Literature review about CPM: common etiologies and typical presentation

We systematically searched PubMed database using the following keywords “Central Pontine Myelinolysis”, “Osmotic demyelination syndrome”, “Diabetes Mellitus” and “Hyperglycemia”. Studies that evaluated the effects of hyponatremia, hypernatremia or normonatremia, and hyperglycemia on CPM were included. Criteria for exclusion: studies that considered pediatric and/or geriatric and/or Japanese population and studies that described ODS due to other neurological etiologies (Figure 3).

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Figure 3. 

Strategy research in the systematic review

ODS is an uncommon neurological disorder caused by damage to the myelin sheath of nerve fibers. CPM is the typical presentation, reflecting greater susceptibility of pontine white matter tracts, consisting of focal, bilaterally symmetric region of myelin destruction; however, extra-pontine involvement (extra-pontine myelinolysis or EPM) is common [1, 2].

CPM was first described in 1959 by Adams and Victor who reported on four patients with quadriplegia and pseudo-bulbar palsy, three of these were chronic alcoholics and all were malnourished [3].

As is shown in Table 2, CPM can occur in a variety of clinical settings [1–24].

CPM, most often reported in association with rapid correction of severe chronic hyponatremia, has also been described associated with other electrolyte derangements such as hypophosphatemia, hypokalemia as well as in the setting of liver transplantation and lithium toxicity [6, 7, 9, 10].

In chronic hyponatremia, electrolytes are lost from intracellular space flowing into cerebrospinal fluid over a few days during which brain cells become isotonic to the extracellular fluid to maintain cell volume through a process called “cerebral adaptation”. As a result, given that they can neither synthesize nor transport osmotic substrates at such rapid rates (which leads to osmotic demyelination), oligodendrocytes will shrink up as a consequence of cell volume loss during rapid correction of tonicity [25].

Clinical manifestations are variable: various degrees of encephalopathy are commonly observed however either totally asymptomatic or mildly symptomatic cases can also occur. Typically patients with ODS present with parkinsonism, quadriparesis, “locked-in” syndrome, coma, bulbar palsy, or, less frequently, with dysphagia, dysarthria, facial paresis, ataxia, nystagmus, tremor, lethargy, confusion, behavioral disturbances, and/or disorientation [26, 27].

In the past, brainstem auditory evoked potentials were used, but modern imaging has superseded its use, and brain MRI is the current accepted standard diagnostic technique because of a greater sensitivity and a superior capacity for the demonstration of the lesions of EPM, than CT. At MRI, hyperintense lesions on T2 weighted, and hypointense lesions on T1 weighted images are suggestive for CPM [25].

Other than supportive treatment, there is no effective treatment for CPM. Supportive treatment should be provided to all patients for at least 6–8 weeks before making any conclusions regarding irreversibility of disease. In cases where CPM is caused by rapid correction of severe chronic hyponatremia lowering serum sodium may be beneficial if initiated early. In literature there is some evidence supporting the beneficial role of plasma exchange techniques that allow removal from blood circulation of myelin toxic substances. Conversely, the use of steroids and intravenous immunoglobulins is not supported by evidence [25].

CPM owing to uncommon etiology

McKee et al. [4] have suggested that myelinolysis can result from any “relatively hypertonic insult”. These authors have speculated that CPM can result from any circumstances wherein serum and extracellular space become hypertonic faster than brain cells can compensate.

Reports of ODS associated with hyperglycemic hyperosmolar state with rebound hypernatremia have been published [14]. Over the last few years, CPM has also been reported in diabetic patients exhibiting deranged metabolic control even in the absence of electrolyte disturbances [2, 15].

In 2015, Saini et al. [28] reported on a case of CPM secondary to hyperglycemia per se rather than secondary to its treatment. The patient presented with ataxia and pseudobulbar manifestations and followed a sub-acute course over a two-week time.

