Clinical manifestations

Presentation and course

Hypoglycemia can be classified as either symptomatic (severe) or asymptomatic (biochemical). In an adult, a diversity of symptoms ranging from anxiety and jitteriness to frank stupor and coma may simulate a multitude of diseases including primary psychiatric or cardiac diseases, or even a drug overdose. Classification of diverse signs and symptoms into two major distinct categories is helpful in understanding the underlying pathogenesis. Palpitations, tachycardia, diffuse weakness, hunger, and anxiety manifest one category of symptoms due to adrenergic discharge and are called “neurogenic (autonomic) symptoms.” These symptoms are caused by hypoglycemic activation of cells in the lateral hypothalamus resulting in primarily sympathetic discharge. The cholinergic pathway may mediate sweating because this reaction can be blocked by atropine. The second major category of hypoglycemic symptoms has been termed "neuroglycopenic." The most common symptoms comprise headache, alteration in behavior including higher cortical dysfunction, unsteadiness, drowsiness, stupor, or coma. These observations are compatible with experimental observations that suggest cortical cell layers are most susceptible to the lowering of glucose, followed by the hippocampus, cerebellum, basal ganglia, and brainstem. Despite the multitude of possible presenting complaints, in each patient the clinical symptoms are predominated by either adrenergic or neuroglycopenic symptoms. Furthermore, each attack, when it recurs, tends to be stereotypic for each individual and patients frequently learn to control the episodes by ingesting sugar. With increasing age, the symptoms of hypoglycemia may become less intense, and the symptom profile changes.

In the past, considerable emphasis was placed on a symptom complex after food ingestion, even supported by a now-discredited 5-hour oral glucose-tolerance test. This questionable clinical entity has been termed postprandial syndrome, reactive or functional hypoglycemia, early-diabetes hypoglycemia, or alimentary hypoglycemia. Nearly all of these cases failed to show convincing evidence of hypoglycemia, and emotional or psychological etiologies have been suggested (94). Postprandial symptoms may rarely occur due to an underlying insulinoma; however, in these cases hypoglycemia can be demonstrated as the cause of postprandial symptoms.

In newborns or infants, glucose homeostasis is somewhat tenuous due to a lack of normal reserve as in an adult. Imbalance of utilization and production of glucose via glycogenolysis (breakdown of hepatic glycogen) and gluconeogenesis (formation of glucose from substrate substances) may result in more frequent episodes of hypoglycemia than in adults. Higher frequency of hypoglycemia in the pediatric population is further complicated by nonspecific symptoms such as irritability, drowsiness, cyanosis, and poor feeding, simulating multiple other medical disorders. Glucose measurement should be routine in any newborn or infant with unusual symptoms. Neonatal transient hypoglycemia is seen in the infant of a diabetic mother and represents a relative benign disorder. The mechanism is, in part, due to the development of relative hyperinsulinemia during gestation in a diabetic mother with resultant lowering of the baby's serum glucose after delivery. Hyperinsulinemic hypoglycemia syndrome is caused by unregulated insulin secretion by pancreatic beta-cells. It is a major cause of hypoglycemic brain injury and mental retardation in infants and young children. Affected children experience frequent hypoglycemic seizures after fasting or the ingestion of a high-protein meal (49).

Malouf and Brust studied neurologic manifestations of hypoglycemia in an inner-city emergency room (64). Of the 125 visits analyzed, 65 presented in stupor or coma, nine presented with seizures, and three with sudden hemiparesis. Most had either diabetes or an alcoholic history, with recent fasting as a trigger of symptomatic hypoglycemia. Seizures are a well-known consequence of hypoglycemia. However, hypoglycemic seizures are rare in adult-onset type 1 diabetes mellitus patients. Among 229 adult-onset type 1 diabetes mellitus patients, two had suffered hypoglycemic seizures and two unprovoked seizures (24).

Recurrent hypoglycemia-induced falls (leading to bone fracture) are common in older persons with diabetes. The etiology of falls in this population is usually multifactorial and includes microvascular and macrovascular complications and age-related comorbidities, with hypoglycemia being one of the major precipitating causes (63; 60).

Acute effects of hypoglycemia in the human eye may affect central vision, possibly due to involvement of the retina (50). An investigation revealed that among 882 diabetic participants with normal/near normal vision at baseline, 2.9% (n = 26) of diabetics developed vision loss (defined as a decrease in visual acuity by > 10 letters) after 4 years. Severe hypoglycemia, smoking, and impaired renal functions were risk factors for vision loss (20).

