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2017 CONTINUUM Endocrine Emergencies With Neurologic Manifestations PDF
2017 CONTINUUM Endocrine Emergencies With Neurologic Manifestations PDF
Endocrine Emergencies
Address correspondence to
Dr Makoto Ishii, Feil Family
Brain and Mind Research
Institute, Department of
Neurology, Weill Cornell
Medical College, 407 E 61st St,
Third Floor, New York, NY
With Neurologic
10065, mishii@med.cornell.edu.
Relationship Disclosure:
Dr Ishii has received personal
Manifestations
compensation for speaking
engagements from Keio Makoto Ishii, MD, PhD
University School of Medicine,
Jikei University School of
Medicine, and the University
of Tsukuba and receives
ABSTRACT
research/grant support Purpose of Review: This article provides an overview of endocrine emergencies
from the National Institutes with potentially devastating neurologic manifestations that may be fatal if left
of Health/National Institute
on Aging (K08AG051179) untreated. Pituitary apoplexy, adrenal crisis, myxedema coma, thyroid storm, acute
and the BrightFocus hypercalcemia and hypocalcemia, hyperglycemic emergencies (diabetic ketoacidosis
Foundation. Dr Ishii is a and hyperglycemic hyperosmolar state), and acute hypoglycemia are discussed,
stockholder in Regeneron
Pharmaceuticals, Inc. with an emphasis on identifying the signs and symptoms as well as diagnosing and
Unlabeled Use of managing these clinical entities.
Products/Investigational Recent Findings: To identify the optimal management of endocrine emergencies,
Use Disclosure:
Dr Ishii reports no disclosure.
using formal clinical diagnostic criteria and grading scales such as those recently
* 2017 American Academy proposed for pituitary apoplexy will be beneficial in future prospective studies. A
of Neurology. 2015 prospective study in patients with adrenal insufficiency found a significant
number of adrenal crisisYrelated deaths despite all study patients receiving standard
care and being educated on crisis prevention strategies, highlighting that current
prevention strategies and medical management remain suboptimal.
Summary: Early diagnosis and prompt treatment of endocrine emergencies are
essential but remain challenging because of a lack of objective diagnostic tools. The
optimal management is also unclear as prospective and randomized studies are
lacking. Additional research is needed for these clinical syndromes that can be fatal
despite intensive medical intervention.
KEY POINT
h Lumbar puncture
has limited utility
Case 8-1
A 65-year-old man with hypertension and prostate cancer presented to the
in differentiating
hospital reporting headache and blurry vision. Three days earlier, he had
pituitary apoplexy
received his first dose of depot leuprolide for androgen deprivation therapy. A
from subarachnoid
few hours after the initial injection, he started to develop a mild headache and
hemorrhage; however,
blurred vision. Both the headache and blurred vision worsened over the
if bacterial meningitis is
following days, prompting the patient to seek medical attention. He stated that
suspected, CSF cultures
his headache had now become persistent and unbearable, and he was now
should be obtained.
unable to move his right eye or raise his right eyelid.
Neurologic examination was notable for a right third cranial nerve palsy. MRI
of the brain revealed a large intrasellar mass with hemorrhage. Blood was
drawn for endocrine evaluation. Hydrocortisone was empirically administered,
and the patient underwent transsphenoidal surgery for diagnosis and resection
of the intrasellar mass. Pathology revealed that the tissue was necrotic and
hemorrhagic, but viable tissue was positive for follicle-stimulating hormone,
consistent with a gonadotroph pituitary adenoma. The patient was in stable
condition after surgery and referred to endocrinology for additional evaluation
and management.
Comment. This patient presented with new onset of worsening headache
and blurry vision, with examination revealing a right oculomotor nerve palsy.
While the differential diagnosis can be relatively broad, the use of leuprolide,
a gonadotrophin-releasing hormone agonist, immediately before symptoms
began suggests an association with the symptoms. In this case, the patient
had a previously undiagnosed gonadotroph pituitary adenoma that, when
stimulated by leuprolide, led to hemorrhage of the adenoma and the
presenting symptoms. Because of the intense headaches and severe
neuro-ophthalmologic symptoms, the patient was taken for urgent imaging
and neurosurgical decompression. If the symptoms were mild and the patient
was stable, a conservative medical approach may have been considered, as
pituitary apoplexies can spontaneously resolve; however, the optimal
management remains unclear without prospective studies comparing surgical
to medical management.
