Clinical Semiology and Neuroradiologic Correlates of Acute Hypernatremic Osmotic Challenge in Adults: A Literature Review

Clinical Characteristics of Patients with Hypernatremic Challenge

The clinical symptoms of CNS injury ranged from subtle changes of cognitive functions to life-threating autonomic and brain stem dysfunction and death. This spectrum of clinical manifestations is similar to that found in hyponatremia.^31,32

In our review, clinical symptoms did not correlate with age, presence of comorbid conditions, initial Na⁺, serum osmolality, or Na⁺ correction rate. This finding would suggest that neither type of clinical symptom nor its severity is influenced by the severity of osmotic challenge. However, in hyponatremia, some studies reported no association between the degree of osmotic derangement and the clinical situation,^33,34 while some reported that lower Na⁺ level and more rapid Na⁺ correction rates³⁵ were associated with a more severe clinical presentation. It appears that the absolute level of Na⁺, whether abnormally high or low, does not result in a specific set of symptoms and that the emerging clinical presentation is shaped by different sets of factors and mechanisms impacting various components of the neuronal apparatus, including neurons, glia, blood-brain barrier, and CSF. The presence of additional metabolic derangements like hypokalemia³⁶ and hyperglycemia² is considered an independent risk factor for ODS development, which is not covered in this review.

All patients included in this review endured acute hypernatremia. While cases of chronic hypernatremia were not included, the distinction between acute and chronic challenge is important because different mechanisms of brain-volume regulation exhibit differential dynamics in acute-versus-chronic osmotic challenge. Data emerging from experimental animal studies indicate that under extreme osmotic challenge, the engagement of organic brain osmoles occurs later in the course of osmotic insult and develops more slowly than the instant changes in inorganic ions, potentially setting a course of different changes in brain tissue. In acute hypernatremia, osmotic differences are actually subtle due to rapid ionic and water shifts across the cell membrane with little effect on cell volume but with significant effect on extracellular space volume, which decreases significantly. In chronic hypernatremia, organic osmoles seem to play a much more important role in helping to maintain the osmotic gradient.^{37⇓⇓–40} The temporal dissociation between these 2 adaptive osmoregulating mechanisms, whether at the acute or chronic stage, could account, at least in part, for the nature and severity of neurologic symptoms. General clinical observations suggest that patients with acute hypernatremia or hyponatremia develop a more clinically severe condition and have worse outcomes that those with chronic challenges.⁴¹

Neuroradiologic Features of Patients with Hypernatremic Challenge

Examination in our study of neuroradiologic features of hypernatremic challenge showed the prevailing appearance of ODS (CPM or EPM or both) followed by cerebral volume changes (edema and shrinkage) and vascular complications (hemorrhage and infarction).

Osmotic Demyelination Syndrome

CPM and EPM (ODS) are classically described as clinical and radiologic manifestations of osmotic myelinolysis, affecting different brain regions, confined to the pons in cases of CPM and extrapontine sites in cases of EPM. The radiologic description of CPM entails the presence of “trident-shaped” symmetric hypointense lesions on T1 and corresponding hyperintense lesions on T2-weighted images located in the brain stem, and sparing of other brain regions.⁴² In cases of EPM, the same features are noted typically in sites such as the internal capsule, basal ganglia, cerebellum, and cerebrum.⁴³

The neuroradiologic features of ODS lesions in the context of hyponatremia are frequently reported not to match the severity of clinical symptoms because the features might be absent despite clinical abnormalities or at times may persist well beyond clinical resolution.^44,45 We observed similar clinical-radiologic dissociation in cases of hypernatremia. This may potentially be explained by the variability of time intervals between the onset of symptoms and radiologic imaging, the sensitivity of the radiologic technique used, or the presence of gliosis-related abnormal signals that persists well beyond clinical recovery.⁴⁶

In reviewed data, other variables seemed to be more correlated. The presence of an indirect CNS comorbid condition (hepatic or renal failure) before hypernatremic challenge rendered the brain more vulnerable to ODS even with mildly elevated Na⁺ levels in comparison with patients with no comorbid conditions. More specifically, those patients presented with more corpus callosum, WM, BG, and hippocampus lesions. Patients with liver disease or those who had transplantation are more at risk for developing CNS complications, including ODS, probably secondary to metabolic and cerebral hemodynamic derangements^47,48 that might render osmotic regulatory mechanisms insufficient.