Many patients with hypoglycemia present with focal neurologic signs and transient charges in MRI, mimicking stroke. In one series, among 80 hypoglycemic patients, 11 patients had rapidly reversible neurologic signs (73). The initial diffusion-weighted MR images demonstrated a hyperintense lesion in the contralateral internal capsule, and there were decreased values on the ADC (apparent diffusion coefficient) map in two of the patients (18%). Chronic kidney disease is associated with a higher risk of stroke and mortality in patients with hypoglycemia. Recurrent hypoglycemia considerably increases the risk of stroke and overall mortality in patients with chronic kidney disease regardless of whether they have diabetes (98).

Unusual manifestations of symptomatic hypoglycemia in an adult include decerebrate rigidity with coma (84), pan-cerebellar ataxia (51), and movement disorders such as paroxysmal choreoathetosis and persistent chorea (36). Highly unusual clinical manifestations of hypoglycemia may be even more common in children and infants, even simulating an acute respiratory failure (61).

Insulin-requiring diabetics are prone to hypoglycemia, with estimates ranging from an average of one to two symptomatic hypoglycemic episodes occurring per week. Up to 25% of patients suffer a seizure or coma in any given year, and 4% of deaths have been attributed to hypoglycemia in known diabetics (14). A similar fatality rate has been documented in 102 diabetic patients with drug-induced hypoglycemic coma (05). Death occurred in five cases. A predisposition toward a bad outcome included older age, concomitant systemic infection, and renal insufficiency. Patients with longstanding diabetes are further predisposed to hypoglycemia due to the "syndrome of hypoglycemia unawareness" (14). Deterioration of the autonomic nervous system and cortical neuronal function lead to poor recognition of hypoglycemic symptoms resulting in a lack of self-treatment (intake of sugar) thereby further aggravating the disease process.

Both type 1 and type 2 diabetes mellitus have been associated with abnormalities in cognitive functions. The exact pathophysiology of cognitive dysfunction in diabetes is not completely understood, but it is supposed that hyperglycemia, vascular disease, hypoglycemia, and insulin resistance play significant roles (54). Hypoglycemia has a very significant impact on the pathogenesis of dementia and cognitive dysfunction among patients with diabetes mellitus (78). To explore the role of hypoglycemia on cognition, a total of 1144 patients with type 1 diabetes were enrolled in the Diabetes Control and Complications Trial and its follow-up study, the Epidemiology of Diabetes Interventions and Complications Study. Patients were evaluated on entry, and a mean of 18 years later, with a battery of cognitive tests. Forty percent of the patients reported having at least one hypoglycemic coma or seizure. However, neither frequency of severe hypoglycemia nor previous treatment-group assignment was associated with significant decline in any of the cognitive parameters (19). Whitmer and coworkers demonstrated that among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia (92). Several possible mechanisms for cognitive decline have been suggested. Type 2 diabetes is a risk factor for Alzheimer disease and vascular dementia. The association between diabetes and Alzheimer disease is particularly strong among carriers of the apolipoprotein E ε4. Impaired fasting glucose and impaired glucose tolerance and insulin resistance have also been associated with cognitive decline (18). Hypoglycemia has been associated with an increased risk for falls in hospitalized patients. Blood glucose levels below 70 mg/dl and insulin use were risk factors for these falls (07).

Hypoglycemia-associated neuroglycopenia may result in diffuse electroencephalographic changes. Neuroglycopenia results in increased slow-wave (theta and delta waves) activity. In a case report, semirhythmic theta activity, akin to changes observed during early sleep, hyperventilation, or as a form of epileptiform discharges, was noted (80). Electroencephalographic changes often coincide with hypoglycemia-induced altered mental state. Patients with hypoglycemia unawareness are at high risk of developing severe hypoglycemia, and in such cases electroencephalographic changes may help in monitoring hypoglycemia noninvasively (08; 79).

Hypoglycemia may be common in the presence of chronic renal disease (02), in part due to poor caloric intake superimposed on diminished renal insulin clearance, and in alcoholic liver disease. In the absence of obvious predisposing factors, surreptitious insulin or sulfonylurea use in healthcare providers or a pancreatic islet tumor may be the underlying etiology.

Prognosis and complications

Even brief hypoglycemia can cause profound dysfunction of the brain. Prolonged, severe hypoglycemia can cause permanent neurologic damage. Complications include permanent brain damage leading to persistent vegetative state and death. Cerebral cortical laminar necrosis of gray matter may result, but at times demyelination may be more apparent. Although generally affecting the same cerebral areas as in the hypoxic-anoxic encephalopathy, cerebellar Purkinje cells may be spared in severe hypoglycemic encephalopathy. Repeated episodes of less severe hypoglycemia may cause permanent cognitive impairment (55). It has been observed that profound and prolonged hypoglycemia, normal or higher body temperature, and a low lactic acid level are predictors of a poor outcome in patients with hypoglycemic encephalopathy (42). Hypoglycemia may accelerate the vascular complications of diabetes by increasing platelet aggregation or fibrinogen formation (25). Hypoglycemia in diabetic patients is associated with cognitive decline (57; 22). Whether severe or nonsevere hypoglycemia precedes cognitive dysfunction is controversial. An analysis failed to demonstrate an association between severe hypoglycemic episode and incident cognitive impairment in 11,495 middle-aged subjects with dysglycemia (17).

