5

var title_f0_5_80="Episcleritis";
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" Episcleritis",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?0/5/80/contributors\">",
" Authors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
0/5/80/contributors\">",
" John H Stone, MD, MPH",
" </a>",
" <br/>",
" Reza Dana, MD, MPH, MSc",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Jonathan Trobe, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Paul L Romain, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?0/5/80/contributor-disclosure\" target=\"_blank\">",
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" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" |",
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" This topic last updated:",
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" May 7, 2012.",
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" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" — Episcleritis is defined by the abrupt onset of inflammation
in the episclera of the eye. Most patients with episcleritis have a mild, isolated
problem that responds readily to topical therapy alone and that does not pose a
threat to vision. Indeed, many patients with episcleritis require no treatment per
se since the condition typically resolves over a short course. A small fraction of
patients with episcleritis has an underlying systemic disease that signifies a
serious health concern and that requires additional therapy.",
" </p>",
" <p>",
" Episcleritis is only one of many potential causes of a red eye. Other
disorders that may cause this syndrome include subconjunctival hemorrhage,
conjunctivitis, blepharitis, keratitis, scleritis, acute anterior uveitis, and
acute angle-closure glaucoma. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/12/17607?
source=see_link\">",
" \"Evaluation of the red eye\"",
" </a>",
" .)",
" </p>",
" <p>",
" Issues related to episcleritis will be reviewed here. The clinical
manifestations, diagnosis, and treatment of scleritis are discussed separately.
(See",
" \"Clinical manifestations and diagnosis of scleritis\"",
" </a>",
" and",
" \"Treatment of scleritis\"",
" </a>",
" .)",
" </p>",
" EPIDEMIOLOGY",
" </span>",
" — Approximately 70 percent of cases of episcleritis occur in
females [",
" <a class=\"abstract\" href=\"UTD.htm?0/5/80/abstract/1\">",
" 1",
" </a>",
" ]. It occurs most frequently in young and middle-aged adults but may affect
all age groups.",
" </p>",
" <p>",
" Episcleritis is usually classified as either simple or nodular (",
" <a class=\"graphic graphic_picture graphicRef76962 \" href=\"UTD.htm?
16/25/16799\">",
" picture 1",
" </a>",
" and",
25/48/26383\">",
" picture 2",
" </a>",
" ). Simple episcleritis is usually sectoral in nature, confined to a carefully
delimited portion of the episclera. However, more diffuse episcleral involvement
can occur.",
" </p>",
" <p>",
" The vast majority of episcleritis cases are isolated and are not associated
with a known underlying systemic immune-mediated disorder (unlike scleritis with
which the association is much higher). However, episcleritis may be associated with
a number of systemic diseases [",
" <a class=\"abstract\" href=\"UTD.htm?0/5/80/abstract/1-3\">",
" 1-3",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Simple episcleritis is observed in association with seronegative
spondyloarthritides, inflammatory bowel disease, and certain forms of vasculitis,
particularly those associated with antineutrophil cytoplasmic antibodies (ANCA).
(See",
" \"Reactive arthritis (formerly Reiter syndrome)\"",
" </a>",
" and",
" \"Clinical manifestations, diagnosis, and management of undifferentiated
spondyloarthritis and related spondyloarthritides\"",
" </a>",
" and",
" \"Skin and eye manifestations of inflammatory bowel disease\"",
" </a>",
" and",
" \"Clinical manifestations and diagnosis of granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Nodular episcleritis is most frequently idiopathic but may be associated
with any of the rheumatic conditions, particularly rheumatoid arthritis. Rheumatoid
arthritis accounts for approximately 6 percent of all cases of episcleritis, but
only a small minority of patients with rheumatoid arthritis develops episcleritis
[",
" 2",
" </a>",
" ]. (See",
" \"Ocular manifestations of rheumatoid arthritis\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" Some reports suggest a possible link between use of the bisphosphonate
drugs,",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/41/17047?source=see_link\">",
" risedronate",
" </a>",
" and",
" pamidronate",
" </a>",
" , and episcleritis [",
" <a class=\"abstract\" href=\"UTD.htm?0/5/80/abstract/4,5\">",
" 4,5",
" </a>",
" ]. However, a clear cause-and-effect relationship has not been established.
Reported occurrence rates are generally less than 1 percent.",
" </p>",
" PATHOGENESIS",
" </span>",
" — Episcleritis is a clinical diagnosis that can be produced
by a variety of systemic immune and nonimmune mechanisms that incite inflammation.
A common cause of episcleritis that has no associated systemic manifestation is the
dry eye syndrome that is not linked to Sjögren's syndrome. One example of a
nonimmune mechanism that may lead to episcleritis is the dry eye syndrome.
Histologic examination reveals widespread vasodilatation, edema, and lymphocytic
infiltration [",
" 1",
" </a>",
" ].",
" </p>",
" <p>",
" Immune mechanisms causing episcleritis may involve acute type I
hypersensitivity responses caused by IgE-mediated degranulation of tissue mast
cells. It can also be induced by immune complex-mediated reactions (type III
hypersensitivity), as occur in some vasculitic diseases, and by systemic
infections, such as syphilis or tuberculosis. In granulomatous diseases, the
pathophysiology of episcleritis is thought to be mediated by a type IV delayed-type
hypersensitivity response, but the underlying antigens are unknown.",
" </p>",
" CLINICAL FEATURES",
" </span>",
" — Episcleritis is commonly acute in onset and may be either
localized or diffuse. Most attacks of simple episcleritis resolve within three
weeks, with or without treatment.",
" </p>",
" <p>",
" Patients with episcleritis usually complain of the abrupt onset of redness,
irritation, and watering of the eye. Pain is unusual but can be observed with
chronic or nodular episcleritis. Vision is not affected. Approximately one-half of
cases are bilateral. Bilateral involvement may be associated with an increased
likelihood of an underlying inflammatory disease, but not all studies have
confirmed this suggestion [",
" 3",
" </a>",
" ]. Physical examination reveals vasodilatation of the superficial episcleral
vessels and edema of the episclera.",
" </p>",
" <p>",
" In one series of 37 patients with episcleritis, the primary clinical features
were as follows [",
" 3",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" The mean age was 45 years, with a range from 9 to 71 years.",
" </li>",
" <li>",
" Seventy percent of the patients were female.",
" </li>",
" <li>",
" Bilateral disease occurred in 49 percent.",
" </li>",
" <li>",
" The great majority of patients (87 percent) had no ocular complications of
their episcleritis. Among the five patients with complications, there were three
cases of mild anterior uveitis, one case of uveitis and interstitial keratitis, and
one case of elevated intraocular pressure.",
" </li>",
" </ul>",
" </p>",
" <p>",
" An important point of this study is that none of the ocular complications were
associated with reduced visual acuity. This contrasts with a group of 97 patients
with scleritis collected over the same time period, among whom 59 percent had
ocular complications and 16 percent had decreased visual acuity [",
" 3",
" </a>",
" ].",
" </p>",
" Distinguishing episcleritis from scleritis",
" </span>",
" — The episclera is a thin and highly vascular connective
tissue that lies beneath the conjunctiva but is superficial to the sclera (",
" <a class=\"graphic graphic_figure graphicRef62615 \" href=\"UTD.htm?