Hippocampal lesions were reported in more than one-third of patients and were associated with higher initial Na⁺ levels. The high hippocampal involvement may be related to its high vulnerability to the neurotoxic effects of osmotic derangements⁴⁹ and systemic stresses in general.^50,51

In reviewed cases, contrast enhancement associated with ODS lesions was reported in 1 patient,²³ which has also been reported in some cases of hyponatremia.⁵² Although inconsistently found, contrast enhancement is in agreement with the pathophysiologic changes observed in experimental models of ODS, in which BBB disruption occurs secondary to osmotic stress and is thought to be one of the leading factors in pathogenesis of ODS. A disruption of the BBB during the first 24 hours of hyponatremia was found to be associated with a 70% risk of developing demyelination.⁵³ By contrast, the risk of developing subsequent demyelination was only 8% when the BBB was intact.⁵³ Furthermore, the use of dexamethasone, known to protect the BBB, was reported to decrease the risk of ODS both in animal studies⁵⁴ and case reports.⁵⁵

Cortical laminar necrosis has been described occasionally in patients with severe ODS that follows rapid correction of hyponatremia.^{56⇓⇓–59} In the present study, we identified 2 patients presenting with cortical laminar necrosis.^23,24 These lesions may be associated with hypoxia-ischemia, which may coexist with ODS, or severe demyelination that subsequently triggers cortical neuronal loss. It has been suggested that cortical lesions in the context of ODS present more often with ischemia than with demyelination.⁶⁰

Topographic Distribution of ODS in Hypernatremia: Relation to Region-Specific Vulnerability

In ODS, regardless of the etiology, CPM is consistently reported to be more common than EPM or CPM/EPM combined.^45,61 However, in a large case series of patients with hyponatremia and ODS, the combined form was more common than EPM and CPM alone.³³ As we have already stated, the reviewed data of hypernatremic osmotic challenge have revealed that EPM was more common than CPM or CPM/EPM combined. Whether this hints at a possible predilection of a hypernatremic challenge for extrapontine sites warrants further investigations.

Age appears to be an important factor in the topographic vulnerability to hyperosmotic conditions. Younger adults had different topographic distributions than older adults, with the white matter, corpus callosum, and basal ganglia particularly affected.

Unlike in the adult population, hypernatremic osmotic brain injury is far more common in the pediatric population. Most interesting, the neurologic manifestations of hypernatremia in the pediatric population are strikingly similar to observations made in adults, with some variation in severity and reversibility. Both CPM^62,63 and EPM presentations are frequently encountered in pediatric patients, with extrapontine lesions reported to be thalamic,^64,65 in the basal ganglia,⁶⁶ and hippocampal.⁶⁷ Despite similar distributions of lesions, pediatric patients have better recovery and the associated MR imaging lesions are more reversible,^41,68 results that may be related to age-associated changes in osmotic regulatory mechanisms. It has been shown that water, electrolytes, and organic osmole (mainly taurine) content in the brain of normonatremic rats decreases with age, implying that young brains might have a greater capacity to counteract osmotic perturbations.⁶⁹

Furthermore, experimental data support the notion that different brain regions exhibit different “buffering capacities” to osmolar stress, a feature depending largely on the individual composition of electrolytes and osmolytes. Sodium and chloride ions were found to be highest in the medulla oblongata, while the lowest values were found in the cerebellum and vice versa for potassium.⁷⁰ Organic osmoles were also found to significantly differ among different gray and white matter regions. More specifically, the cortex and cerebellum had the highest concentration of glutamate, glutamine, taurine, and betaine, whereas glycine was predominantly present in the pons and medulla. However, other organic osmoles, such as myo-inositol, creatine, glycerylphosphorylcholine, and glycerylphosphorylethanolamine, were found to be distributed evenly across all brain regions.⁷¹

Furthermore, different dynamics of changes in ionic and organic osmoles may also contribute to different susceptibility of different brain regions to osmotic challenge. Animal studies show upregulation of Na/myo-inositol co-transporters in the early stages of acute hypernatremia⁷² and an absence of changes in the concentration of brain organic osmoles. Most interesting, during the de-adaptation (recovery) phase, all osmoles except myo-inositol seem to return to a normal range. This may suggest that myo-inositol may play a role either in the development of cerebral edema accompanying correction of hypernatremia,⁷¹ or alternatively, it may play a protective role as suggested by some experimental studies, which demonstrated that it reduces cell loss resulting from hypernatremia.⁷³ Furthermore, myo-inositol is involved in the maintenance of brain cell volume during severe hypernatremia but not in hyponatremia.⁷⁴ Thus, re-establishment of organic osmoles in hyponatremia may differ among brain regions, with the pons and midbrain exhibiting the least recovery capacity and the cortex and cerebellum having greater potential to regain lost organic osmoles.⁷⁵ Therefore, it is conceivable that brain response to osmotic challenges is influenced by the inherent region-specific differences in inorganic and organic metabolic makeup, preferential temporal and concentration-dependent involvement of osmolytes, and morphologic and functional characteristics of the adjacent BBB apparatus.