Studies suggest that the developing brain in the pediatric population is more sensitive to permanent neurologic damage as a result of hypoglycemia. In children, asymptomatic hypoglycemia is a common occurrence, particularly at night, when the combination of excessive insulin action and suppressed counter-regulatory hormone responses are of common occurrence (46). Serious long-term neurologic impairments may range from mild neurocognitive dysfunction to severe mental retardation, epilepsy, microcephaly, or even hemiparesis or aphasia (30). Occipital cortex injury associated with neonatal hypoglycemia can produce long-term disability in the form of epilepsy and visual impairment. A study demonstrated that neonatal hypoglycemic brain injury is associated with the subsequent development of infantile spasms (96).

Hypoglycemic neuropathy is characterized by "dying back" pattern of axonal degeneration. Wallerian-like axonal degeneration starts at the nerve terminal and progresses to a more proximal part of the axon. Motor axons are more severely affected than sensory axons (69). Jamali and Mohseni evaluated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic rats (44). Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. It was suggested that hypoglycemia had a more severe impact on somatic motor nerves than on somatic sensory nerves, whereas hyperglycemia affected only somatic sensory nerves (77).

Clinical vignette

A 45-year-old, insulin-dependent diabetic woman was admitted for a cholecystectomy. She had no prior history of stroke or any other past neurologic problems. On the morning of the planned surgery, she developed sudden right-sided weakness with speech difficulty. Her examination showed that she was alert with expressive aphasia and a right hemiparesis. Cardiovascular examination and carotid auscultation were normal.

A finger stick glucometer reading showed her serum glucose level to be below 50 mg/dL. She had resolution of all neurologic dysfunction within minutes of intravenous glucose infusion. Subsequent laboratory measurement confirmed the level to be 22 mg/dL drawn during the time of the "stroke." It was later learned that she received her regular dose of insulin, and her breakfast was held in anticipation of the surgery.

This case reveals stroke-like manifestations due to hypoglycemia in the absence of other symptoms to suggest the true diagnosis. Absence of typical systemic hyperadrenergic symptoms is not uncommon; in fact, it seems to be the rule in patients who present with focal neurologic dysfunction. Decreased carbohydrate intake in diabetics seems to be the most common denominator in triggering symptomatic hypoglycemia.

Biological basis

Etiology and pathogenesis

The etiology of hypoglycemia is due to low plasma glucose. The level of glucose that may result in symptoms may vary and overlap with asymptomatic levels. A plasma level down to 10 mg/dL without symptoms rarely occurs (38), but levels as high as 60 mg/dL may cause symptoms. Overall, levels below 30 mg/dL are far more likely to result in a clinical syndrome compatible with hypoglycemia.

By far the most common underlying medical condition predisposing to hypoglycemia is diabetes. Two important studies–the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study–convincingly demonstrated the definite benefits of intensive glycemic control both in type 1 and type 2 diabetes. These studies suggested that diabetic complications could be reduced by rigorous glycemic control. However, this rigorous glycemic control has led to an increased frequency of hypoglycemia (88; 89). Recurrent episodes of hypoglycemia impair sympathoadrenal counterregulatory responses to a subsequent episode of hypoglycemia. In patients with diabetes, this autonomic failure markedly increases the risk of severe hypoglycemia. Risk factors for hypoglycemia include endogenous insulin deficiency, a history of hypoglycemia, hypoglycemia unawareness, aggressive glycemic therapy, recent exercise, sleep, and renal failure. Unrecognized nocturnal hypoglycemia with a normal or even hyperglycemic range in the morning, the so-called Somogyi effect (32), may result in a false sense of good control, or even worse, lead to an increase of an oral hypoglycemic agent or insulin dosage. Alcoholism with poor nutritional intake, undetected insulinomas, sepsis, or shock in hospitalized patients all have been recognized as precipitating factors.