KEY POINTS
h Empiric corticosteroid insipidus may occur.1 Because of re- hypoadrenalism, empiric corticosteroid
replacement should be ports of spontaneous clinical improve- replacement should be initiated and
initiated for patients ment and shrinkage of apoplectic tapered to a maintenance dose once
with acute pituitary pituitary adenomas, a conservative ap- the patient recovers from the acute
apoplexy with proach has been suggested in select period.7 Additionally, patients will likely
hemodynamic instability, cases with absent or mild and stable need long-term hormonal replacement
altered consciousness, neuro-ophthalmic signs.1,7 Currently, because of the hypopituitarism caused
reduced visual acuity, no randomized prospective trials have by the apoplexy.17
severe visual field been performed comparing the out-
deficits, or signs of comes of surgery to conservative man- ADRENAL CRISIS (ADDISONIAN
hypoadrenalism. CRISIS)
agement to help guide treatment of
h Adrenal insufficiency patients with pituitary apoplexy; how- Adrenal insufficiency can be classified
can be classified as a ever, grading systems have recently as a primary disorder (eg, autoimmune
primary disorder (eg, been developed to better classify and destruction of the adrenal gland) or a
autoimmune
improve the management of patients secondary disorder (eg, hypopituita-
destruction of the
with pituitary apoplexy (Figure 8-2 rism caused by pituitary apoplexy)
adrenal gland) or a
secondary disorder (eg,
and Table 8-1).7,16 For all patients or may result more commonly from
hypopituitarism caused with pituitary apoplexy who have drug-induced adrenal insufficiency
by pituitary apoplexy) hemodynamic instability, altered con- (eg, glucocorticoid withdrawal after
or may result from sciousness, reduced visual acuity, se- chronic exogenous glucocorticoid ther-
drug-induced adrenal vere visual field deficits, or signs of apy) (Table 8-2).18Y20 Primary adrenal
insufficiency (eg,
glucocorticoid withdrawal
after chronic exogenous
glucocorticoid therapy).
FIGURE 8-2 Flowchart illustrating assessment using the Pituitary Apoplexy Grading System.
While chronic and higher doses of healthy and stable patient, followed by
glucocorticoid have the highest risk for monitoring for any signs and symptoms
adrenal insufficiency after glucocorti- of adrenal insufficiency. For patients
coid withdrawal, a recent systemic with longer durations of glucocorticoid
review and meta-analysis found no therapy, a slow steady taper over several
administration form, dosing, treatment weeks to months, depending on the
duration, or underlying disease for duration and dose of glucocorticoid
which adrenal insufficiency can be therapy, will likely be needed.
excluded.23 Therefore, neurologists
need to be vigilant when withdrawing Clinical Presentation
glucocorticoids from their patients and In an adrenal crisis, patients often
test for adrenal insufficiency in any present with gastrointestinal symptoms,
patients who develop unexplained nausea, vomiting, muscle cramps, and
symptoms after glucocorticoid with- hypotension, which may be erroneously
drawal. Unfortunately, clinical evidence diagnosed as gastroenteritis or an acute
to support any specific glucocorticoid- abdomen, potentially leading to a delay
tapering regimen to help avoid adrenal in treatment. Neurologic manifestations
insufficiency is lacking. One reasonable can include altered mental status (eg,
option would be to stop without a taper delirium), convulsions, myopathy, and
after short-term (1 to 2 weeks) glucocor- flexion contractures.21 Without prompt
ticoid use of any dosing in an otherwise medical attention, patients can quickly
KEY POINTS
h Myxedema coma is mortality rate of 20% to 30%.28,29 Typi- Clinical presentation. The cardinal
typically triggered by a cally, myxedema coma is triggered by a hallmarks of myxedema coma are
systemic illness, such as systemic illness, such as a pulmonary or hypothermia and depressed mental
a pulmonary or urinary urinary infection; congestive heart fail- status or coma (Case 8-2).29 On pre-
infection; congestive ure; stroke; trauma; or certain medica- sentation, patients can have extreme
heart failure; stroke; tions in a patient with previously hypothermia (to 26.7-C [80-F]) that
trauma; or certain undiagnosed or untreated hypothyroid- may mask an infection.28 Physical exam-
medications in a patient ism (Table 8-3).28 Cold seems to be a ination often reveals extreme signs
with previously strong inciting factor, as up to 90% of of hypothyroidism, including dry, brittle
undiagnosed or cases occur during the winter months.29 skin and hair; doughlike nonpitting
untreated hypothyroidism.
