Neurodemyelinating syndrome associated with hyponatremia

Osmotic demyelination syndrome (ODS) is a serious neurological disorder characterized by central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), the incidence of which is unknown and the specific mechanism is not well understood
。 In 1976, Tomlinson first proposed the treatment of chronic severe hyponatremia that rapid correction of blood sodium levels may lead to serious complications ODS1
.
Since then, there has been evidence that long-term alcoholism, malnutrition, long-term diuretic use, liver failure, burns, etc.
may also be risk factors
for ODS.
This article will introduce the ODS related to hyponatremia caused by neurological diseases, and review the pathogenesis and clinical diagnosis and treatment
.

1 Neurological disease and hyponatremia

Among the problems of water and salt metabolism caused by neurological diseases, hyponatremia is more common
.
Central hyponatremia is mainly associated
with primary neurological disorders (including craniocerebral injury, intracranial inflammation, intracranial hemorrhage, intracranial tumors, etc.
), neurosurgery, and neurotropic drug taking.
Can present with cerebral salt wasting syndrome (CSWS) and syndrome of inappropriate antidiuretic hormone (SIADH)2
.
CSWS is mainly caused by brain dysfunction leading to changes in kidney function, and sodium salt is lost
in urine.
SIADH is mainly caused
by the excessive secretion of antidiuretic hormone (ADH).

When various factors cause dysfunction of the hypothalamic-pituitary system, hyponatremia is closely
related to the occurrence of ODS.
The most common is sellar tumors
.
Tsutsumi 3 and Srimanee et al.
4 reported ODS caused by hyponatremia associated with sellar craniopharyngiomas and pituitary gonados, respectively, pointing out that changes in pituitary hormones led to uncontrollable blood sodium levels during the correction of hyponatremia and were more likely to occur ODS
.

2 Clinical manifestations and diagnosis of ODS associated with hyponatremia

Hyponatremia-related ODS occurs, the first phase is an encephalopathy manifestation caused by low sodium, and then relieves when the sodium level is rapidly corrected to normal, but neurological symptoms will worsen after a period of time, which is the second phase of progression, indicating the beginning
of ODS.
The spectrum of clinical manifestations of ODS is broad and can be absent from any clinical symptoms or transient encephalopathy, aphasia, behavioral changes, numbness, and coma
in addition to typical syndrome manifestations (pseudobulbar palsy and spastic paralysis).
CPM findings include dysarthria and dysphagia (secondary to damage to the cortical medullary tract); If the lesion involves the dorsal part of the pons, pupillary and eye movement abnormalities
will be present.
In addition, patients may have impaired consciousness, and severe cases may manifest as "locked-in syndrome"
.
EPM mainly affects the hypothalamus, neostriatum and other regions
symmetrically.
If the presentation of EPM is superimposed on CPM dysphagia (secondary to damage to the cortical medullary tract), which at first retarded paresis (corticospinal tract damage) gradually becomes spastic (damage to the base of the pons), then diagnosis becomes very difficult, and the patient can clinically present with altered mental behavior and motor abnormalities
.

The diagnosis of ODS depends on clinical presentation and radiographic evidence
.
Clinically, regardless of the cause of hyponatremia and the specific treatment, a rapid rise in blood sodium (≥10 mEq/L/day) may lead to myelination
.
In particular, in the correction of chronic hyponatremia (more than 48 hours), more attention should be paid to the possibility of ODS5
.

MRI is preferred when the clinical manifestations described above are present, and MRI of CPM is characterized by low T1 phase and high T2 phase intensity
.
Moreno et al.
conducted MRI studies on 13 patients with clinical diagnosis of ODS: although the clinical manifestations varied in severity and the difference in underlying diseases, all patients had typical ODS imaging manifestations in the T2 phase and FLAIR phase brainstems6
.
Diffusion weighted imaging (DWI) can detect lesions that are not detectable on the T2 phase, and cases have reported changes in DWI imaging within 24 hours of the onset of a paralyzed patient, while conventional MRI cannot detect significant changes during this time5
.

It is worth noting that there is a time delay in imaging changes from onset to MRI
.
Generally, MRI may show more meaningful changes
after 10 to 14 days of onset.
However, because the MRI performance of CPM is very specific, so many people are accustomed to making a diagnosis based on MRI, and it is easy to miss such patients at an early stage, and the diagnostic criteria reported in the literature have not mentioned pathological evidence
.
Despite this, MRI does not provide information about prognosis and does not predict disease outcome by the extent and duration of lesions7
.
Moreover, many clinical cases suggest that the extent of lesions on MRI imaging is not necessarily related to the degree of clinical neurological impairment or the course of the disease itself6,8
.