Hyperglycemia, by leading to an increased plasma osmolality, has been blamed to cause pontine demyelination both in type-2 diabetes and in a T1D patient [15, 28, 29]. This complication has also been described in a patient with latent autoimmunity diabetes displaying significant glucose fluctuations [30].

Although the possible pathogenic mechanisms responsible for development of CPM in patients with diabetes are still a matter of debate, a few hypotheses have been proposed in earlier studies. In patients with poorly controlled diabetes, hyperosmolarity resulting from increased blood glucose with greater osmolar shifts might cause brain edema. An explanation might be that in chronically uncontrolled diabetes, osmotic stress induces protein damage and aggregation within brain oligodendrocytes.

More specifically, it has been postulated that serum hyperosmolarity induces the release of nitric oxide and inflammatory mediators and this may damage tight junctions. Furthermore, toxic substances released by damaged endothelial cells may injure oligodendrocytes [31].

In the setting of hyperosmolar hyperglycemia, several theories have been proposed to explain the pathogenesis of osmotic demyelination: rapid changes in osmolality associated with the fluctuations in serum glucose, subacute changes in brain cells secondary to hyperglycemia, and hypertonic insult associated with hyperglycemia [31].

Moreover, risk factors for CPM in diabetics include concurrent diabetic nephropathy requiring dialysis, infection with hepatitis C virus, and arterial hypertension [32].

The only treatment for non-sodium-dependent osmotic demyelination is supportive care [27].

In this case report, diagnosis of CPM was based on the evidence of injury to central pons, which was clinically compatible with myelinolysis due to metabolic derangement. Generally, CPM is caused by osmotic demyelination due to rapid correction of hyperosmolarity in hypernatremia. Only in very rare cases does this condition occur in patients with diabetes and normal serum sodium concentration: in these, it would seem plausibly caused by the hyperosmotic effects of glucose which carries oligodendrocyte fluids into the extracellular compartment. In our case, this effect was also presumably facilitated by concurrent dehydration caused by chronic diarrhea.

In literature, CPM has been attributed to sudden, severe, and sustained hyperglycemia, especially when another risk factor is present such as malnutrition, alcohol abuse, chronic diseases, and liver cirrhosis, which are all listed as risk factors for CPM. Reports of hypoglycemic-induced CPM/ODS are rare; glucose deprivation can lead to cytotoxic edema secondary to the failure of ion pumps in the cell membrane that manifests itself with MRI changes typical of CPM [24]. Furthermore, over-treatment resulting in hyperglycemia will activate the nicotinamide adenine dinucleotide phosphate (NADPH) pathway in neurons, causing cytotoxic oxidative stress. Our literature research shows the possible involvement of drugs, although there is no often a causal correlation with CPM/ODS; however, the hypothesis of drug influence should be kept in mind in unexplained neurological manifestation suggestive for CPM [10, 22]. For example, it is known that fluoroquinolones can cause or exacerbate hypoglycemia as consequence of direct stimulation of insulin secretion from the β-cells of the pancreas and typically occurs 4–6 days after the start of antibiotic therapy: this can play a crucial role in diabetic patients [24].

There are only few other similar published cases of CPM complicating the management of the correction of the variability of glucose levels in patient with diabetes. Conversely, there are more cases of CPM due to other predisposing factors (either chronic comorbidities or drugs). Despite the variability of etiologies, many patients were diabetics and this might highlight the close link of CPM with diabetes. CPM should always be considered in the differential diagnosis of neurological manifestations in patients with diabetes.

In conclusion, CPM, a potentially fatal condition, follows a favorable course provided that it is promptly recognized and managed. Our case suggests that, in diabetic patients presenting with signs and symptoms of CPM, recent episodes of decompensated glucose control as well as a large variability of glucose serum levels must both be taken into consideration to reduce the risk of brain damage. In conclusion, it is necessary to monitor neurological and cognitive status in patients with diabetes and/or other clinical conditions in which both an inappropriately rapid correction of osmolarity and any hypertonic insult in normal osmolarity status could potentially cause CPM.