8/23/8561\">",
" figure 1",
" </a>",
" ). Episcleritis must be distinguished from scleritis, a potentially dangerous
cause of a red eye. In contrast to episcleritis, which is characteristically
associated with bright red episcleral discoloration and not with pain (",
16/25/16799\">",
" picture 1",
" </a>",
" ), classic cases of scleritis present with intense ocular pain, photophobia,
and a deep-red or purplish scleral hue. In addition, in episcleritis, there is no
edema or thinning of the sclera. Such changes in the sclera are readily visible
with the aid of a slit-lamp biomicroscope. (See",
" \"Clinical manifestations and diagnosis of scleritis\"",
" </a>",
" .)",
" </p>",
" <p>",
" In cases that are not classic, the distinction between these two disorders may
be difficult on gross (unmagnified) physical examination alone. In such cases, the
application of",
" phenylephrine",
" </a>",
" eye drops leads to swift, transient resolution of episcleral redness,
permitting more careful evaluation of the underlying sclera.",
" </p>",
" Distinguishing episcleritis from conjunctivitis",
" </span>",
" — Episcleritis must also be distinguished from
conjunctivitis, a much more common cause of a red eye. Patients with all types of
conjunctivitis (bacterial, viral, allergic) complain of morning crusting and
daytime redness and discharge.",
" </p>",
" <p>",
" In conjunctivitis, the erythema or injection of the eye is diffuse, involving
the bulbar (globe) conjunctiva for 360º as well as the palpebral or tarsal
conjunctiva (the mucus membrane on the inner surface of the lids) (",
0/40/642\">",
" picture 3",
" </a>",
" ). If the conjunctival injection is localized rather than diffuse,
episcleritis is more likely. (See",
" \"Conjunctivitis\"",
" </a>",
" .)",
" </p>",
" Distinguishing episcleritis from herpes keratitis",
" </span>",
" — Failure to recognize herpetic keratitis as a cause of a red
eye (and the inappropriate treatment of that entity with topical glucocorticoids)
can lead to severe ocular damage. In contrast to herpetic keratitis, episcleritis
is usually not associated with pain. However, if there is any question about the
diagnosis, immediate consultation with an ophthalmologist for a slit-lamp
examination is essential before the start of therapy. (See",
" \"Clinical manifestations and diagnosis of herpes simplex virus type 1
infection\"",
" </a>",
" .)",
" </p>",
" Systemic disease associations",
" </span>",
" — The majority of patients with episcleritis do not have an
underlying infectious or systemic inflammatory disease. In a study from a tertiary
care medical center, 30 percent of patients had a systemic rheumatic disease, and 5
percent had a systemic infection [",
" 3",
" </a>",
" ]. Among the patients with an underlying systemic condition, the following
individual diseases were detected:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Rheumatoid arthritis — 11 percent of the overall cohort",
" </li>",
" <li>",
" Inflammatory bowel disease — 8 percent",
" </li>",
" <li>",
" Vasculitis — 5 percent",
" </li>",
" <li>",
" Systemic lupus erythematosus — 3 percent",
" </li>",
" <li>",
" Other rheumatic disease — 3 percent",
" </li>",
" <li>",
" Herpes zoster ophthalmicus — 3 percent",
" </li>",
" <li>",
" Lyme disease — 3 percent",
" </li>",
" </ul>",
" </p>",
" <p>",
" Among community-based populations, the proportion of episcleritis patients who
have an underlying systemic inflammatory or infectious condition is probably
substantially lower.",
" </p>",
" DIAGNOSIS",
" </span>",
" — In a patient with a first episode of episcleritis, the only
type of evaluation required in addition to a complete eye examination is a thorough
history and physical examination. A referral to an ophthalmologist is highly
recommended to minimize chances of a misdiagnosis (eg, labeling an early case of
scleritis as episcleritis).",
" </p>",
" <p>",
" If the general history and physical examination are normal, the patient should
be reassured that the disorder is probably benign and that additional
investigations are needed only if episcleritis recurs or new symptoms develop.",
" </p>",
" <p>",
" More extensive evaluation is required in patients with recurrent episcleritis,
evidence of other ocular disease, or abnormal findings on the general history and
physical examination. Both routine and specialized serologic assays are important
in the evaluation of patients suspected of having an underlying rheumatic or
infectious illness.",
" </p>",
" Basic tests",
" </span>",
" — The following routine tests should be sent for all patients
suspected of having a systemic disease as the cause of their episcleritis [",
" 3,6",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Complete blood count — Patients with systemic conditions frequently
have abnormalities of the white blood cell count, platelet count, or hematocrit.",
" </li>",
" <li>",
" Serum chemistry profile — This should include creatinine, blood urea
nitrogen, electrolytes, albumin, total protein, and aminotransferases.",
" </li>",
" <li>",
" Urinalysis with microscopy — Urinalysis with microscopic examination
of the urine sediment is essential to excluding glomerulonephritis and other renal
disorders.",
" </li>",
" <li>",
" Acute phase reactants — Patients with episcleritis associated with a
systemic illness, but not those with isolated disease, are likely to have extremely
high acute phase reactant levels. Both the erythrocyte sedimentation rate and serum
C-reactive protein should be measured.",
" </li>",
" </ul>",
" </p>",
" Specialized serologic assays",
" </span>",
" — Blood tests targeted to specific systemic inflammatory
diseases associated with episcleritis include:",
" </p>",
" <p>",
" <li>",
" Rheumatoid factor — A positive rheumatoid factor assay is a
nonspecific result, but extremely high titers of rheumatoid factor are usually
found in the setting of rheumatoid vasculitis. (See",
" \"Origin and utility of measurement of rheumatoid factors\"",
" </a>",
" and",
" \"Clinical manifestations and diagnosis of rheumatoid vasculitis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Antibodies to cyclic citrullinated peptides — Antibodies to cyclic
citrullinated peptides (anti-CCP antibodies) have a high specificity for rheumatoid
arthritis. (See",
" \"Clinically useful biologic markers in the diagnosis and assessment of
outcome in rheumatoid arthritis\"",
" </a>",
" .)",
" </li>",
" <li>",
" Antineutrophil cytoplasmic antibodies — Antineutrophil cytoplasmic
antibody (ANCA) assays are positive in most patients with granulomatosis with
polyangiitis (Wegener’s) or microscopic polyangiitis and in a smaller
proportion of patients with the Churg-Strauss syndrome. Patients with inflammatory
bowel disease may also have ANCA.",
" <br/>",
" <br/>",
" If an immunofluorescence assay for ANCA is positive in either a cytoplasmic
or perinuclear pattern (ie, C-ANCA or P-ANCA), then further investigation through
specific enzyme immunoassays is important. Among the vasculitides, only antibodies
to proteinase-3 (C-ANCA) or myeloperoxidase (one of a variety of P-ANCAs) have
specific associations with granulomatosis with polyangiitis (Wegener’s),
microscopic polyangiitis, and the Churg-Strauss syndrome. Patients with
inflammatory bowel disease typically have P-ANCAs that are directed against non-
myeloperoxidase antigens, assays for which are not widely clinically available.
(See",
" \"Clinical spectrum of antineutrophil cytoplasmic antibodies\"",
" </a>",
" .)",
" </li>",
" <li>",
" Antinuclear antibody testing — Antinuclear antibody (ANA) testing is
useful for the exclusion of connective tissue diseases related to systemic lupus
erythematosus. A strongly positive ANA assay should be followed by a rheumatology
consultation and possibly by additional serologic testing to determine the specific
disease responsible for the ANA positivity. The additional testing may include
serum complement levels (C3, C4), antibodies to double-stranded DNA, and antibodies
to the Ro, La, Sm, or RNP antigens. (See",
" \"Measurement and clinical significance of antinuclear antibodies\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" Chest imaging",
" </span>",
" — A chest x-ray should be performed in patients suspected of
having a systemic condition. Any abnormality detected on chest x-ray should be
defined more completely by a computed tomography scan of the chest.",
" </p>",
" Other testing",
" </span>",
" — Additional specialized testing (eg, endoscopic procedures
to exclude inflammatory bowel disease in a patient with severe episcleritis) is
mandated only if there are nonocular morbidities or elements in the medical history
and physical examination suggestive of a particular condition.",
" </p>",
" TREATMENT",
" </span>",
" — Episcleritis is not sight-threatening and, in most
patients, is an episodic, self-limited process. Symptomatic relief should be the
goal of therapy. For the achievement of symptomatic relief, there are four levels
of therapy:",
" </p>",
" <p>",
" <li>",
" Topical lubricants",
" </li>",
" <li>",
" Topical nonsteroidal antiinflammatory drugs (NSAIDs)",
" </li>",
" <li>",
" Topical glucocorticoids",
" </li>",
" <li>",
" Oral NSAIDs",
" </li>",
" </ul>",
" </p>",
" <p>",
" For some of these treatment modalities, a handful of randomized clinical
trials have been performed.",
" </p>",
" </span>",
" — The initial management of episcleritis consists of the
application of topical lubricants. Any over-the-counter preparation of",
" artificial tears",
" </a>",
" will suffice, provided it is used four to six times daily. If more frequent
use is required, we suggest the use of preparations that do not contain
preservatives in order to avoid preservative-induced toxicity. Such preservative-
free preparations can be used as frequently as required and for as long as the
patient remains symptomatic.",
" </p>",
" <p>",
" A small randomized trial found similar effects on the signs and symptoms of
episcleritis with",
" artificial tears",
" </a>",
" or topical",
" ketorolac",
" </a>",
" (an NSAID) [",
" 7",
" </a>",
" ].",
" </p>",
" Topical NSAIDs",
" </span>",
" — Patients with significant discomfort, in whom topical
lubricants fail, may be given a topical NSAID two to four times daily for several
weeks. It is important to exclude dry eyes or other ocular surface epithelial
disorders before committing patients to topical NSAIDs, given the potential
toxicity of these medications to such eyes. We suggest topical",
" diclofenac",
" </a>",
" four times daily. We do not recommend a topical NSAID as primary therapy [",
" 7",
" </a>",
" ].",
" </p>",
" </span>",
" — For patients who require therapy beyond NSAIDs, topical
glucocorticoids are sufficient in more than 80 percent of cases. It is extremely
important to emphasize that chronic glucocorticoid use is associated with a
significantly increased risk of cataracts, glaucoma, secondary infection, and
corneoscleral thinning. The use of topical glucocorticoids should be directed by an
ophthalmologist and should be employed only when the patient remains highly
symptomatic despite optimal use of other treatments.",
" </p>",
" <p>",
" A randomized, double-blind clinical trial indicated that",
" fluorometholone",
" </a>",
" acetate (0.1 percent) and",
" prednisolone",
" </a>",
" acetate (1 percent) were comparable in efficacy in the treatment of external
ocular inflammation (conjunctivitis, episcleritis, and scleritis) [",
" 8",
" </a>",
" ].",
" </p>",
" Oral NSAIDs",
" </span>",
" — In our clinical experience, patients who do not respond to
the above topical therapies or those with recurrent disease will usually respond to
oral NSAIDs, such as",
" indomethacin",
" </a>",
" ,",
" naproxen",
" </a>",
" , or",
" flurbiprofen",
" </a>",
" . Therapy should be initiated with low doses (eg, indomethacin 25 mg three
times daily). Doses of indomethacin should be modified in older patients.",
" </p>",
" <p>",
" Rarely, all the above strategies may fail in patients with nodular
episcleritis. In such cases, a brief course of oral",
" prednisone",
" </a>",
" starting at 0.5 to 0.75",
" <span class=\"nowrap\">",
" mg/kg",
" </span>",
" daily with a quick taper over one to two weeks can help the resolution.",
" </p>",
" PROGNOSIS",
" </span>",
" — Although episcleritis does not produce significant ocular
complications and does not impair vision, mild complications including corneal
infiltrates and low-grade uveitis occur rarely. (See",
" <a class=\"local\" href=\"#H4\">",
" 'Clinical features'",
" </a>",
" above.):",
" </p>",
" <p>",
" <li>",
" Small peripheral corneal infiltrates, visible only with the slit-lamp
biomicroscope, are a rare occurrence. These infiltrates represent inflammation
within the stroma of the cornea. The changes are small, localized, and
nonprogressive and do not affect vision. Patients with significant limbal or
corneal inflammation should be followed more carefully to ensure that they do not
progress to frank scleritis.",
" </li>",
" <li>",
" Some patients develop transient low-grade anterior uveitis with severe
attacks [",
" 3",
" </a>",
" ]. Uveitis, defined as intraocular inflammation, is best diagnosed at the
slit lamp by an ophthalmologist; however, the onset of photophobia, pain, and
decreased vision should alert the clinician that uveitis has complicated a case.