3 Pathophysiology of ODS

There are different opinions on the exact mechanism of ODS caused by too rapid correction of hyponatremia, among which the more representative is the apoptosis hypothesis
.
This hypothesis suggests that glial apoptosis due to metabolic stress is the most fundamental cause of ODS9
.

As ODS-sensitive cells, glial cells play a significant
role in regulating extracellular osmotic pressure and electrolyte balance.
When sodium is low, the brain interstitium is in a hypotonic state, and glial cells transport water into the cells through water channels, causing the cells to swell.

To avoid further cell swelling, cells will transfer osmotic active substances out of the cell to reduce the osmotic pressure in the cytoplasm, thereby limiting water accumulation
.
Once serum sodium rises, normal extracellular osmotic pressure is restored and water is transported from the ion-deficient and hypotonic cells into the interstitium, resulting in relative cell dehydration
.
In order to reduce their own shrinkage, cells must activate the pathway to maintain intracellular osmotic pressure, at this time, glial cells must activate the Na+-K+-ATP pump (NKAT) to transport ions, thus bringing metabolic pressure, and the metabolic characteristics and structure of glial cells determine that they are very sensitive to energy exhaustion, and finally activate apoptosis
through the glutamate toxic metabolic pathway.

In fact, CPM is more common in ODS, and myelinolysis tends to occur in the pons and is closely related to
its anatomy and physiology.
Within the pons, axons and glial cells gather in a lattice to form a compact linear structure, limiting the flexibility of space and the increase
in cell volume.
Therefore, at low sodium, these cells can only lose more ions instead of increasing the volume to maintain cell stability, which makes them more likely to destroy
at low sodium.
At the same time, this lattice aggregation limits the storage and transport of sugar, and because the pons is supplied by the basilar artery perforator vessel, the blood vessels supplying the middle of the pons are very thin and the pressure is low, so the perfusion itself is relatively poor
.
This perfusion disadvantage becomes apparent when metabolism decreases9
.

Evidence suggests that glial aggregation is particularly important
during the ODS course.
Takefuji10 studied the aggregation of microglia at the site of myelinolysis and the cytokines
they released.
DDAVP was given to rats supplemented with a liquid diet to establish a low-sodium model
.
After 7 days, hypertonic saline is injected quickly to correct serum sodium levels
.
The rats gradually developed severe dyskinesia and found significant demyelinating changes
in their midbrains and cerebral cortex.
At the same time, a large number of microglia aggregation was observed in the demyelinating region and expressed pro-inflammatory factors
such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and inducible nitric oxide synthase (iNOS).
。 The experimental group treated these rats with rapidly corrected hyponatremia with lovastain (lovastatin inhibits microglia aggregation and reduces the expression of TNF-α at the demyelinating site), and found that the condition of neurological impairment and the degree of demyelination were significantly improved
.
This suggests that lovastatin may have an inhibiting effect on demyelination
.
Lwama 11 observed early and late stages in rat models of rapid sodium supplementation to ODS and found that the number of microglia at the demyelination site gradually increased over time, and TNF-α, interleukin (IL)-1β, IL-6, and MMP2, 9, and 12
could be expressed at an early stage.
Later microglia can simultaneously express neurotrophic factors and engulf demyelinating products
.
The number of astrocytes increases with time at the demyelinating site and extends the foot process, expressing nerve growth factor and glial cell line-related trophic factors
in the later stage.
Therefore, microglia gradually transform from initial destruction to protection in ODS as the disease progresses, and astrocytes play a protective role in the later stage
.
In the early stage of rapid correction of blood sodium, an excessive pro-inflammatory response in microglia may be used as a target for
ODS therapy.

4 Treatment and prevention of ODS in hyponatremia caused by neurological diseases

4.
1 Treatment of ODS

There are some key principles for dealing with ODS, to identify risk factors in time, such as excessive alcohol intake, nutritional deficiency caused by significant weight loss, etc.
, of course, more attention should be paid to correcting the blood sodium rate should not be too fast
.

Recent studies have shown that antidiuretic hormone therapy improves CPM when symptoms of myelinolysis begin to appear12
.
If hypernatremia is overcorrected, desmopressin tablets (AVP) have a significant effect
on inhibiting progression.
In patients who have reached or exceeded the limit of sodium supplementation and still pass hypotonic urine, intravenous desmopressin may be given to prevent or reverse excessive increases in
serum sodium levels.