"Relative hypoglycemia" is a condition where the threshold for detecting low blood sugar increases, making it harder for patients to recognize hypoglycemia. This is particularly important in critically ill patients, as studies show that higher blood sugar levels in intensive care are linked to higher mortality in nondiabetics, but lower mortality in diabetics with high prehospitalization HbA1c levels. The detection of hypoglycemia involves glucose-responsive sensory neurons, which may be impaired in diabetes, raising the threshold for hypoglycemia perception. This impairment could increase the mortality risk in critically ill diabetic patients under standard glycemic management (83).

Many other drugs have also been implicated in producing hypoglycemia. The most common are ethanol, salicylates, quinine, haloperidol, pentamidine, trimethoprim-sulfamethoxazole, propoxyphene, and B-adrenergic–blocking agents. Factitious illness via self-administered insulin or oral hypoglycemic agents has been seen mostly in health care workers.

Patients with iatrogenic causes of hypoglycemia are frequently encountered in the emergency department. The most frequent iatrogenic cause is insulin administration for the treatment of hyperkalemia and hyperglycemia. Patients, with alcohol intoxication or poor nutritional status, are also likely to have low blood glucose levels (12).

Hypoglycemia can be a serious complication of bariatric surgery. In a prospective cohort study of patients who underwent Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding surgeries, approximately 39% of patients experienced postoperative hypoglycemia. In a small percentage of patients, hypoglycemia required hospitalization (28).

The maintenance of normal glucose levels results when the homeostatic balance of glucose production and utilization occurs. Glucose synthesis by glycogenolysis (breakdown of stored glycogen) and gluconeogenesis (synthesis from noncarbohydrate precursors), along with absorption of ingested carbohydrates, is balanced against the removal of glucose due to metabolism by the liver, muscle, brain, and other organ systems. Interplay and fine-tuning of these various physiologic pathways are regulated by the hormonal system and the neurotransmitter epinephrine. Insulin plays a dominant role in synthesis and utilization of glucose that results in lowered glucose levels, with counter-regulatory substances consisting of glucagon, epinephrine, growth hormone, and cortisol. Dynamic interplay of these substances affects glucose production and utilization, resulting in maintenance of glucose within a normal range.

Whenever plasma glucose levels fall, hormonal and sympathoadrenal mechanisms get activated to restore blood glucose levels to normal. These regulatory mechanisms are possibly initiated by neuronal glucose sensors, which are present throughout the brain. Brain neurons acting as glucose sensors, such as in ventromedial hypothalamic nucleus, may sense changes in plasma and extracellular glucose. The counterregulatory mechanisms against hypoglycemia include reduction of insulin secretion, increasing glucagon secretion, adrenergic activation, and increased growth hormone and cortisol secretion. Metabolically, these mechanisms lead to increased glucose production, initially through glycogenolysis and later through gluconeogenesis; decreased muscle glucose oxidation and storage; and increased release and use of alternative fuels, primarily free fatty acids. They also lead to hypoglycemic symptoms and hunger, which increase food intake (39).

Recurrent hypoglycemia impairs protective mechanisms meant for maintaining the blood sugar and results in hypoglycemia-associated autonomic failure. During hypoglycemia-associated autonomic failure, the glycemic threshold is reset so that glucose levels must fall further below before the counterregulatory responses get activated. Recurrent episodes of hypoglycemia result in the syndrome of hypoglycemia unawareness. This refers to loss of the warning symptoms that previously cautioned the patient to recognize the occurrence of hypoglycemia and take timely measures. Repeated hypoglycemia can lead to impaired awareness, increasing the risk of severe hypoglycemia up to 6-fold (13).

The development of impaired awareness of hypoglycemia and counter-regulatory failure greatly increases the risk of severe hypoglycemia. Scoring systems have been developed that can be used in the clinical setting and assist with identification of this group of individuals at risk for severe hypoglycemia. The mainstay of treatment of impaired awareness of hypoglycemia is the avoidance of hypoglycemia (35). Hypoglycemia unawareness is reversible by 2 to 3 weeks of meticulous avoidance of hypoglycemia (16). The exact mechanism by which central glucose sensing is integrated to lead to effective initiation of the counterregulatory responses is unknown. Furthermore, the mechanisms by which this regulatory system becomes impaired during hypoglycemia-associated autonomic failure are also unknown. Animal data suggest that during hypoglycemia a decrease in glucose concentration within the ventromedial hypothalamus may provide an important signal that rapidly inactivates ventromedial hypothalamus GABAergic neurons, reducing inhibitory GABAergic tone, which in turn enhances the counterregulatory responses to hypoglycemia (99). In patients with diabetes mellitus who lose awareness of being hypoglycemic, involvement of corticolimbic brain and centers serving higher executive functions as well as the hypothalamus has been demonstrated (11).