These patients may benefit from a short course of topical glucocorticoids. (See",
" \"Uveitis: Treatment\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" Most patients with episcleritis have a mild, isolated problem that responds to
topical therapy alone and that does not pose a threat to vision.",
" </p>",
" <p>",
" However, a minority has an underlying systemic disease that signifies a
serious health concern and that requires additional therapy. In some patients,
episcleritis is an early presentation of a more severe and destructive ocular
immune problem such as scleritis. Accurate distinction between episcleritis and
scleritis is critical. (See",
" 'Distinguishing episcleritis from scleritis'",
" </a>",
" above.)",
" </p>",
" Epidemiology",
" </span>",
" — Episcleritis is classified as either simple or nodular.
Simple scleritis is usually sectoral in nature, confined to a carefully delimited
portion of the episclera. However, more diffuse episcleral involvement can occur.",
" </p>",
" <p>",
" <li>",
" Seventy percent of episcleritis patients are women.",
" </li>",
" </ul>",
" </p>",
" Clinical features",
" </span>",
" — Patients with episcleritis usually complain of the abrupt
onset of redness, irritation, and watering of the eye. Pain is unusual but can be
observed with chronic or nodular episcleritis. Vision is not affected.
Approximately one-half of cases are bilateral.",
" </p>",
" <p>",
" <li>",
" Ocular complications are uncommon in episcleritis and are usually mild (eg,
mild anterior uveitis). When other forms of eye disease are present, systemic
diseases should be sought carefully.",
" </li>",
" <li>",
" Episcleritis must be distinguished carefully from scleritis and from
conjunctivitis, both of which have different approaches to therapy.",
" </li>",
" </ul>",
" </p>",
" Diagnosis",
" </span>",
" — In a patient with a first episode of episcleritis, the only
type of evaluation required in addition to a complete eye examination is a thorough
history and physical examination.",
" </p>",
" <p>",
" <li>",
" Additional investigations are needed only if episcleritis recurs, if there
is evidence of other ocular disease, or if there are abnormal findings on the
general history and physical examination.",
" </li>",
" <li>",
" Both routine and specialized serologic assays are important in the
evaluation of patients suspected of having an underlying rheumatic or infectious
illness. (See",
" 'Basic tests'",
" </a>",
" above and",
" 'Specialized serologic assays'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" Treatment",
" </span>",
" — The absolute and relative efficacies of therapies for
episcleritis come from small clinical trials and from clinical experience. We
suggest the following sequence of therapies using subsequent therapies if the
earlier therapies do not provide adequate symptomatic relief (",
" <a class=\"grade\" href=\"._grade_5?title=Grade 2B\">",
" Grade 2B",
" </a>",
" ):",
" </p>",
" <p>",
" <li>",
" Topical lubricants — We recommend artificial tear preparations that do
not contain preservatives, such as Refresh Plus or Bion Tears (",
" Grade 1B",
" </a>",
" ). (See",
" 'Topical lubricants'",
" </a>",
" above.)",
" </li>",
" <li>",
" Topical NSAIDs — We suggest topical",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/29/38352?
" diclofenac",
" </a>",
" four times daily (",
" <a class=\"grade\" href=\"._grade_6?title=Grade 2C\">",
" Grade 2C",
" </a>",
" ). (See",
" 'Topical NSAIDs'",
" </a>",
" above.)",
" </li>",
" <li>",
" Topical glucocorticoids — We suggest either",
" fluorometholone",
" </a>",
" acetate (0.1 percent) or",
" prednisolone",
" </a>",
" acetate (1 percent) (",
" Grade 1B",
" </a>",
" ). Both of these medications are applied four times daily. (See",
" 'Topical glucocorticoids'",
" </a>",
" above.)",
" </li>",
" <li>",
" Oral NSAIDs — We suggest",
" indomethacin",
" </a>",
" (",
" <a class=\"grade\" href=\"._grade_6?title=Grade 2C\">",
" Grade 2C",
" </a>",
" ). This medication is usually prescribed as 25 mg taken by mouth three times
daily. (See",
" 'Oral NSAIDs'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?0/5/80/abstract/1\">",
" McGavin DD, Williamson J, Forrester JV, et al. Episcleritis and scleritis. A
study of their clinical manifestations and association with rheumatoid arthritis.