In severe myelinolysis, later supportive care is essential
.
Based on the hypothesis that metabolic stress leads to glial apoptosis, some people believe that metabolic stress should be minimized in supportive care and high-energy and antioxidant substances
should be maximized.
Specifically, timely supplementation of high-dose vitamins, especially in patients with subclinical thiamine deficiency, should be supplemented with thiamine and free radical scavengers (vitamins E, C)9
.

Reported treatments for CPM, such as thyroid-stimulating hormone-releasing hormone, methylprednisolone, and immunoglobulin, lack evidence-based evidence and unclear mechanisms of action, so convincing is limited13
.
Minocycline has recently been found to be effective in reducing brain demyelinating and clinical improvement, effectively reducing the risk of death after rapid correction of hyponatremia14
.
The theoretical basis may be related to
minocycline reducing blood-brain barrier permeability, inhibiting glial cell activation, reducing IL-1α expression and protein nitrosylation.

4.
2 Prevention of ODS — management of hyponatremia

The key to the prevention of hyponatremia-related ODS lies in the rational management
of hyponatremia.
Obviously, the causes of low sodium (syndrome of abnormal secretion of antidiuretic hormone, adrenal insufficiency, salt-wasting nephropathy, etc.
) must be clarified, and the treatment of the cause must be paid special attention
.

4.
2.
1 Treatment of asymptomatic hyponatremia

In patients with hyponatremia without obvious symptoms, the general principle is that intervention
is not urgently needed.
Some patients may not have any significant symptoms
due to chronic adaptation, even if the blood sodium level has dropped to 115-120mmol/L.
However, some patients may have mild impairments
such as tiredness, drowsiness, nausea, gait abnormalities, and abnormal attention.
Clinically, such patients should be identified in a timely manner to avoid the persistence of some reversible hypervolume factors
.

4.
2.
2 Treatment of symptomatic hyponatremia

The treatment of hyponatremia, either the etiology or the specific measures to correct the blood sodium, is not directly related to the occurrence of ODS, and the speed of correction of blood sodium is critical
.
The treatment of any patient with hyponatremia must consider the issue of sodium correction velocity15
.

Many people are aware that the dilemma of dealing with hyponatremia is "it seems wrong to do or not to do", referring to the consequences of rapid and slow sodium correction, on the one hand, rapid sodium supplementation will lead to ODS, and on the other hand, cerebral edema caused by slow sodium supplementation of hyponatremia, which cannot be completely balanced in treatment5
.

4.
2.
2.
1 Treatment of acute hyponatremia (hyponatremia occurs less than 48 h).

Retrospective studies have shown that acute hyponatremia has a good
prognosis for rapid sodium correction.
Even with rapid and large increases in serum sodium, neurological complications
are rare in patients.
Rapid sodium correction in acute hyponatremia has also been reported to lead to myelination in some cases16, but evidence suggests that a sodium correction rate of less than 3 to 4 mmol/L may increase the risk of death from acute or postoperative hyponatremia15
.
Given that the risk of death from cerebral edema is much higher than the risk of individual ODS due to rapid sodium supplementation, rapid correction of serum sodium levels is still used for acute hyponatremia
.
However, there is no objective and uniform standard
for judging acute and chronic in clinical practice.
Therefore, as long as it is suspected to be chronic, it is not possible to simply and quickly correct the sodium
.

4.
2.
2.
2 Treatment of chronic hyponatremia (hyponatremia for more than 48 hours or the duration of hyponatremia cannot be determined)

Limiting the sodium correction speed does not exceed 10-12mml/L within 24 hours, and does not exceed 18mmol/L within 48h, which can usually avoid the occurrence
of ODS.
But the specific treatment is not absolute
.
When patients have malnutrition, alcoholism, advanced liver disease, etc.
, they are more likely to have ODS
.
Pietrini V 17 reported hyponatremia in patients after radical breast cancer resection, CPM still developed after sodium supplementation at a standard rate, and Georgy V et al.
18 reported a 37-year-old alcoholic woman with a blood sodium level of 105 mmol/L, who did not exceed 8 mmol/L per day and still developed CPM.