Myxedema coma is more common in edema; hoarse voice; macroglossia;
h The cardinal hallmarks older women, with 80% occurring in and delayed reflexes. Hypotension
of myxedema coma are women older than 60 years; however, and shock may be seen from decreased
hypothermia and rarely, younger patients, including preg- cardiac contraction and potentially fatal
depressed mental status
nant women, may be affected.28 bradyarrhythmias.29 Prolonged mechan-
or coma.
ical ventilation is usually needed for
severe hypoventilation.28 Gastrointesti-
nal bleeding caused by myxedema-
TABLE 8-3 Factors Precipitating associated coagulopathy may also be
Myxedema Comaa
seen.29 Neurologic manifestations of
myxedema coma include depressed
b Drugs
mental status, cerebellar signs, and, in
Withdrawal of
up to 25% of cases, seizures, including
levothyroxine
reports of status epilepticus.28,30 Pa-
Anesthetics
tients may not initially present with
Sedative hypnotics
frank coma but with milder signs of
Narcotics depressed mental status, only to gradu-
Amiodarone ally decline to a coma during the
Lithium carbonate hospitalization. Laboratory testing often
b Infections, sepsis shows hyponatremia as well as anemia
b Stroke and acidosis.28 Lumbar puncture often
b Congestive heart failure finds a high opening pressure with an
b Low temperature elevated CSF protein level.28 If an
b Trauma infection is suspected or if no obvious
b Metabolic disturbances inciting factor that triggered the myx-
Acidosis
edema coma is found, cultures should
be obtained to find a potential source
Hypoglycemia
of infection.
Hyponatremia
Diagnosis and management. Thy-
Hypercapnia
roid testing usually finds an abnor-
b Other mally high thyroid-stimulating hormone
Gastrointestinal bleeding (TSH) level, but, as up to 10% of the
Excessive ingestion of hypothyroidism in myxedema coma can
raw bok choy be due to hypothalamic or pituitary
a
Modified with permission from dysfunction, the TSH levels may be
Klubo-Gwiezdzinska J, Wartofsky L, Med
Clin North Am.28 B 2012 Elsevier. low or inappropriately normal.28,31 Free
sciencedirect.com/science/article/pii/ thyroid hormones (thyroxine [T4] and
S0025712512000168.
triiodothyronine [T3]) should there-
fore be measured in all patients with
786 ContinuumJournal.com June 2017
KEY POINTS
h Patients with thyroid insidiously; however, a precipitating
TABLE 8-4 Factors Precipitating
storm have variable factor (eg, infection) can trigger a Thyrotoxic Storma
clinical manifestations, thyroid storm in a susceptible patient
with exaggerated signs who is thyrotoxic, leading to a true b Drugs
and symptoms of medical emergency with exaggerated Withdrawal of antithyroid
thyrotoxicosis signs and symptoms of thyrotoxicosis, drug treatment
accompanied by including severe encephalopathy.18 Radioactive iodine
multiorgan Epidemiology and pathophysiology. treatment
decompensation. The exact incidence of thyroid storm is Thyroxine/triiodothyronine
h No set serum thyroxine difficult to accurately assess, but recent overdose
(T4) or triiodothyronine reports estimate that 1% to 2% of all Cytotoxic chemotherapy
(T3) criteria exist hospital admissions for thyrotoxicosis Aspirin overdose
for diagnosing a are due to a thyroid storm.32 Thyroid Iodinated contrast dyes
thyroid storm, but a storm most commonly affects women
full laboratory Organophosphate toxicity
and those with Graves disease.32 The
evaluation including b Sepsis, infection
exact mechanisms leading to a thyroid
thyroid-stimulating b Seizure disorder
hormone, free T3,
storm are not known, but they likely
b Pulmonary thrombo-embolism
and free T4 (even involve an increased response to thyroid
hormones, increased availability of free b Burn injury
with a normal
thyroid hormones, and enhanced bind- b Surgery, trauma, vigorous
thyroid-stimulating
palpation of thyroid
hormone level) should ing of thyroid hormone to its receptor.