The brain does not store glycogen and perform gluconeogenesis; it relies on a continuous supply of glucose from blood, and oxidative metabolism is the only source of energy except in extreme starvation. This is the basis of the high frequency of cerebral dysfunction in cases of transient hypoglycemia.

Rarely, profound, prolonged hypoglycemia can cause brain death. Hypoglycemia causes neuronal death only when the EEG becomes flat. This usually occurs after plasma glucose levels have fallen below 18 mg/dL. At that time, because of abrupt energy failure, the excitatory amino acid glutamate is released into the extracellular space. Excessive stimulation of glutamate receptor/ion channel complexes triggers massive influx of calcium inside the cell and a cascade of biochemical changes results in neuronal cell apoptosis. Hypoglycemia often differs from ischemia in its neuropathologic distribution. In hypoglycemia necrosis of the dentate gyrus of the hippocampus can occur, and a predilection for the superficial layers of the cortex is sometimes seen. Cerebellar Purkinje cells and brainstem neurons are spared in hypoglycemic brain damage (47; 09; 75; 04). Data from tissue culture studies show that hypoglycemia inhibits oligodendrocyte development and myelination and that hypoglycemia triggers apoptotic cell death in oligodendrocyte precursor cells (95). An experimental study demonstrated that fasting predisposed rats to development of hypoglycemic seizures because fasting and insulin-induced hypoglycemia could lead to impairment in the function of the substantia nigra reticulata (90).

Annual outbreaks of unexplained encephalopathy with high mortality among children in East India (the highest litchi cultivation region of the country) were always considered because of some kind of viral encephalitis. Extensive investigations revealed that unexplained encephalopathy was associated with hypoglycin A and methylenecyclopropylglycine toxicity. Hypoglycin A or methylenecyclopropylglycine are naturally occurring fruit-based toxins that cause hypoglycemia and many other metabolic derangements. On admission, 204 (62%) of 327 had blood glucose concentration of 70 mg/dL or less (87). A subsequent report indicates that the acute hypoglycemic encephalopathy is, in fact, a consequence of undernutrition, prolonged fasting, and heavy litchi intake (82). It has been demonstrated that an inadequate glycogen store in affected children results in initiation of gluconeogenesis and fatty acid β-oxidation, but methylenecyclopropylglycine present in the litchi blocks this compensatory mechanism.

In patients of type 1 diabetes mellitus using a continuous glucose monitoring system, impaired awareness of hypoglycemia is associated with increased risk of severe hypoglycemia (58). Intensive glucose-lowering therapy in vulnerable adults (75 years or older, with two or more activities of daily living limitations, end-stage renal disease, or three or more chronic conditions) is associated with a significant risk of severe hypoglycemia (62).

Postmortem examination in a patient revealed superficial laminar necrosis throughout the cerebral cortex. Neuronal necrosis was also found in the hippocampus and dentate gyrus, although the CA3 region appeared normal. In addition to these lesions, which are consistent with hypoglycemia-induced brain damage, the cerebral white matter exhibited severe loss of myelin and axons with reactive astrocytosis and macrophage infiltration. Old infarcts were also present in the bilateral occipital lobes. Because the cerebral blood flow is reported to be decreased during severe hypoglycemia, the present findings suggest that white matter lesions and boundary-zone infarctions may develop primarily in uncomplicated hypoglycemia (70). A variety of other mechanisms that are thought to be involved in the pathogenesis of hypoglycemic neuronal death include production of reactive oxygen species, neuronal zinc release, activation of poly (ADP-ribose) polymerase, and mitochondrial permeability transition (15).

Structural central nervous system abnormalities in early-onset type 1 diabetes mellitus have also been reported. Diabetic children with severe hypoglycemia (presenting as coma or seizure) were compared with age-matched peers with no history of such events using magnetic resonance imaging. Early age of onset of type 1 diabetes per se was associated with a high incidence of central nervous system abnormalities, particularly mesial temporal sclerosis, suggesting hippocampal damage (37).

Epidemiology

Approximately 90% of all patients who receive insulin experience hypoglycemic episodes. It is estimated that an insulin-requiring diabetic suffers an average of one to two episodes of symptomatic hypoglycemia per week, and up to 4% of deaths of insulin-requiring diabetics may be directly related to hypoglycemia (75). To characterize the epidemiology of hypoglycemia in United States emergency departments, Ginde and colleagues analyzed data from 1993 to 2005 (34). There were approximately 5 million emergency department visits for hypoglycemia during those years, and 25% resulted in hospital admission. Emergency visit rates were higher in hypoglycemic patients aged less than 45 years and more than 75 years, females, blacks, and Hispanics.