Br J Ophthalmol 1976; 60:192.",
" </a>",
" </li>",
" <li>",
" Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;
60:163.",
" </a>",
" </li>",
" <li>",
" Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical
features and treatment results. Am J Ophthalmol 2000; 130:469.",
" </a>",
" </li>",
" <li>",
" Aurich-Barrera B, Wilton L, Harris S, Shakir SA. Ophthalmological events in
patients receiving risedronate: summary of information gained through follow-up in
a prescription-event monitoring study in England. Drug Saf 2006; 29:151.",
" </a>",
" </li>",
" <li>",
" Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis and other ocular side
effects associated with pamidronate disodium. Am J Ophthalmol 2003; 135:219.",
" </a>",
" </li>",
" <li>",
" Sainz de la Maza M, Jabbur NS, Foster CS. Severity of scleritis and
episcleritis. Ophthalmology 1994; 101:389.",
" </a>",
" </li>",
" <li>",
" Williams CP, Browning AC, Sleep TJ, et al. A randomised, double-blind trial
of topical ketorolac vs artificial tears for the treatment of episcleritis. Eye
(Lond) 2005; 19:739.",
" </a>",
" </li>",
" <li>",
" Leibowitz HM, Hyndiuk RA, Lindsey C, Rosenthal AL. Fluorometholone acetate:
clinical evaluation in the treatment of external ocular inflammation. Ann
Ophthalmol 1984; 16:1110.",
" </a>",
" </li>",
" </ol>",
" </div>",
" <div id=\"topicVersionRevision\">",
" Topic 5610 Version 4.0",
" </div>",
" </div>",
" <div id=\"footer\">",
" <div id=\"supportFooter\">",
" <span class=\"sfInfo\">",
" © 2013 UpToDate, Inc. All rights reserved.",
" </span>",
" |",
" </span>",
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" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" AsanBook Dig. Med. Lib.",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0604-61.234.146.186-93025ABAAB-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f0_5_80=[""].join("\n");
var outline_f0_5_80=[" <div id=\"toggleOutline\">",
" <a href=\"#\" title=\"Collapse Topic Outline\">",
" <img alt=\"\" src=\"./../images/orange_arrow_left.myextg\"/>",
" </a>",
" </div>",
" <div id=\"innerOutline\">",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <div id=\"outline\">",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H20\" id=\"summRecButton\">",
" <span>",
" SUMMARY & RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" <li class=\"plainItem\">",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" EPIDEMIOLOGY",
" </a>",
" </li>",
" PATHOGENESIS",
" </a>",
" </li>",
" CLINICAL FEATURES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" Distinguishing episcleritis from scleritis",
" </a>",
" </li>",
" Distinguishing episcleritis from conjunctivitis",
" </a>",
" </li>",
" Distinguishing episcleritis from herpes keratitis",
" </a>",
" </li>",
" Systemic disease associations",
" </a>",
" </li>",
" DIAGNOSIS",
" </a>",
" </li>",
" Basic tests",
" </a>",
" </li>",
" Specialized serologic assays",
" </a>",
" </li>",
" Chest imaging",
" </a>",
" </li>",
" Other testing",
" </a>",
" </li>",
" TREATMENT",
" </a>",
" </li>",
" </a>",
" </li>",
" Topical NSAIDs",
" </a>",
" </li>",
" </a>",
" </li>",
" Oral NSAIDs",
" </a>",
" </li>",
" PROGNOSIS",
" </a>",
" </li>",
" </a>",
" </li>",
" Epidemiology",
" </a>",
" </li>",
" Clinical features",
" </a>",
" </li>",
" Diagnosis",
" </a>",
" </li>",
" Treatment",
" </a>",
" </li>",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"RHEUM/5610\" rel=\"outline_link\">",
" GRAPHICS",
" <a class=\"graphics_icon\" href=\"#\" title=\"View All Related Graphics\">",
" View All",
" </a>",
" </div>",
" </h1>",
" <div id=\"relatedGraphics\">",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"RHEUM/5610|FIG\">",
" <a href=\"#\" title=\"FIGURES\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?8/23/8561\" title=\"figure
1\">",
" Eye anatomy",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"RHEUM/5610|PIC\">",
" <a href=\"#\" title=\"PICTURES\">",
" PICTURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_picture\" href=\"UTD.htm?16/25/16799\"
title=\"picture 1\">",
" Diffuse episcleritis",
" </a>",
" </li>",
" Nodular episcleritis",
" </a>",
" </li>",
" Viral conjunctivitis",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <div id=\"relatedTopics\">",
" <ul>",
source=related_link\">",
" Clinical manifestations and diagnosis of granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis",
" </a>",
" </li>",
" Clinical manifestations and diagnosis of herpes simplex virus type 1
infection",
" </a>",
" </li>",
" Clinical manifestations and diagnosis of rheumatoid vasculitis",
" </a>",
" </li>",
" Clinical manifestations and diagnosis of scleritis",
" </a>",
" </li>",
" Clinical manifestations, diagnosis, and management of undifferentiated
spondyloarthritis and related spondyloarthritides",
" </a>",
" </li>",
" Clinical spectrum of antineutrophil cytoplasmic antibodies",
" </a>",
" </li>",
" Clinically useful biologic markers in the diagnosis and assessment of
outcome in rheumatoid arthritis",
" </a>",
" </li>",
" Conjunctivitis",
" </a>",
" </li>",
" Evaluation of the red eye",
" </a>",
" </li>",
" Measurement and clinical significance of antinuclear antibodies",
" </a>",
" </li>",
" Ocular manifestations of rheumatoid arthritis",
" </a>",
" </li>",
" Origin and utility of measurement of rheumatoid factors",
" </a>",
" </li>",
" Reactive arthritis (formerly Reiter syndrome)",
" </a>",
" </li>",
" Skin and eye manifestations of inflammatory bowel disease",
" </a>",
" </li>",
" Treatment of scleritis",
" </a>",
" </li>",
" Uveitis: Treatment",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_5_81="Resistance of Streptococcus pneumoniae to beta-lactam
antibiotics";
" </div>",
" </noscript>",
" <img alt=\"UpToDate\" src=\"./../images/wk_utd-rgb.myextg\" width=\"220px\">",
" </img>",
" </div>",
" <sup>",
" ®",
" </sup>",
" </a>",
" <br>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Resistance of Streptococcus pneumoniae to beta-lactam antibiotics",
" </div>",
" <div>",
" </a>",
" Author",
" </a>",
" <br/>",
" Daniel M Musher, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Daniel J Sexton, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Anna R Thorner, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Feb 28, 2013.",
" </div>",
" INTRODUCTION",
" </span>",
" — From the beginning of the antibiotic era to the mid-1970s,
Streptococcus pneumoniae (pneumococci) remained uniformly susceptible to all
classes of antibiotics that had been active against the organisms, with the
possible exception of",
" tetracycline",
" </a>",
" . Thus, the medical profession had a rude awakening in 1977 and 1978 when
outbreaks of infection due to antibiotic-resistant pneumococci occurred in Durban
and Johannesburg, South Africa [",
" 1,2",
" </a>",
" ]. These outbreaks originated in infectious diseases hospitals where children
with serious viral infections were routinely treated \"prophylactically\" with
antibiotics. Although they were originally called penicillin-resistant pneumococci
(PRP), these organisms appeared to have acquired genetic material that encoded
resistance both to penicillin and to other commonly used antibiotics.",
" </p>",
" <p>",
" In the ensuing decades, resistance of pneumococci to a variety of
antimicrobial agents has evolved from an ominous medical curiosity to a worldwide
health problem. Pneumococcal resistance has increased to a point that it is
clinically relevant in the following classes of antibiotics:",
" </p>",
" <p>",
" <li>",
" Beta-lactams (penicillins, cephalosporins, and carbapenems)",
" </li>",
" <li>",
" Macrolides (",
" erythromycin",
" </a>",
" ,",
" azithromycin",
" </a>",
" ,",
" clarithromycin",
" </a>",
" and lincosamides [",
" clindamycin",
" </a>",
" ])",
" </li>",
" <li>",
" Tetracyclines and folate inhibitors (",
" trimethoprim-sulfamethoxazole",
" </a>",
" [TMP-SMX])",
" </li>",
" <li>",
" Fluoroquinolones (",
" ciprofloxacin",
" </a>",
" ,",
" levofloxacin",
" </a>",
" ,",
" gemifloxacin",
" </a>",
" ,",
" moxifloxacin",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p>",
" A number of studies have addressed apparent risk factors for the acquisition
of antibiotic-resistant pneumococcal strains [",
" 3-6",
" </a>",
" ]. These include:",
" </p>",
" <p>",
" <li>",
" Previous antibiotic use",
" </li>",
" <li>",
" Previous time spent in day care (for children) or in an institutional
setting including nursing home, long-term care facility, or a shelter for the
homeless (for adults)",
" </li>",
" <li>",
" Recent respiratory infections",
" </li>",
" </ul>",
" </p>",
" <p>",
" The mechanisms of action and resistance, definitions of resistance in relation
to clinically achievable drug concentrations, and clinical data on the outcome of
therapy in otitis, sinusitis, acute exacerbations of chronic bronchitis, pneumonia,
meningitis, and bacteremia will be reviewed here for the beta-lactams. Resistance
to the other classes of drugs is discussed separately. (See",
" \"Resistance of Streptococcus pneumoniae to the fluoroquinolones,
doxycycline, and trimethoprim-sulfamethoxazole\"",
" </a>",
" and",
" \"Resistance of Streptococcus pneumoniae to the macrolides, azalides,
lincosamines, and ketolides\"",
" </a>",
" .)",
" </p>",
" MECHANISM OF ACTION AND RESISTANCE",
" </span>",
" — Beta-lactam antibiotics inhibit pneumococcal growth by
irreversibly binding the active site of enzymes that are needed for the synthesis
of peptidoglycan, the major constituent of the cell wall. When penicillin-
susceptible pneumococci are incubated with low concentrations of radiolabeled
penicillin and then subjected to protein electrophoresis and radioautography, five
distinct bands, each representing a different enzyme, are detected. In strains that
have reduced susceptibility to penicillin, the affinity of the antibiotic for one
or more of these enzymes is reduced; incubation with low concentrations of
penicillin, followed by radioautography detects reduced or absent labeling of one
or more of the five bands (",
14/38/14959\">",
" figure 1",
" </a>",
" ) [",
" 7",
" </a>",
" ]. However, labeling can generally be restored at higher antibiotic
concentrations.",
" </p>",
" <p>",
" These observations explain the central clinical teaching that pneumococcal
resistance to penicillin can frequently be overcome with the doses of penicillin
that are generally prescribed. These same general principles apply for
cephalosporins and carbapenems. However, there are differences in the capacity of
these drugs to overcome the resistance, and clinicians need to know where each
falls in the spectrum of efficacy at increased concentrations (",
" <a class=\"graphic graphic_table graphicRef76028 \" href=\"UTD.htm?