Hyponatremia has been reported in a 19-year-old woman with a 4-year history of anorexia nervosa8 and CPM and EPM
visible on MRI one week after slow sodium supplementation according to guidelines.
Sajith 19 reported that repeated vomiting in a 41-year-old woman led to chronic hyponatremia, and acute Parkinsonian-like disease developed after slow sodium correction, and MRI suggested EPM
.
It is noteworthy and fortunate that the prognosis of these cases is relatively good, and the recovery of neurological function is good
.

Complications often arise
from the fact that the patient has "self-correction" of hyponatremia during hyponatremia.
In the absence of secretory release of ADH, patients may excrete large amounts of diluted urine, which can cause blood sodium levels to rise above 2 mmol/L per hour, and life-threatening sodium overdose may occur within 12 hours
.
Because of these risks, the rate of exogenous sodium correction is generally adjusted to approximately 8 mmol/L per day, and frequent monitoring of serum sodium levels and urination is required15
.

Clinically, the mastery of the rate of rise in blood sodium levels is often obtained by indirect examination, and the actual speed of sodium correction may be much
faster than expected.
In addition, oral patients are advised to take foods with normal sodium content without adding sodium to normal, and the purpose is also to correct hyponatremia
as slowly as possible.
Initial treatment is also recommended to maintain patients at mildly hyponatremia levels, and sodium replacement may be slower
in patients with risk factors for myelinolysis (hypokalemia, liver disease, malnutrition, burns).
In the case of severe hyponatremia, considering that the serious damage of hyponatremia itself has exceeded myelinolysis, rapid and restrictive sodium supplementation can be used, such as for patients with chronic hyponatremia and epilepsy, which needs to be treated
promptly.
In general, it is feasible if the total increase in serum sodium does not exceed 10 mmol/L in 24 hours or 18 mmol/L in 48 hours15
.

In addition, AVP receptor antagonists are also gaining attention in the treatment of hyponatremia20
.
AVP receptor antagonists can selectively increase renal excretion of free water and can therefore be used as effective drugs
for the treatment of hyponatremia.
The current commonly used drug is conivaptan (conivaptan) 21
.
The use of cognavadane in patients with normal and high volume hyponatremia has been approved
by the FDA.
Theoretically, AVP receptor antagonists and hypertonic saline can be used concurrently in the initial treatment of patients with symptomatic hyponatremia, and hypertonic saline can be discontinued
when the patient's blood sodium level rises to a certain degree and clinical symptoms improve.
Thereafter, diuretics are used to complete the remaining sodium replacement targets
.
However, the formal development of this treatment regimen requires further clinical trial evidence
.

After the symptoms of hyponatremia are corrected, the rate of sodium replacement needs to be further slowed, and the patient's serum sodium level and rate of rise need to be monitored frequently
.
In addition, in the prevention of ODS, animal experiments on Soupart22 show that urea can quickly reduce cerebral edema and intracranial pressure, thereby improving hyponatremia and reducing the incidence of myelinolysis, which has a special cerebroprotective effect
.

5 Prognosis of ODS

Ramesha7 reported that 25 patients with ODS had blood sodium levels below 120mEq/l, clinical neurological symptoms, and all patients received intravenous infusion of 3% NaCl
.
The results showed that 11 had a "good" outcome and 13 had a "bad" outcome
.
Of the 11 ethnicities with good outcomes, 7 fully recovered, the remaining patients achieved functional independence, leaving only mild cognitive impairment or extrapyramidal sequelae, and 12 of the 13 people with adverse outcomes died and 1 was in a persistent vegetative state
.
In univariate analysis, three factors were strongly associated with adverse outcomes: hyponatremia serum sodium level ≤ 115 mEq/l; with hypokalemia; GCS score ≤ 10
on admission.
However, clinical features, primary disease, ODS type, EEG and MRI characteristics cannot be used as prognostic evaluation indicators
.
In multivariate analysis, only blood sodium levels had the most significant
effect.

6 Outlook

Cases of ODS in patients with non-severe hyponatremia and strict slow sodium supplementation suggest that there are more in-depth pathogenesis to be studied, and these mechanisms may be related to the regulation of certain cytokines in the apoptosis system, especially those that are also related to energy metabolism
.
In future experimental studies, while establishing animal models of osmotic pressure, we should explore whether there are abnormalities of energy metabolism at the same time.
Meaningful structural mutations should be found in animal models with abnormal glucose metabolic pathways to explain predisposing factors
for ODS.
In the treatment of hyponatremia, AVP receptor antagonists need to be verified
by further clinical trials.