Dysfunction of the hepatic cardiac, renal, and endocrine systems may predispose to hypoglycemia. Hypoglycemia in cases of congestive heart failure has been attributed to hepatic congestion, or to a reduced delivery of substrate (66) leading to inefficient hepatic gluconeogenesis. Frequent poor nutritional status in such patients suggests that relative depletion of liver glycogen storage may be an additional aggravating factor. An unusually high incidence of hypoglycemia in hypoplastic left heart syndrome has been reported in infants (06). Similarly, hypoglycemia in sepsis may also be due to hepatic dysfunction. Hypoglycemia in the setting of renal failure is frequent, particularly in hospitalized patients, and may be the second most common associated medical condition after diabetes. Fischer and colleagues noted that nearly half of hospitalized patients with hypoglycemia also had chronic renal insufficiency (27). Concurrent diabetes and malnutrition in these patients hamper our understanding of the underlying mechanism, but alteration of insulin clearance and glucose metabolism due to renal failure is suspected. Clinical manifestations of hypoglycemia may be atypical, in part due to poor autonomic nervous system response, but overall neuroglycopenic symptoms predominate. Symptoms can mimic a primary CNS disorder, such as hypertensive encephalopathy, subdural hematoma, encephalitis, or even a lacunar stroke.

Prevention

Symptomatic hypoglycemia is most common in diabetic patients in nonhospitalized settings. Overzealous control with insulin, variation of oral intake and physical activity, and constantly changing physiologic requirements may all contribute to the poor regulation of glucose homeostasis. A better understanding of physiologic requirement, glucose utilization, and hormonal control, along with improved means of insulin delivery, will help prevent hypoglycemia in this population.

To avoid hypoglycemia in patients with type 1 diabetes mellitus, insulin should be given as continuous subcutaneous infusion via a minipump or multiple daily insulin administrations (25). Prolonged starvation or skipping of meals in susceptible individuals is another aggravating factor irrespective of the underlying cause of hypoglycemia. Frequent meals containing carbohydrates, or other means of feeding, such as via gastric tubes or intravenous solution, may be necessary to prevent hypoglycemia.

Thus, predominant strategies to prevent recurrent hypoglycemia include patient education, use of modern insulin analogues, insulin pumps, and continuous glucose monitoring. Transplantation of islets or whole pancreas is indicated in those with recurrent disabling hypoglycemia (13).

The American Diabetes Association has suggested that measures like individualized treatment with hypoglycemic agents with a low risk of hypoglycemia and proven cardiovascular safety, avoidance of overtreatment, and simplifying treatment regimens help prevent hypoglycemic episodes in the elderly (31). A model incorporating five variables (age, emergency department visit 6 months prior, insulin use, use of oral agents that do not induce hypoglycemia, and severe chronic kidney disease) helps predict hypoglycemia during hospitalization at the time of admission (85).

Differential diagnosis

Confusing conditions

Artifactual hypoglycemia may occur in the setting of leukemia, polycythemia, or severe hemolysis, and may represent a laboratory aberration. Cases of this nonphysiologic hypoglycemia are due to continued glucose utilization by a high number of cells after the blood has been obtained and before the glucose level is measured.

Symptoms due to hypoglycemia may mimic those of anxiety attacks, pheochromocytomas, thyrotoxicosis, hot flashes in postmenopausal women, or cardiac syncope, all mediated in part by adrenergic overactivity. In cases of predominant neuroglycopenic symptoms, complex partial seizures, transient ischemic attacks, strokes, encephalopathy, encephalitis, complex migraines, or abnormal sleep behavior may have to be considered (71; 21). Michelucci and colleagues described a peculiar patient with recurrent attacks resembling epileptic seizures that ultimately turned out to be pseudo-nonconvulsive status epilepticus. The patient did not respond to antiepileptic drugs. During one such attack, lab investigation detected severe hypoglycemia, and abdominal imaging subsequently revealed an insulinoma (68).

Hypoglycemia can also be encountered in nondiabetic persons. Nondiabetic hypoglycemia is of two kinds. Prediabetics and persons with bariatric surgery generally have post-prandial hypoglycemia. Pancreatic tumors (insulinomas) and inadvertent use of hypoglycemic agents, binge alcohol intake, and diseases like liver, kidney, and heart diseases can be associated with fasting hypoglycemia (23). Factitious hypoglycemia is a deliberate use of insulin or oral hypoglycemic drugs to harm oneself. Factitious hypoglycemia should be considered in nondiabetic patients presenting with hypoglycemia, even though other disorders can cause hypoglycemia in nondiabetic patients. Insulin as well as oral hypoglycemic agents can be used to induce hypoglycemia. Oueslati and colleagues noted that young age, family history of diabetes, and a low fasting glucose level were the factors associated with factitious hypoglycemia (74).