25/44/26316\">",
" table 1",
" </a>",
" ). The extent to which these principles apply to the macrolides (depending
upon the molecular basis for the resistance) or the fluoroquinolones is
controversial. They clearly do",
" <strong>",
" not",
" </strong>",
" apply to folate inhibitors or tetracyclines, since resistance to these
antibiotic classes cannot be overcome by increasing the dose. (See",
" \"Resistance of Streptococcus pneumoniae to the macrolides, azalides,
lincosamines, and ketolides\"",
" </a>",
" and",
" \"Resistance of Streptococcus pneumoniae to the fluoroquinolones,
doxycycline, and trimethoprim-sulfamethoxazole\"",
" </a>",
" .)",
" </p>",
" Definitions and prevalence of resistance",
" </span>",
" — The definitions of susceptibility have been changed and can
be confusing (",
16/13/16605\">",
" table 2",
" </a>",
" ) [",
" 8,9",
" </a>",
" ]. The original definitions of resistance to beta-lactams were in the setting
of meningitis and were related to drug concentrations in cerebrospinal fluid (CSF).
CSF levels are only a small fraction of those levels in plasma or in the alveoli
(which closely follow those in plasma). If antibiotic susceptibility is
concentration-dependent, then organisms that are resistant to levels achievable in
CSF may actually be susceptible when they cause otitis, sinusitis, or pneumonia [",
" 10",
" </a>",
" ].",
" </p>",
" Penicillin",
" </span>",
" — When young children are treated for bacterial meningitis
with 250",
" mg/kg",
" </span>",
" per day of penicillin in six divided doses, mean serum concentrations are 80",
" mcg/mL",
" </span>",
" at the peak, 2",
" mcg/mL",
" </span>",
" after two hours, and <1",
" mcg/mL",
" </span>",
" at the trough [",
" 11",
" </a>",
" ]. In contrast, levels in the cerebrospinal fluid (CSF) range from
approximately 0.1 to 1.0",
" mcg/mL",
" </span>",
" [",
" 11",
" </a>",
" ]. With the knowledge that the minimum inhibitory concentration (MIC) of
penicillin for pneumococci had nearly always been <0.06",
" mcg/mL",
" </span>",
" prior to the appearance of resistance and using CSF concentrations as a guide,
the following definitions were originally proposed (",
16/13/16605\">",
" table 2",
" </a>",
" ):",
" </p>",
" <p>",
" <li>",
" Susceptible — MIC ≤0.06",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Intermediately resistant (also called reduced susceptibility) — MIC
0.12 to 1",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Resistant — MIC ≥2",
" mcg/mL",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p>",
" These parameters remain appropriate for the treatment of meningitis. With a
better understanding of the principles of serum versus CSF concentrations, as
explained above, in 2008, the penicillin breakpoints were increased substantially
for non-meningitis pneumococcal infections (",
16/13/16605\">",
" table 2",
" </a>",
" ) [",
" 8,9",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Susceptible — MIC ≤2",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Intermediate — MIC = 4",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Resistant — MIC ≥8",
" mcg/mL",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p>",
" In the early 2000s, using the older definitions of resistance, approximately
60 percent of pneumococci in the United States were susceptible to penicillin, 20
percent were intermediately resistant, and 20 percent were resistant [",
" 12,13",
" </a>",
" ]. With current definitions, about 85 percent of pneumococci are susceptible
to penicillin, 10 percent are intermediately resistant, and 5 percent are resistant
[",
" 14,15",
" </a>",
" ]. In general, children tend to be colonized or infected by more resistant
isolates than do adults, and invasive isolates in both children and adults tend to
be more susceptible than those that colonize the upper respiratory tract or cause
otitis media. Therefore, the overall results for penicillin susceptibility as
reported by the United States Centers for Disease Control and Prevention (which
tests isolates that cause invasive disease) show higher rates of susceptibility
than studies that include colonizing isolates, with >92 percent of pneumococci
being fully penicillin-susceptible [",
" 16",
" </a>",
" ].",
" </p>",
" <p>",
" Higher rates of penicillin resistance have been described in other countries.
This was illustrated in a review of 685 S. pneumoniae isolates from 14 centers in
11 Asian countries that were collected from January 2000 to June 2001 [",
" 17",
" </a>",
" ]. Overall, 52 percent were not susceptible to penicillin, with rates of
resistance as high as 74 percent in Vietnam.",
" </p>",
" <p>",
" Several major conclusions follow from these observations:",
" </p>",
" <p>",
" <li>",
" The medical literature from the early 2000s and earlier reported
disproportionately high rates of penicillin resistance",
" </li>",
" <li>",
" Using current definitions of susceptibility and surveillance data, isolates
that cause invasive non-CNS pneumococcal disease in adults are likely to be fully
penicillin-susceptible",
" </li>",
" <li>",
" Rates of penicillin resistance vary depending on the geographic region, with
higher rates occurring in Asia than in North America",
" </li>",
" </ul>",
" </p>",
" <p>",
" Despite the improved rates of penicillin susceptibility reported for
pneumococcal isolates in the United States, it is important to note that penicillin
susceptibility remains in flux.",
" </p>",
" Impact of the pneumococcal conjugate vaccine",
" </span>",
" — Use of protein conjugate pneumococcal vaccines in children
reduces carriage of vaccine strains, and therefore reduces the spread of these
strains to adults. In the United States, widespread use of PCV7, a protein
conjugate pneumococcal vaccine that contains polysaccharides from seven serotypes
that commonly colonized and infected young children, was followed by a >90
percent reduction in invasive disease caused by vaccine serotypes in both children
and adults [",
" 18",
" </a>",
" ].",
" </p>",
" <p>",
" However, \"replacement strains\" (ie, strains that are not contained in PCV7)
have increased in prevalence; some of these strains, such as serotypes 19A and 6A,
have very high rates of penicillin resistance. The newer 13-valent pneumococcal
vaccine, PCV13, includes polysaccharides from serotypes 19A and 6A, so disease
caused by these types is expected to become much less common. These issues are
discussed in greater detail separately. (See",
" \"Impact of universal infant immunization with pneumococcal (Streptococcus
pneumoniae) conjugate vaccines in the United States\"",
" </a>",
" and",
source=see_link&anchor=H3#H3\">",
" \"Invasive pneumococcal (Streptococcus pneumoniae) infections and
bacteremia\", section on 'Impact of childhood vaccination'",
" </a>",
" .)",
" </p>",
" Amoxicillin",
" </span>",
" — Most clinicians prescribe",
" amoxicillin",
" </a>",
" instead of penicillin because of its better absorption from the
gastrointestinal tract and longer half-life. These pharmacodynamic considerations
help to explain the discrepancies between definitions of susceptibility to
penicillin and amoxicillin (",
16/13/16605\">",
" table 2",
" </a>",
" ).",
" </p>",
" Cephalosporins",
" </span>",
" — Similar concepts apply to the cephalosporins [",
" 12",
" </a>",
" ]. With",
" ceftriaxone",
" </a>",
" , for example, 50",
" mg/kg",
" </span>",
" given IV yields peak serum levels of 250",
" mcg/mL",
" </span>",
" and peak CSF levels of 2 to 5",
" mcg/mL",
" </span>",
" (",
26/63/27645\">",
" figure 2",
" </a>",
" ) [",
" 19",
" </a>",
" ]. The drug declines in the bloodstream with a half-life of six hours.
