proton NMR spectroscopy and MRI studies were approved by the local institutional review board, and written informed consent was obtained from the child's parents and those of normal control subjects of similar age.
Proton NMR Spectroscopy
After MRI, quantitative proton NMR spectroscopy was performed in the parietal and occipital regions of the patient's cerebral cortex, containing primarily white matter and gray matter, respectively. Spectra from the same regions in 50 normal infants were also acquired. The water content of the brain and the volume of cerebrospinal fluid were evaluated by measuring the large difference in T2 transverse relaxation time between them with a quantitative assay described in detail elsewhere6. Subsequent studies of the patient were performed in the same region of the occipital cortex with use of a single axial MRI sequence to verify the location. The images and proton spectra were acquired with a conventional 1.5-T Signa General Electric magnetic resonance scanner.
The first study, performed four days after admission, was obtained from a 12-ml volume of tissue situated across the midline in the gray matter of the occipital cortex and a region of largely white matter in the posterior parietal cortex, with a stimulated echo sequence, a repetition time of 3.0 seconds (and also of 1.5 and 5.0 seconds), an echo time of 30 msec, and a mixing time of 13.7 msec, with 64 repetitions. Quantitation, performed according to the method of Ernst et al.6 and Kreis et al.,7 was confirmed by the determination of the transverse relaxation times (T1 and T2) of the patient's principal cerebral metabolites. The patient's T1 and T2 relaxation times did not differ from those of normal infants8.
Difference spectroscopy, which consists of subtracting the spectra obtained at successive examinations, after scaling them to their appropriate absolute peak intensities,8 was performed for the identification of metabolites. The amount of excess organic osmolytes (idiogenic osmoles) was calculated as the total amount of myo-inositol, choline, creatine, glutamine, and N-acetylaspartate less the mean values obtained for these substances in 50 normal infants8. The excess of each metabolite in the patient could then be calculated and expressed in millimoles or milliosmoles per kilogram.
Results
MRI revealed partial holoprosencephaly, with a normal pituitary stalk but no cerebral edema or tumor. Proton NMR spectroscopy of occipital gray matter (Figure 1Figure 1
Short-Echo-Time Proton NMR Spectrum of Cortical Gray Matter in an Infant with Severe Dehydration.) and parietal white matter (not shown) revealed several striking abnormalities. The principal abnormality was a reversal of the normal ratio of peak intensities between the neuronal metabolite N-acetylaspartate and the putative osmolyte myo-inositol. The ratio of N-acetylaspartate to myo-inositol (normally approximately 2.33)8 was only 0.3 when this infant was first studied. In addition, the ratios of choline, glutamine (plus glutamate), and scyllo-inositol (or taurine) to creatine were increased, whereas the ratio of N-acetylaspartate to creatine was reduced. The relaxation values for the metabolites, which if altered by disease can contribute to differences in spectra, did not differ from those in normal infants. The explanation for the changing metabolite ratios became clear after quantitative procedures involving proton NMR spectroscopy were applied6,7. The principal change was in the concentration of myo-inositol, which was three times normal, whereas that of N-acetylaspartate was normal or only minimally reduced as compared with the concentration in an age-matched normal subject. Concentrations of choline and glutamine (plus glutamate) were also increased.The sequential spectra obtained during correction of the dehydration are shown in Figure 2Figure 2
Changes in the Concentrations of Principal Cerebral Organic Osmolytes during the Correction of Severe Dehydration.. The myo-inositol concentration fell progressively, as did those of choline and creatine. The concentration of N-acetylaspartate increased slightly, then returned to normal. The negative peaks in the difference spectra indicate metabolites that were lower in concentration after treatment. The water content of the brain (84 percent on day 4 and 82 percent on day 12) and the T2 relaxation time for water were normal for age8.The calculated concentrations of the five principal metabolites shown in spectra of the infant's brain (myo-inositol, choline, creatine, glutamine, and N-acetylaspartate) on days 4 to 36 are shown in Table 1Table 1
Results of Clinical Proton NMR Spectroscopy for Cerebral Osmometry of the Brain of an Infant with Hypernatremia and Normal Subjects.. The concentration of myo-inositol on day 4 was three times higher than that in normal subjects of the same age. Other substances with elevated concentrations at that time of measurement were choline, scyllo-inositol, creatine, and glutamine (plus glutamate). These levels all decreased to normal during the 36-day study period. If we assume that myo-inositol and the other organic molecules are the same osmolytes identified in earlier studies in animals (with the exception that scyllo-inositol is found in the human brain, rather than taurine, which is found in rat brain), then the excess intracellular osmotic pressure in the brain can be estimated, both when the child was dehydrated and obtunded and later, after correction. We estimate an excess of 17 mOsm initially, falling to about 6 mOsm after 7 days, and returning to normal only after 36 days. The change in total brain water was not significant (the standard error associated with the method was ±3 percent).Discussion
Holoprosencephaly is commonly associated with a deficiency of thirst and with dehydration,2,12 leading to hypernatremia and neurologic symptoms. These changes were associated with increased concentrations of osmotically active solute in the brain. We have also found changes in these metabolites in adults13 and children recovering from diabetic ketoacidosis and in patients with hypernatremia and hyponatremia14.
The direct determination of patterns of disordered cerebral organic osmolytes by proton NMR spectroscopy may be valuable in guiding therapy. In the presence of severe changes in intracellular osmolytes in the brain (as in this infant), a much slower correction of the plasma sodium concentration, possibly over a period of 7 to 10 days, may be indicated. Conversely, a normal pattern of cerebral osmolytes may permit the safe and rapid replacement of fluids. Repeating proton NMR spectroscopy after 7 to 10 days, or earlier in the event of seizures, may show that a normal cerebral-osmolyte profile has yet to be achieved and may lead to even slower replacement therapy. Central pontine myelinolysis, a rare but fatal complication of severe hypernatremia, may become predictable and it may be possible to prevent it.
Disorders of cerebral osmotic regulation may be more prevalent than has been hitherto assumed. A simplified procedure for NMR spectroscopy of the brain, automated single-voxel acquisition proton NMR spectroscopy (Probe, General Electric Medical Systems),15 now brings this means of measuring osmolyte accumulation within the scope of any hospital with an MRI scanner of 1.5-T field strength.
Supported by a grant from the L.K. Whittier Foundation, South Pasadena, Calif.
We are indebted to Linda Fisher, M.D., for advice on the medical treatment of this child and to Richard Yadley, M.D., for reading the MRI scans.
Source Information
From the Magnetic Resonance Spectroscopy Unit, Huntington Medical Research Institutes (J.H.L., B.D.R.); and Huntington Memorial Hospital (E.A.) -- both in Pasadena, Calif.
Address reprint requests to Dr. Ross at Huntington Medical Research Institutes, 660 S. Fair Oaks Ave., Pasadena, CA 91105.
- References
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Full Text
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