Diagnostic workup

Measurement of insulin-related substances produced by the pancreas may help in identifying the etiology of hypoglycemia. Proinsulin is normally converted to insulin and C-peptide prior to secretion from the pancreatic beta-cell. Plasma glucose, beta-cell polypeptides, counter-regulatory hormones (glucagon, growth hormone, cortisol), and B-hydroxybutyrate levels may be measured during a symptomatic episode.

Once symptomatic hypoglycemia is suspected (see Whipple triad), further confirmation and diagnostic evaluation may be needed to document and define the underlying etiology. The 72-hour test is the classic diagnostic exam for this purpose. The patient is hospitalized and undergoes fasting except for calorie-free beverages. When used as a confirmatory screening test, poor correlation or absence of signs and symptoms (or both) related to low glucose precludes the diagnosis of a hypoglycemia disorder. Low glucose (less than 40 mg/dL) in the absence of symptoms, however, does not discriminate a normal physiologic response to fasting versus a pathologic hypoglycemic state. In the case of symptomatic hypoglycemia, further biochemical analysis helps to define the underlying cause. Elevated plasma proinsulin, insulin, and C-peptide levels suggest the presence of an insulinoma or sulfonylurea hypoglycemia. Separate plasma sulfonylurea concentration measurement, if detected, will help differentiate the two entities. Factitious hypoglycemia produced by self-administered insulin is associated with suppressed levels of C-peptide and proinsulin, but with high insulin. Deficiency of glucagon or epinephrine (eg, after bilateral adrenalectomy) does not seem to cause symptomatic hypoglycemia.

Additional tests may be necessary if the 72-hour test is not diagnostic. The C-peptide suppression test is based on the premise that pancreatic beta-cell secretion is suppressed to a lesser degree in persons with insulinomas than in normal persons. A set dose of insulin is infused over 60 minutes, and patients with insulinomas demonstrate relatively higher levels of C-peptide concentration than normal individuals. Further tests with intravenous tolbutamide, insulin antibody measurement, and mixed-meals may provide further clues to identifying the cause of underlying hypoglycemia. Recurrent severe hypoglycemia can produce EEG abnormalities in patients with type 1 diabetes. The abnormalities were found to be more pronounced in the temporal regions. A history of severe hypoglycemia was correlated with a global increase in theta activity (40). EEG has little specificity in differentiating etiologies in metabolic encephalopathy.

MRI techniques, particularly diffusion-weighted imaging and apparent diffusion coefficient mapping, are useful for demonstrating cerebral structural lesions in patients with hypoglycemic encephalopathy. MRI in hypoglycemic encephalopathy has demonstrated lesions in the cortex, hippocampus, and basal ganglia. The most severely affected patients manifest bilateral basal ganglia signal abnormality, which correlates with the neuropathologic change in patients with fatal hypoglycemia (26; 03). Diffusion-weighted MRI findings were described in two patients with hypoglycemic coma (59). One patient had diffuse cortical lesions and a poor outcome. The other, with transient white matter abnormalities, had made a complete recovery. The authors suggested that the distinctive patterns of diffusion-weighted MR imaging abnormalities in hypoglycemic patients may be used as a predictor of clinical outcome. Kim and Koh reported another patient in whom extensive white matter abnormalities showed as high signals on diffusion-weighted imaging and low signals on apparent diffusion coefficient maps, sparing cortical and deep gray matter (53). Another report demonstrated rapid reversal of diffusion-weighted MRI abnormalities after glucose infusion in a patient with hypoglycemic coma (65). Reversible lesions involving the splenium of the corpus callosum have also been reported in cases of hypoglycemic brain injury (52). An MR imaging study demonstrated bilateral diffusion-restrictive lesions in the posterior limb of the internal capsule, cerebral cortex, corona radiata, centrum semiovale, hippocampus, and basal ganglion (48). The lesions showed complete resolution on follow-up in six patients. Three patients with cortical involvement of two or more lobes showed partial recovery or death, but most of the other patients with white matter involvement or cortical involvement in only one lobe experienced complete recovery. On early MR imaging, hypoglycemic brain injury may first appear in the internal capsule and then spread into the hemispheric white matter. The absence of a lesion or the presence of a focal internal capsule lesion may suggest a good outcome. However, diffuse hemispheric white matter lesions may indicate a poor 1-week outcome. In a prospective study, 13 of 36 patients showed no MR imaging abnormalities. Diffusion-weighted imaging revealed focal lesions involving the internal capsule in 13 patients and lesions involving bilateral hemispheric white matter in 10 patients. After glucose administration, the patients without lesions and the patients with focal internal capsule lesions recovered completely within 1 day. However, patients with diffuse white matter lesions did not recover within 1 week, despite glucose administration (45).