Clearly, treatment of non-CNS infections in adults with 1 gram ceftriaxone given
every 24 hours (approximately 12.5",
" mg/kg)",
" </span>",
" should be effective against all but the most highly resistant isolates (eg,
those with MIC >8",
" mcg/mL).",
" </span>",
" In contrast, organisms with MIC <1",
" mcg/mL",
" </span>",
" that cause meningitis should be susceptible to 2 grams every 12 hours, those
with MIC 1 to 2",
" mcg/mL",
" </span>",
" might be regarded as intermediate, and those with MIC >2 are likely to be
resistant (although some cases would certainly respond based upon achievable CSF
levels). Results for",
" cefotaxime",
" </a>",
" (2 g every six hours) or",
" cefepime",
" </a>",
" (2 g every eight hours) are similar.",
" </p>",
" <p>",
" Current definitions of susceptibility to",
" ceftriaxone",
" </a>",
" are as follows [",
" 20",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Susceptible — MIC <1",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Intermediately resistant — MIC = 2",
" mcg/mL",
" </span>",
" </li>",
" <li>",
" Resistant — MIC >4",
" mcg/mL",
" </span>",
" </li>",
" </ul>",
" </p>",
" <p>",
" According to these definitions, in the United States, 94 percent of
pneumococci are susceptible, 4 percent are intermediate, and 2 percent are
resistant to",
" ceftriaxone",
" </a>",
" [",
" 20-22",
" </a>",
" ]. Even the newer definitions are overly conservative for treating all
infections other than meningitis; the reader should conclude that nonmeningeal
infections caused by pneumococcus ought to respond to currently used doses of
ceftriaxone,",
" cefotaxime",
" </a>",
" , or",
" cefepime",
" </a>",
" . The same applies to imipenem or",
" ertapenem",
" </a>",
" . A low rate of ceftriaxone resistance (2.8 percent) was also noted in Asia
[",
" 17",
" </a>",
" ].",
" </p>",
" RESISTANCE AND THE OUTCOME OF THERAPY",
" </span>",
" — Resistance of pneumococci to beta-lactam antibiotics is
relative and can generally be overcome by increasing the dose of drugs in this
class. In cases other than meningitis, approximately 95 percent of pneumococcal
infections will respond to treatment with beta-lactam antibiotics. However, in
treating meningitis, one needs to pay particular attention to the measured
susceptibility of the infecting organism.",
" </p>",
" Otitis media",
" </span>",
" — After young children with otitis receive 30",
" mg/kg",
" </span>",
" of",
" amoxicillin",
" </a>",
" , mean concentrations in the middle ear fluid are approximately 4 to 7",
" mcg/mL",
" </span>",
" [",
" 23,24",
" </a>",
" ]. Meticulous studies have shown that the outcome of amoxicillin treatment for
pneumococcal otitis media correlates well with the amoxicillin susceptibility of
the infecting organism [",
" 25",
" </a>",
" ]. These data validate the current recommendations to administer 80 to 90",
" mg/kg",
" </span>",
" per day of amoxicillin in two divided doses, which is effective for all but
the most resistant pneumococci [",
" 26,27",
" </a>",
" ]. In contrast, a drug like",
" cefaclor",
" </a>",
" (",
25/44/26316\">",
" table 1",
" </a>",
" ), which has a high MIC for penicillin-resistant pneumococci relative to
achievable serum levels, is much less likely to produce a cure [",
" 28",
" </a>",
" ]. (See",
" \"Acute otitis media in children: Treatment\"",
" </a>",
" .)",
" </p>",
" Acute purulent rhinosinusitis",
" </span>",
" — Similar data are not available to relate the outcome of
treatment for acute purulent rhinosinusitis to antibiotic resistance. Nevertheless,
it seems likely that the same considerations would apply as for otitis media. Data
obtained before penicillin resistance was prevalent suggest that rhinosinusitis
responds very well to treatment with",
" amoxicillin",
" </a>",
" [",
" 29",
" </a>",
" ], and recommendations for treating rhinosinusitis are nearly identical to
those for otitis. (See",
" \"Acute sinusitis and rhinosinusitis in adults: Treatment\"",
" </a>",
" .)",
" </p>",
" Pneumonia and bacteremia",
" </span>",
" — Interpretation of the data about the efficacy of the
treatment of pneumococcal pneumonia is hampered by shifting definitions of
susceptibility and by the profusion of studies of community-acquired pneumonia
(CAP) in which the microbial etiology of the infection is frequently not
determined. (See",
" \"Treatment of community-acquired pneumonia in adults in the outpatient
setting\"",
" </a>",
" and",
" \"Treatment of community-acquired pneumonia in adults who require
hospitalization\"",
" </a>",
" .)",
" </p>",
" <p>",
" Using earlier definitions of susceptibility, some studies have shown that
resistance to beta-lactam antibiotics does not affect the outcome of treating
extrameningeal infections with these drugs [",
" 30-32",
" </a>",
" ]. The explanation for this observation would be that the attained drug levels
at the doses ordinarily used are sufficient to overcome resistance. By contrast,
others have found that treatment of non-CNS infections caused by penicillin-
resistant pneumococci with beta-lactam antibiotics is associated with an increased
likelihood of a fatal outcome, particularly in the elderly and patients with
underlying diseases [",
" 33-35",
" </a>",
" ]. (See",
" \"Antibiotic studies for the treatment of community-acquired pneumonia in
adults\", section on 'Beta-lactam resistance'",
" </a>",
" .)",
" </p>",
" <p>",
" In some reports, combination therapy with a beta-lactam antibiotic plus a
macrolide improved the outcome of bacteremic pneumococcal pneumonia [",
" 36-38",
" </a>",
" ] compared to a beta-lactam alone. A possible explanation for this relates to
the anti-inflammatory effects of the macrolides [",
" 39",
" </a>",
" ].",
" </p>",
" <p>",
" In summary, while at present extrameningeal infections appear to respond to
currently recommended doses of beta-lactam antibiotics, it is possible that the
failure rate will eventually increase with increasing prevalence of more highly
resistant strains, even though studies to date have not clearly demonstrated this
phenomenon [",
" 40",
" </a>",
" ].",
" </p>",
" Meningitis",
" </span>",
" — There is substantial risk that meningitis caused by beta-
lactam resistant pneumococci will not respond to treatment with beta-lactam
antibiotics [",
" 41",
" </a>",
" ]. Meningitis caused by strains with a",
" ceftriaxone",
" </a>",
" MIC >2",
" mcg/mL",
" </span>",
" appears likely to fail to respond to treatment with recommended doses of this
drug [",
" 42",
" </a>",
" ], whereas those with MIC = 1",
" mcg/mL",
" </span>",
" may or may not respond (",
16/13/16605\">",
" table 2",
" </a>",
" ) [",
" 42-44",
" </a>",
" ]. Because of differences in definitions of susceptibility, as noted above,
careful attention must be paid to the actual MICs under discussion in order to
assess published studies.",
" </p>",
" <p>",
" These findings justify the recommendation that initial therapy of pneumococcal
meningitis be with",
" vancomycin",
" </a>",
" in addition to",
" ceftriaxone",
" </a>",
" or",
" cefotaxime",
" </a>",
" [",
" 41,45",
" </a>",
" ]. The cephalosporin is regarded as a more effective antimicrobial agent with
more reliable penetration of the blood brain barrier, but the vancomycin is added
in case the organism is cephalosporin-resistant. When susceptibility studies are
completed, the vancomycin can be discontinued if the infecting organism is
susceptible to beta-lactam antibiotics. However, if the organism is intermediate or
resistant, vancomycin should be continued for the entire treatment period. (See",
" \"Treatment of bacterial meningitis caused by specific pathogens in adults\",
section on 'Streptococcus pneumoniae'",
" </a>",
" and",
" \"Pneumococcal meningitis in children\", section on 'Overview of treatment'",
" </a>",
" .)",
" </p>",
" <p>",
" Several studies have shown that adding",
" dexamethasone",
" </a>",
" reduces the likelihood of neurologic complications following treatment for
pneumococcal meningitis in adults; this subject is discussed separately. (See",
" \"Dexamethasone to prevent neurologic complications of bacterial meningitis
in adults\"",
" </a>",
" .)",
" </p>",
" SUMMARY",
" </span>",
" </p>",
" <p>",
" <li>",
" Early in the antibiotic era, pneumococci were uniformly penicillin-
susceptible. Resistance to penicillin and other beta-lactams arose when mutations
appeared in enzymes that are needed to synthesize the cell wall, the active site at
which beta-lactams block the replication of pneumococci. (See",
" 'Introduction'",
" </a>",
" above and",
" 'Mechanism of action and resistance'",
" </a>",
" above.)",
" </li>",
" <li>",
" Beta-lactam resistance is largely dose-dependent; as a result, it can be
overcome by the doses of beta-lactams currently in use. In cases other than
meningitis, approximately 95 percent of pneumococcal infections will respond to
treatment with beta-lactams. (See",
" 'Resistance and the outcome of therapy'",
" </a>",
" above.)",
" </li>",
" <li>",
