Diabetic ketoacidosis (DKA) is an acute and serious complication of diabetes mellitus, mostly type one. It is associated with a high risk of morbidity and mortality if not treated promptly. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1 Several acute neurological complications may occur in DKA, with cerebral injury that may lead to cerebral edema, being the most common. Other less common and less known acute neurological complications include stroke and electrolyte derangements. The latter can lead to seizures or cardiac arrest with consequent brain hypoxic-ischemic injury. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1–Reference Chegini, Didehdar, Khoshbayan, Rajaeih, Salehi and Shariati8 In this article, we summarize the common and lesser-known acute neurological complications of DKA. Importantly, we emphasize that the clinical presentations of some acute neurological complications of DKA overlap, and thus the correct diagnosis may be overlooked. Prompt recognition of the various neurological complications and targeted treatment is essential for the successful management of these patients.
Although not the focus of this article, it is important to be aware that a mixed picture of DKA and hyperosmolar hyperglycemic state may also present with severe neurologic presentations and poor outcomes.
Cerebral injury and edema
This is the most common acute neurological complication of DKA. Cerebral edema, the most severe presentation of cerebral injury in DKA, occurs in about 1% of pediatric DKA. Risk factors include new-onset diabetes, longer duration of symptoms, young age (< 5 years), hypocapnia, severe acidosis and use of sodium bicarbonate boluses. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1 Mortality of fulminant cerebral edema in DKA is 20%–25%. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1 Presentation of cerebral injury varies from headache, irritability and altered mental status to abnormal respiratory pattern and cranial nerve palsy. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1 Patients can deteriorate rapidly. Although rapid fluid administration has been hypothesized as a mechanism for development of cerebral edema, this association has not been proven, with accumulating evidence against such a hypothesis. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Kupperman, Ghetti and Schunk2 Cerebral edema may occur prior to the administration of fluids, and more conservative fluid administration has not changed the rate of cerebral edema. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Kupperman, Ghetti and Schunk2 A randomized controlled trial in DKA management in children used neurologic outcomes (Glascow Coma Scale (GCS) and clinically apparent brain injury) to assess the selection of fluids and rate of administration. Reference Kupperman, Ghetti and Schunk2 Neither factors were found to significantly influence neurologic outcomes. The best-supported hypothesis for cerebral injury is cerebral ischemia and reperfusion injury. Reference Glaser9 If the patient has clinical features of cerebral edema (Table 1), the intravenous fluid rate should be decreased. Hypertonic saline or mannitol is critical to treat the increased intracranial pressure, and neuroimaging in this scenario is not usually indicated. Intracranial pressure monitoring can be employed for patients with more severe neurological impairment. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1
Summary of the acute neurological complications of pediatric diabetic ketoacidosis
DKA = diabetic ketoacidosis.
Electrolyte abnormalities
Electrolyte abnormalities, particularly hyponatremia and hypokalemia, are seen almost universally in DKA. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Kupperman, Ghetti and Schunk2 There is typically no neurologic effect of hyponatremia because serum osmolality is elevated due to hyperglycemia. Reference Kupperman, Ghetti and Schunk2 However, severe hypokalemia, hypophosphatemia and hypomagnesemia can present with weakness that begins in the lower limbs and progresses upward. This weakness can involve the respiratory and gastrointestinal muscles, causing respiratory failure and ileus, respectively. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1–Reference Gallo de Moraes and Surani3 Calcium should be monitored as well. Cardiac arrhythmias may occur with severe hypokalemia, which can lead to hypoxic-ischemic encephalopathy as a consequence of cardiac arrest (Table 1). Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Kupperman, Ghetti and Schunk2
Stroke
DKA induces a pro-thrombotic state which increases the risk of cerebral and sinus venous thrombosis. Ischemic and hemorrhagic strokes occur rarely in DKA. Reference Azad, Kaur, Kumar Singh and Arya4 Presentations of strokes can include headache, nausea/vomiting, altered mental status, nuchal rigidity, seizures and focal neurological deficits. Cerebral edema may mask the presence of a stroke. Reference Azad, Kaur, Kumar Singh and Arya4 CT with CT venogram and brain MRI can help distinguish cerebral edema from the various causes of stroke. It is important to balance the need to hydrate stroke patients with the need to decrease fluids if cerebral edema is also present. Anticoagulation is typically recommended for cerebral and sinus venous thrombosis.