Cortical laminar necrosis is a metabolic brain injury pattern usually observed after cerebral hypoxia, hypoglycemic encephalopathy, or ischemia. It is characterized neuropathologically by delayed selective neuronal necrosis and occurs in hypoglycemic encephalopathy. High signals along the cortical bands on diffusion-weighted MRI suggest cortical laminar necrosis (97). Hyperintense MR lesions on diffusion-weighted imaging are reported to be reversible (01). The diffusion-weighted imaging in a patient with hemiplegia associated with hypoglycemia showed increased signal intensities and a reduction of apparent diffusion coefficient values localized in the splenium of corpus callosum and asymmetrically in the corona radiata (10). Diffusion-weighted magnetic resonance imaging, in another reported patient, detected increased signal intensity in the pons. These reports indicate that the patient's hemiplegia results from acute brain injury (86).

In pediatric patients with hypoglycemia, the topography of the brain lesions depended on age: from the neonatal period to 6 months of age, lesions predominantly involved the posterior white matter; between 6 and 22 months of age the basal ganglia, and after 22 months the parietotemporal cortex (33).

A novel noninvasive machine learning method has been developed to detect hypoglycemia using only car driving and eye tracking data. This method was evaluated in two studies involving individuals with type 1 diabetes, using a driving simulator under different blood glucose conditions. The first study focused on pronounced hypoglycemia, whereas the second addressed mild hypoglycemia. Results demonstrated high accuracy in detecting both pronounced and mild hypoglycemia (with respective area under the curve values of 0.88 ± 0.10 and 0.83 ± 0.11). These findings indicate that this machine learning approach, relying solely on car driving and eye tracking data, is a promising alternative for detecting hypoglycemia, especially beneficial for drivers (56). Another study presents a novel method to detect hypoglycemic events in patients with type 1 diabetes using accelerometer data from smartwatches (43). By analyzing triaxial accelerometer data from 33 patients over a month, the study extracted various features to train machine learning models. The study found that patients experienced an average of 1.06 hypoglycemic events per day, lasting about 27.31 minutes each. Continuous glucose monitor readings validated these results.

Management

Restoration to euglycemia after an episode of hypoglycemia is ideal in a diabetic patient. However, in a nondiabetic patient, overtreatment of hypoglycemia does not have any lasting ill effects and is preferable in the management of an acutely symptomatic patient. A blood sample should be obtained from a patient with presumed hypoglycemia in order to measure glucose and hormonal essays (eg, insulin and C-peptide). As soon as the blood samples are collected, intravenous injection of glucose as a bolus of 50% solution can be given, and if necessary, continuous infusion of 5% or 10% glucose solution can be infused until oral feeding can be resumed. Thiamine should be administered in susceptible patients to minimize the occurrence of Wernicke encephalopathy. An important weapon in the treatment of severe hypoglycemia is the use of glucagon, a treatment that is underutilized (76). Continuous glucose monitoring is indicated in patients with enhanced risk for recurrent episodes of hypoglycemia with impaired hypoglycemia awareness. Newer hypoglycemic drugs, like sodium-glucose cotransporter-2 (SGLT2) inhibitors, are associated with a lesser risk of hypoglycemia (41).

Artificial pancreas technology, a major advancement in type 1 diabetes care, combines continuous subcutaneous insulin infusion pumps and continuous glucose monitors into a closed-loop system. This system, controlled by a sophisticated algorithm, automates blood glucose regulation, reducing the burden on individuals with diabetes. These technologies improve glycated hemoglobin (HbA1c) levels, increase time in optimal glycemic range, limit severe hypoglycemia, and alleviate diabetes-related stress (72).

After relief of acute symptomatic hypoglycemia, correction of the underlying cause is important to prevent recurrences. In cases of insulinomas, CT, MRI, and celiac-axis angiography may not be sensitive, and more invasive procedures, such as transhepatic portal venous sampling for insulin or intraoperative ultrasound, may be needed for successful localization. Autoimmune hypoglycemia may be difficult to distinguish from factitious hypoglycemia due to similar biochemical features. Offending medication should be eliminated or adjusted immediately in cases of drug-induced hypoglycemia. Depending on the duration of action, frequent feeding or even nocturnal intragastric feeding may be necessary, as has been demonstrated in rare cases of glycogen storage diseases.

Outcomes

The prognosis of patients with severe hypoglycemic encephalopathy is generally grave. Only a small fraction of patients recover sufficiently to get discharged from the ICU. Patients who remained in coma for 6 months never regained consciousness (81).