be conducted in all Similar to myxedema coma, a precipi- b Metabolic disturbances
suspected cases. tating factor, such as an infection or Diabetic ketoacidosis
trauma, can trigger the thyroid storm in Hypoglycemia
a patient who is thyrotoxic; however, b Other
25% to 43% of patients presenting with Parturition
a thyroid storm have no clear inciting Emotional stress
factor.28,32 Factors precipitating thro- a
Modified with permission from
toxic storm are listed in Table 8-4. Klubo-Gwiezdzinska J, Wartofsky L, Med
Clinical presentation. Patients with Clin North Am.28 B 2012 Elsevier.
sciencedirect.com/science/article/pii/
thyroid storm have variable clinical man- S0025712512000168.
ifestations, with exaggerated signs and
symptoms of thyrotoxicosis accompa-
nied by multiorgan decompensation.32
Some of the cardinal manifestations levels can be seen due to thyroid-
include a high fever out of proportion mediated increased bone resorption.28,32
to any infection; diaphoresis and tachy- A moderate leukocytosis can be seen
cardia out of proportion to the fever; even in the absence of infection.
arrhythmias; and gastrointestinal symp- Diagnosis and management. The
toms, including nausea, vomiting, diar- diagnosis of thyroid storm remains
rhea, and possibly jaundice in severe challenging and is largely based on
cases.28 Encephalopathy is commonly clinical findings. No set serum T4 or
seen in the form of agitation, emotional T3 criteria exist for diagnosing a
lability, confusion, paranoia, psychosis, thyroid storm, but a full laboratory
and eventually coma.28 Additionally, evaluation, including TSH, free T3,
cases of patients presenting with sei- free T4, and electrolytes will be useful
zures or status epilepticus and stroke in establishing the thyrotoxicosis and
have been reported.33 On laboratory associated electrolyte abnormalities.32
evaluation, increased serum calcium The goals of treatment of thyroid storm
b Parathyroid Disease
Primary hyperparathyroidism due to benign parathyroid adenoma,
parathyroid carcinoma, or parathyroid multiglandular hyperplasia as
part of multiple endocrine neoplasia syndromes
Tertiary hyperparathyroidism
b Malignancy
Parathyroid hormoneYrelated protein (humoral hypercalcemia of malignancy)
Local osteolysis mediated by cytokine release
Lytic bone metastasis
Multiple myeloma
Ectopic production of 1,25-dihydroxyvitamin D by the tumor (eg, lymphoma)
b Endocrinopathies
Adrenal insufficiency
Multiple endocrine neoplasia type 1, type 2A
Thyrotoxicosis
Pheochromocytoma
VIPoma (pancreatic endocrine tumor that secretes vasoactive intestinal
peptide)
b Granulomatous Disease
Tuberculosis
Sarcoidosis
Endemic mycosis: histoplasmosis, coccidioidomycosis
Leprosy
Crohn disease
Berylliosis
b Medications
Estrogens
Lithium
Thiazide diuretics
Excess vitamin D or vitamin A ingestion
b Miscellaneous
Familial hypocalciuric hypercalcemia
Immobilization
a
Modified with permission from Ahmad S, et al, Am J Med.36 B 2015 Elsevier. sciencedirect.com/science/
article/pii/S0002934314009152.