" Because of the relatively poor ability of beta-lactams to cross the blood
brain barrier, only about 80 percent of isolates will be susceptible at achievable
concentrations. Therefore, resistance is of much greater consequence in cases of
meningitis. Pneumococcal susceptibility to beta-lactams is currently reported
separately for isolates that cause meningitis and those that cause infections at
other sites (",
16/13/16605\">",
" table 2",
" </a>",
" ). (See",
" 'Meningitis'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
" REFERENCES",
" </h1>",
" <li>",
" Appelbaum PC, Bhamjee A, Scragg JN, et al. Streptococcus pneumoniae
resistant to penicillin and chloramphenicol. Lancet 1977; 2:995.",
" </a>",
" </li>",
" <li>",
" Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply
resistant pneumococci. N Engl J Med 1978; 299:735.",
" </a>",
" </li>",
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" Bédos JP, Chevret S, Chastang C, et al. Epidemiological features of
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" </a>",
" </li>",
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" Moreno F, Crisp C, Jorgensen JH, Patterson JE. The clinical and molecular
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" </a>",
" </li>",
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" Ruhe JJ, Myers L, Mushatt D, Hasbun R. High-level penicillin-nonsusceptible
Streptococcus pneumoniae bacteremia: identification of a low-risk subgroup. Clin
Infect Dis 2004; 38:508.",
" </a>",
" </li>",
" <li>",
" Vanderkooi OG, Low DE, Green K, et al. Predicting antimicrobial resistance
in invasive pneumococcal infections. Clin Infect Dis 2005; 40:1288.",
" </a>",
" </li>",
" <li>",
" Markiewicz Z, Tomasz A. Variation in penicillin-binding protein patterns of
penicillin-resistant clinical isolates of pneumococci. J Clin Microbiol 1989;
27:405.",
" </a>",
" </li>",
" <li>",
" MIC Interpretive Standards for S. pneumoniae. Clinical Laboratory Standards
Institute (CLSI) 2008; 28:123.",
" </a>",
" </li>",
" <li>",
" Weinstein MP, Klugman KP, Jones RN. Rationale for revised penicillin
susceptibility breakpoints versus Streptococcus pneumoniae: coping with
antimicrobial susceptibility in an era of resistance. Clin Infect Dis 2009;
48:1596.",
" </a>",
" </li>",
" <li>",
" Musher DM, Bartlett JG, Doern GV. A fresh look at the definition of
susceptibility of Streptococcus pneumoniae to beta-lactam antibiotics. Arch Intern
Med 2001; 161:2538.",
" </a>",
" </li>",
" <li>",
" Hieber JP, Nelson JD. A pharmacologic evaluation of penicillin in children
with purulent meningitis. N Engl J Med 1977; 297:410.",
" </a>",
" </li>",
" <li>",
" Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial
resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus
influenzae, and Moraxella catarrhalis in the United States: results from the TRUST
Surveillance Program, 1999-2000. Clin Infect Dis 2002; 34 Suppl 1:S4.",
" </a>",
" </li>",
" <li>",
" Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-
resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;
343:1917.",
" </a>",
" </li>",
" <li>",
" Centers for Disease Control and Prevention. Active Bacterial Core
Surveillance Report, Emerging Infections Program Network, Streptococcus pneumoniae,
2009 file://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf (Accessed on
June 28, 2012).",
" </li>",
" <li>",
" Jacobs MR, Good CE, Windau AR, et al. Activity of ceftaroline against recent
emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob
Agents Chemother 2010; 54:2716.",
" </a>",
" </li>",
" <li>",
" Centers for Disease Control and Prevention (CDC). Effects of new penicillin
susceptibility breakpoints for Streptococcus pneumoniae--United States, 2006-2007.
MMWR Morb Mortal Wkly Rep 2008; 57:1353.",
" </a>",
" </li>",
" <li>",
" Song JH, Jung SI, Ko KS, et al. High prevalence of antimicrobial resistance
among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study).
Antimicrob Agents Chemother 2004; 48:2101.",
" </a>",
" </li>",
" <li>",
" Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive
pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010; 201:32.",
" </a>",
" </li>",
" <li>",
" Del Rio M, McCracken GH Jr, Nelson JD, et al. Pharmacokinetics and
cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of
pediatric patients with bacterial meningitis. Antimicrob Agents Chemother 1982;
22:622.",
" </a>",
" </li>",
" <li>",
" Centers for Disease Control and Prevention (CDC). Effect of new
susceptibility breakpoints on reporting of resistance in Streptococcus pneumoniae--
United States, 2003. MMWR Morb Mortal Wkly Rep 2004; 53:152.",
" </a>",
" </li>",
" <li>",
" Karlowsky JA, Thornsberry C, Jones ME, et al. Factors associated with
relative rates of antimicrobial resistance among Streptococcus pneumoniae in the
United States: results from the TRUST Surveillance Program (1998-2002). Clin Infect
Dis 2003; 36:963.",
" </a>",
" </li>",
" <li>",
" Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among
Streptococcus pneumoniae in the United States: have we begun to turn the corner on
resistance to certain antimicrobial classes? Clin Infect Dis 2005; 41:139.",
" </a>",
" </li>",
" <li>",
" Harrison CJ, Welch DF. Middle ear effusion amoxicillin concentrations in
acute otitis media. Pediatr Infect Dis J 1998; 17:657.",
" </a>",
" </li>",
" <li>",
" Seikel K, Shelton S, McCracken GH Jr. Middle ear fluid concentrations of
amoxicillin after large dosages in children with acute otitis media. Pediatr Infect
Dis J 1998; 17:969.",
" </a>",
" </li>",
" <li>",
" Dagan R, Johnson CE, McLinn S, et al. Bacteriologic and clinical efficacy of
amoxicillin/clavulanate vs. azithromycin in acute otitis media. Pediatr Infect Dis
J 2000; 19:95.",
" </a>",
" </li>",
" <li>",
" Ramakrishnan K, Sparks RA, Berryhill WE. Diagnosis and treatment of otitis
media. Am Fam Physician 2007; 76:1650.",
" </a>",
" </li>",
" <li>",
" Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and
management of acute otitis media. Pediatrics 2013; 131:e964.",
" </a>",
" </li>",
" <li>",
" Dagan R, Leibovitz E, Fliss DM, et al. Bacteriologic efficacies of oral
azithromycin and oral cefaclor in treatment of acute otitis media in infants and
young children. Antimicrob Agents Chemother 2000; 44:43.",
" </a>",
" </li>",
" <li>",
" Williams JW Jr, Aguilar C, Makela M, et al. Antibiotics for acute maxillary
sinusitis. Cochrane Database Syst Rev 2000; :CD000243.",
" </a>",
" </li>",
" <li>",
" Kaplan SL, Mason EO Jr, Barson WJ, et al. Three-year multicenter
surveillance of systemic pneumococcal infections in children. Pediatrics 1998;
102:538.",
" </a>",
" </li>",
" <li>",
" Moroney JF, Fiore AE, Harrison LH, et al. Clinical outcomes of bacteremic
pneumococcal pneumonia in the era of antibiotic resistance. Clin Infect Dis 2001;
33:797.",
" </a>",
" </li>",
" <li>",
" Yu VL, Chiou CC, Feldman C, et al. An international prospective study of
pneumococcal bacteremia: correlation with in vitro resistance, antibiotics
administered, and clinical outcome. Clin Infect Dis 2003; 37:230.",
" </a>",
" </li>",
" <li>",
" Choi EH, Lee HJ. Clinical outcome of invasive infections by penicillin-
resistant Streptococcus pneumoniae in Korean children. Clin Infect Dis 1998;
26:1346.",
" </a>",
" </li>",
" <li>",
" Turett GS, Blum S, Fazal BA, et al. Penicillin resistance and other
predictors of mortality in pneumococcal bacteremia in a population with high human
immunodeficiency virus seroprevalence. Clin Infect Dis 1999; 29:321.",
" </a>",
" </li>",
" <li>",
" Feikin DR, Schuchat A, Kolczak M, et al. Mortality from invasive
pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public
Health 2000; 90:223.",
" </a>",
" </li>",
" <li>",
" Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe
bacteremic pneumococcal pneumonia. Arch Intern Med 2001; 161:1837.",
" </a>",
" </li>",
" <li>",
" Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers
mortality among severely ill patients with pneumococcal bacteremia. Am J Respir
Crit Care Med 2004; 170:440.",
" </a>",
" </li>",
" <li>",
" Musher DM. New modalities in treating pneumococcal pneumonia. Hosp Pract
(Minneap) 2011; 39:89.",
" </a>",
" </li>",
" <li>",
" Corrales-Medina VF, Musher DM. Immunomodulatory agents in the treatment of
community-acquired pneumonia: a systematic review. J Infect 2011; 63:187.",
" </a>",
" </li>",
" <li>",
" Klugman KP. Bacteriological evidence of antibiotic failure in pneumococcal
lower respiratory tract infections. Eur Respir J Suppl 2002; 36:3s.",
" </a>",
" </li>",
" <li>",
" Kaplan SL. Management of pneumococcal meningitis. Pediatr Infect Dis J 2002;
21:589.",
" </a>",
" </li>",
" <li>",
" Kaplan SL, Mason EO Jr. Management of infections due to antibiotic-resistant
Streptococcus pneumoniae. Clin Microbiol Rev 1998; 11:628.",
" </a>",
" </li>",
" <li>",
" Tan TQ, Schutze GE, Mason EO Jr, Kaplan SL. Antibiotic therapy and acute
outcome of meningitis due to Streptococcus pneumoniae considered intermediately