Another interesting difference emerging from these data is the topographic distribution of EPM lesions. In reviewed data, white matter and corpus callosum lesions were the most frequently reported (41.4%), while cortex involvement was the least reported (10.3%). In hyponatremic challenge, the cerebellum was the most frequently reported site, while the caudate was the least reported one.⁶¹ It would be relevant to explore whether the difference in susceptibility to different osmotic challenges may be related to the differential dynamics of response of various brain regions to osmotic challenge as indicated earlier.

Cerebral Volume Changes

In reviewed cases, cerebral edema associated with hypernatremic challenge correlated with older age but not with clinical symptoms, rise in the Na⁺ level, correction rate, or severity of outcome. In most studies, conventional CT or MR imaging was used to delineate edema-related pathologies. Only 2 studies also used DWI and ADC mapping.^30,76 The potential advantage of using DWI and ADC stems from the role of cytotoxic and vasogenic edema in the development of lesions, especially in white matter regions, given its highly compartmentalized structure. Using serial ADC mapping at different time points after the onset of symptoms showed lower ADC values early after the onset of symptoms and a gradual increase to normal or above-normal values thereafter.⁷⁷ This finding corresponded to the emergence of cytotoxic edema (lower ADC) and subsequent vasogenic edema (higher ADC) at different time intervals. It appears that coupling of DWI and ADC yields higher specificity for ODS lesions, in which lower ADC values correlate better with ODS.⁷⁶

Vascular Complications

Although less frequently reported in this cohort of patients, vascular events (infarction and hemorrhage) were not uncommon. Five patients had cerebral infarction, and 1 patient had cerebral hemorrhage. Vascular complications were not significantly associated with age, comorbid history, Na⁺ level, osmolality, and correction rate, nor were they linked to outcome.

It is not clear whether these vascular complications in hypernatremia are osmotically driven. Experimental data suggest that cerebral blood flow may be affected by disruption of the BBB and a concomitant widespread vascular endothelium reaction. Most interesting, changes in CBF may be regionally distributed, varying between cortical and subcortical regions depending on the dynamics of development and correction of hypernatremia,⁵³ suggesting a differential endothelium response and sensitivity to osmotic stress. Whether CBF changes might account for cerebral events (infarctions or hemorrhages) seen in patients with hypernatremic osmotic challenge would require further study.

Outcomes of Hypernatremic Osmotic Challenge

In reviewed cases, a slower Na⁺ correction rate (>48 hours) was not associated with the presence of radiologic changes or outcome. However, the exact correction rate was not provided in most of studies; this omission prevented statistical analysis.

In our review, satisfactory recovery was reported in 26.7% of patients, persistent neurologic dysfunction, in 56.7%; and death, in 16.7%. In reviews of ODS in the context of hyponatremia, favorable recovery was seen in one-third³³ and two-thirds,⁴⁵ while mortality was reported in one-fifth of patients.^33,45

In our review, the outcome was not correlated with the severity of clinical presentation, Na⁺ level, or correction rate, findings compatible with previous observations in cases of hyponatremia³⁴ and ODS of different etiologies.^45,78 However, we found that younger adults had worse outcomes compared with older adults. Moreover, the GCS score was not associated with the outcome, probably due to under-reporting of actual GCS scores in most studies. In a case series of 25 patients with hyponatremia and ODS, older age, premorbid conditions, and pattern of ODS were not found to be predictive of better outcome. However, higher GCS scores, better scores in functional scales, less severe hyponatremia, and absence of hypokalemia predicted favorable outcome after correction of a hyponatremic state.³³

Finally, clinical outcome was better predicted by the presence, load, and pattern of ODS lesions among reviewed cases. More specifically, the presence of EPM lesions, mainly WM, BG, and hippocampal lesions (but not CPM) reduced the probability of full recovery. Similar associations between radiologic features and outcome were not observed in ODS in the setting of hyponatremia.^33,45,79