KEY POINT
h Disorders of parathyroid Epidemiology and pathophysiology. intestinal calcium absorption, and
hormone and vitamin D Disorders of parathyroid hormone and severe vitamin D deficiency can also
are the major causes vitamin D are the major causes of lead to significant hypocalcemia.34,44
of hypocalcemia, hypocalcemia, with acquired hypopara- Certain medications can also decrease
with acquired thyroidism as a complication of thyroid calcium, such as antiepileptic drugs,
hypoparathyroidism as a and neck surgeries being the most chemotherapy drugs, and bisphos-
complication of thyroid common cause of hypocalcemia in phonates.34,45 Hypomagnesemia can
and neck surgeries adults (Table 8-6).34,43,44 The rate of reduce parathyroid secretion or cause
being the most hypoparathyroidism after total thyroid- resistance to parathyroid hormone.34
common cause of ectomies is estimated to be from 0.5% Clinical presentation. Systemic
hypocalcemia in adults.
to 6.6%.43 Since calcium is bound to manifestations of hypocalcemia include
proteins, serum calcium levels can fall myocardial dysfunction, such as pro-
when serum protein is reduced, such longation of the QT interval on ECG
as during volume overload, chronic and cardiomyopathy in long-standing
illness, malnutrition, or nephrotic syn- hypocalcemia.46,47 Acute hypocalcemia
drome. Vitamin D is important for can affect both the peripheral nervous
KEY POINTS
h Diabetic ketoacidosis is Epidemiology and pathophysiology. well understood, but a greater degree of
characterized by the DKA is characterized by the triad of dehydration appears to exist due to
triad of uncontrolled uncontrolled hyperglycemia, metabolic osmotic diuresis. Importantly, in hyper-
hyperglycemia, metabolic acidosis, and increased total body ketone glycemic hyperosmolar state, despite a
acidosis, and concentration.54 The estimated annual relative insulin deficiency resulting in
increased total body incidence in the United States varies inadequate glucose utilization, endoge-
ketone concentration. with age from 4 to 8 per 1000 patients nous insulin secretion appears to be
h Hyperglycemic in all age groups to 13.4 per 1000 pa- greater than in DKA and is adequate to
hyperosmolar state is tients in those younger than 30 years.55 prevent lipolysis and subsequent keto-
characterized by severe Hospital admission for DKA has in- genesis.54 Despite the different etiolo-
hyperglycemia, creased by approximately 75% over gies, both DKA and hyperglycemic
hyperosmolality, and the past 2 decades.56 While DKA used hyperosmolar state frequently have an
dehydration in the to be seen almost exclusively in type 1 inciting factor that triggers the crisis. The
absence of significant diabetes mellitus, it is now becoming most common precipitant of DKA and
ketoacidosis.
more common in type 2 diabetes hyperglycemic hyperosmolar state is
h The most common mellitus, with one-third of all DKA infection, but other causes include
precipitant of diabetic hospitalizations in the United States omission of or inadequate insulin dos-
ketoacidosis and occurring in patients with type 2 ing, pancreatitis, myocardial infarction,
hyperglycemic
diabetes mellitus.55 The overall mor- stroke, and certain drugs (eg, corticoste-
hyperosmolar state is
tality rate of DKA in adults in the roids, thiazide diuretics, sympathomi-
infection, but other
causes include omission
United States is less than 1% and metics, and antipsychotics).54,55 In the
of or inadequate insulin slightly higher than 5% in the elderly elderly, immobilization or an illness that
dosing, pancreatitis, and patients with severe comorbid restricts water intake can contribute to
myocardial infarction, medical conditions; however, DKA re- severe dehydration and hyperglycemic
stroke, and certain mains a significant cause of mortality hyperosmolar state.55 In young patients
drugs (eg, in children and young adults with with type 1 diabetes mellitus, psycho-
corticosteroids, type 1 diabetes mellitus.55 logical and eating disorders are contrib-
thiazide diuretics, Hyperglycemic hyperosmolar state is uting factors in 20% of recurrent DKA.54
sympathomimetics, and characterized by severe hyperglycemia, Both DKA and hyperglycemic hyper-