Extrapontine myelinolysis
Extrapontine myelinolysis is reported very rarely in children with DKA and involves symmetric demyelination of extrapontine sites. It is often, but not always, associated with rapid shifts in serum osmolarity due to rapid correction of hyponatremia. Reference Gencpinar, Tekguc, Senol, Duman and Dursun5 However, if cerebral edema is also present, then hypertonic saline should not be given slowly in DKA for fear of causing extrapontine myelinolysis, since extrapontine myelinolysis is rare and sodium is rarely actually low in DKA. The presentation can vary but typically includes altered mental status and focal neurological deficits. Reference Gencpinar, Tekguc, Senol, Duman and Dursun5 Brain MRI is recommended for diagnosis.
Posterior reversible encephalopathy syndrome (PRES)
PRES is characterized by headaches, altered mental status, seizures and visual disturbance. Reference Jones, Redler and Witherick6 PRES may be triggered by various conditions, including hypertension, renal failure and autoimmune diseases. It has been reported to occur very rarely in DKA, likely secondary to several factors, for example, renal failure. Reference Jones, Redler and Witherick6 PRES generally resolves with treatment of the triggering insult.
Acute peripheral neuropathy
Acute peripheral neuropathy is extremely rare in DKA, and although it shares the presenting features of pain and decreased sensation to the extremities, it is distinct from chronic neuropathy. Reference Bazyńska-Wilk, Wysocka-Mincewicz and Śweircz7 Proposed mechanisms for acute neuropathy include rapid shifts in blood glucose and vascular endothelial dysfunction. Reference Bazyńska-Wilk, Wysocka-Mincewicz and Śweircz7 Symptoms can be treated with alpha-lipoic acid. Reference Bazyńska-Wilk, Wysocka-Mincewicz and Śweircz7
Mucormycosis
DKA is an important risk factor for mucormycosis. Mucormycosis is a fungal infection caused by filamentous fungi of the Mucoraceae family. This infection carries high morbidity and mortality even with early diagnosis and treatment. Mucormycosis is a risk especially in patients with long-term poorly controlled diabetes rather than in patients with new-onset diabetes presenting with DKA. Symptoms are nonspecific and mostly respiratory in nature but can progress to a neurological presentation including altered mental status, blindness and cranial nerve palsy. Reference Chegini, Didehdar, Khoshbayan, Rajaeih, Salehi and Shariati8
Conclusions
Acute neurological complications of DKA can develop at any time, from onset of illness to treatment and anion gap closure. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Kupperman, Ghetti and Schunk2 Early symptoms of neurological complications can be subtle. Neurological monitoring should be performed at least hourly to determine the level of consciousness until the acidosis resolves. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1 Any worsening level of consciousness should prompt consideration of cerebral injury and possible edema. If clinical features for cerebral edema occur, treatment should be initiated rapidly. When the neurological status does not improve after DKA is corrected, an expeditious search for the lesser-known acute neurological complications and further testing, including neuroimaging, should be considered, since many of these complications share similar clinical features. Reference Gripp, Trottier, Thakore, Sniderman and Lawrence1,Reference Azad, Kaur, Kumar Singh and Arya4–Reference Jones, Redler and Witherick6,Reference Chegini, Didehdar, Khoshbayan, Rajaeih, Salehi and Shariati8 For example, cerebral injury, stroke, extrapontine myelinolysis, PRES and cerebral mucormycosis present with headache, altered mental status, irritability, seizures and focal neurological deficits.
Authors contributions
Michael Salman conceived writing the article. He mentored the second author, helped with the literature search and edited all drafts. Katherine Falla did the literature search, wrote the first draft and edited subsequent drafts.
Funding statement
None.
Competing interests
None.