antipsychotics). hyperosmolality, and dehydration in the osmolar state are associated with an
h Both diabetic absence of significant ketoacidosis.54 inflammatory state with elevation of
ketoacidosis and Hyperglycemic hyperosmolar state is proinflammatory cytokines, which may
hyperglycemic most commonly seen in older patients explain the relatively high incidence of
hyperosmolar state with type 2 diabetes mellitus but can thrombotic events during a hyper-
classically present with
be seen in younger patients and in pa- glycemic crisis.55
polyuria, polydipsia,
tients with type 1 diabetes mellitus.53,55 Clinical presentation. A major
weight loss, vomiting,
dehydration, weakness,
The mortality rate in hyperglycemic difference in clinical presentation
and altered hyperosmolar state is generally higher between DKA and hyperglycemic
mental status. than in DKA, with estimates ranging hyperosmolar state is that the meta-
between 5% and 20% in the United bolic alterations in DKA usually evolve
States and United Kingdom.53,54 in less than 24 hours, while a hyper-
In DKA, the absolute or relative glycemic hyperosmolar state typically
insulin deficiency combined with an evolves over several days to weeks.54
increase in counterregulatory hormones In both conditions, the hyperglycemic
(eg, glucagon, growth hormone, corti- crisis can be the presenting manifes-
sol, and catecholamines) results in tation of the underlying diabetes
hyperglycemia, ketonemia, and meta- mellitus. Both DKA and hyperglycemic
bolic acidosis.56 The pathogenesis of hyperosmolar state classically present
hyperglycemic hyperosmolar state is less with polyuria, polydipsia, weight loss,
794 ContinuumJournal.com June 2017
FIGURE 8-3 Brain CT (A) and brain MRI (B) of a patient with hemichorea-hemiballismus
secondary to a hyperglycemic-hyperosmolar state. CT shows hyperdensity in the
left caudate and putamen, which was confirmed by subsequent T1-weighted MRI.
Reprinted with permission from Vale TC, et al, Neurology.57 B 2013 American
Academy of Neurology. neurology.org/content/80/16/e178.short.
TABLE 8-7 Diagnostic Criteria for Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar
Statea
Diabetic Ketoacidosis
Diagnostic Criteria Hyperglycemic
and Classification Mild Moderate Severe Hyperosmolar State
Plasma glucose (mg/dL) 9250 9250 9250 9600
Arterial pH 7.25Y7.30 7.00Y7.24 G7.00 97.30
Serum bicarbonate (mEq/L) 15Y18 10Y15 G10 915
Urine ketone Positive Positive Positive Small
Serum ketone Positive Positive Positive Small
Effective serum osmolality Variable Variable Variable 9320
Anion gap 910 912 912 Variable
Mental status Alert Alert/drowsy Stupor/coma Variable
a
Modified with permission from Nyenwe EA, Kitabchi AE, Diabetes Res Clin Pract.55 B 2011 Elsevier. sciencedirect.com/science/article/pii/S0168822711005146.
KEY POINT The goals of therapy in DKA and toring are critical to ensure that rapid
h The goals of therapy hyperglycemic hyperosmolar state are changes and overcorrection leading to
in hyperglycemic to correct the dehydration, hypergly- hypoglycemia and hypokalemia are
crises are to correct
cemia, and electrolyte abnormalities avoided. Hydration alone has been
the dehydration,
and to identify and treat the underly- shown to be sufficient to reduce blood
hyperglycemia, and
electrolyte abnormalities
ing inciting factor.53,54,56 Fluid resusci- glucose and osmolality.53 Adequate
and to identify and tation should begin with the goal of fluid replacement is essential before
treat the underlying replacing approximately half of the starting insulin, as a risk of potentially
inciting factor. water deficit in 12 hours.53,56 Close devastating cardiovascular collapse ex-
hemodynamic and laboratory moni- ists if insulin is administered before
Diabetic Hyperglycemic
Typical Deficits Ketoacidosis Hyperosmolar State
Total water (L) 6 9
Water (mL/kg of body weight) 100 100Y200
Serum sodium (mEq/L) 7Y10 5Y13
Y
Cl (mEq/L) 3Y5 5Y15
+
K (mEq/L) 3Y5 4Y6
PO4 (mmol/L) 5Y7 3Y7
2+
Mg (mEq/L) 1Y2 1Y2
2+
Ca (mEq/L) 1Y2 1Y2
a
Modified with permission from Nyenwe EA, Kitabchi AE, Diabetes Res Clin Pract.55 B 2011 Elsevier.
sciencedirect.com/science/article/pii/S0168822711005146.
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