susceptible to broad-spectrum cephalosporins. Antimicrob Agents Chemother 1994;
38:918.",
" </a>",
" </li>",
" <li>",
" Fiore AE, Moroney JF, Farley MM, et al. Clinical outcomes of meningitis
caused by Streptococcus pneumoniae in the era of antibiotic resistance. Clin Infect
Dis 2000; 30:71.",
" </a>",
" </li>",
" <li>",
" Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the
management of bacterial meningitis. Clin Infect Dis 2004; 39:1267.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.3 - C21.34",
" </span>",
" <br/>",
" Licensed to:",
" Morehouse School of Medicine",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [1104-118.195.65.244-820E8C5BBF-S473950.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY",
" </span>",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" MECHANISM OF ACTION AND RESISTANCE",
" </a>",
" </li>",
" Definitions and prevalence of resistance",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" - Penicillin",
" </a>",
" </li>",
" <li class=\"bulletItem2\">",
" Impact of the pneumococcal conjugate vaccine",
" </a>",
" </li>",
" - Amoxicillin",
" </a>",
" </li>",
" - Cephalosporins",
" </a>",
" </li>",
" RESISTANCE AND THE OUTCOME OF THERAPY",
" </a>",
" </li>",
" Otitis media",
" </a>",
" </li>",
" Acute purulent rhinosinusitis",
" </a>",
" </li>",
" Pneumonia and bacteremia",
" </a>",
" </li>",
" Meningitis",
" </a>",
" </li>",
" SUMMARY",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"ID/7034\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"ID/7034|FIG\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?14/38/14959\"
title=\"figure 1\">",
" Radioautography bands PCN pneumococci",
" </a>",
" </li>",
title=\"figure 2\">",
" Ceftriaxone CSF concentrations in serum and cerebrospinal fluid of infants
and children",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"ID/7034|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?25/44/26316\" title=\"table
1\">",
" Beta-lactams against PRP",
" </a>",
" </li>",
2\">",
" Susceptibility of pneumococci",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Acute otitis media in children: Treatment",
" </a>",
" </li>",
" Acute sinusitis and rhinosinusitis in adults: Treatment",
" </a>",
" </li>",
" Antibiotic studies for the treatment of community-acquired pneumonia in
adults",
" </a>",
" </li>",
" Dexamethasone to prevent neurologic complications of bacterial meningitis in
adults",
" </a>",
" </li>",
" Impact of universal infant immunization with pneumococcal (Streptococcus
pneumoniae) conjugate vaccines in the United States",
" </a>",
" </li>",
" Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia",
" </a>",
" </li>",
" Pneumococcal meningitis in children",
" </a>",
" </li>",
" Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline,
and trimethoprim-sulfamethoxazole",
" </a>",
" </li>",
" Resistance of Streptococcus pneumoniae to the macrolides, azalides,
lincosamines, and ketolides",
" </a>",
" </li>",
" Treatment of bacterial meningitis caused by specific pathogens in adults",
" </a>",
" </li>",
" Treatment of community-acquired pneumonia in adults in the outpatient
setting",
" </a>",
" </li>",
" Treatment of community-acquired pneumonia in adults who require
hospitalization",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_5_82="Diagnosis of growth hormone deficiency in children";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Diagnosis of growth hormone deficiency in children",
" </div>",
" <div>",
" </a>",
" Authors",
" </a>",
" <br/>",
" Erick J Richmond, MD",
" </a>",
" <br/>",
" Alan D Rogol, MD, PhD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Mitchell Geffner, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Alison G Hoppin, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Dec 27, 2012.",
" </div>",
" INTRODUCTION",
" </span>",
" — Growth hormone (GH) has been available for management of
the short stature associated with growth hormone deficiency (GHD) for more than 50
years; recombinant DNA-derived human growth hormone (rhGH) has been available since
1985. While availability is no longer a problem, there still remains a number of
difficulties with the diagnosis of GHD, resulting mainly from the lack of
appropriate tools to make (or exclude) the diagnosis reliably.",
" </p>",
" <p>",
" The incidence of short stature associated with GHD has been estimated to be
about 1:4000 to 1:10000 [",
" 1",
" </a>",
" ]. It is the primary indication for GH treatment in childhood, which presently
requires daily subcutaneous injections for the patient and substantial cost for the
healthcare system. Based on these premises, it is clear that an accurate diagnosis
is essential [",
" 2,3",
" </a>",
" ].",
" </p>",
" <p>",
" The diagnosis of GHD in children is reviewed here. The treatment of this
disorder is discussed separately. The evaluation of a child with short stature also
is discussed separately. (See",
" \"Treatment of growth hormone deficiency in children\"",
" </a>",
" and",
" \"Diagnostic approach to short stature\"",
" </a>",
" .)",
" </p>",
" AUXOLOGY",
" </span>",
" — The scientific study of growth and development of children
(auxology) began some 250 years ago [",
" 4",
" </a>",
" ] and is still an indispensable tool in pediatrics. Most pediatric
endocrinologists agree that the foundation for the diagnosis of growth hormone
deficiency (GHD) in childhood is based on a comparison of the child's growth
pattern to established norms. A consensus view concluded that clinical assessment
of the growth-retarded child is the single most useful parameter in diagnosing
growth disorders and challenged the status of growth hormone (GH) measurements as
the diagnostic \"gold standard\" [",
" 5",
" </a>",
" ].",
" </p>",
" <p>",
" Errors in length or height measurements may be the result of unreliable
equipment. For this reason, all apparatus should be checked frequently. More often,
measuring procedures are at fault, perhaps in the positioning of the subject or in
locating proper landmarks. (See",
" \"Measurement of growth in children\"",
" </a>",
" .)",
" </p>",
" <p>",
" Neonates and children younger than two years may be difficult to measure
accurately; the neonatometer (length stadiometer) and supine table are the
recommended devices to reduce errors in measuring. The vertical stadiometer is used
to measure standing height, which is recommended for children two to three years or
older [",
" 6",
" </a>",
" ].",
" </p>",
" <p>",
" Length or height data should be plotted on the appropriate growth chart.
Length is for children measured lying down and should be used up to two to three
years of age (",
" <a class=\"graphic graphic_figure graphicRef67950 graphicRef80511 \"
href=\"UTD.htm?38/48/39687\">",
" figure 1A-B",
" </a>",
" ); height is for children measured standing and should be used for children
over two to three years (",
href=\"UTD.htm?43/30/44519\">",
" figure 2A-B",
" </a>",
" ). The severity of short stature is quantified by determining the height
percentiles or Z-scores from these charts or from calculators for boys (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?21/47/22262?
" calculator 1",
" </a>",
" ) or for girls (",
" calculator 2",
" </a>",
" ).",
" </p>",
" <p>",
" Height velocity can be calculated from serial height determinations and
plotted on appropriate velocity charts (",
href=\"UTD.htm?32/1/32792\">",
" figure 3A-B",
" </a>",
" ). A period of at least six months is necessary for reliable calculation of
height velocity of children above the age of two years. (See",
" \"Diagnostic approach to short stature\", section on 'Evaluation'",
" </a>",
" .)",
" </p>",
" MOLECULAR GENETICS OF GROWTH HORMONE DEFICIENCY",
" </span>",
" — As many as 3 to 30 percent of children with growth hormone
deficiency (GHD) have an affected parent, sibling, or child [",
" 7,8",
" </a>",
" ]. Several genetic causes of GHD have been described (see",
" \"Causes of hypopituitarism\", section on 'Genetic diseases'",
" </a>",
" ):",
" </p>",
" <p>",
" <li>",
" POU1F1 mutations — The POU1F1 gene (known as Pit-1 in rodents) is
responsible for pituitary-specific transcription of genes for growth hormone (GH),
prolactin, thyrotropin, and the growth hormone releasing hormone (GHRH) receptor
[",
" 9,10",
" </a>",
" ]. Mutations of the POU1F1 gene are transmitted as autosomal recessive or
codominant traits and cause variable peptide hormone deficiencies with or without
anterior pituitary hypoplasia [",
" 11-13",
" </a>",
" ].",
" </li>",
" <li>",
" Prop-1 mutations — Prop-1 mutations result in failure to activate",
" POU1F1/Pit-1",
" </span>",
" gene expression and probably cause pituitary hypoplasia",
" and/or",
" </span>",
" familial multiple pituitary hormone deficiency [",
" 14",
" </a>",
" ]; paradoxical cystic hyperplasia of the pituitary also has been reported
[",
" 15",
" </a>",
" ]. This is the most common known genetic cause of combined pituitary hormone
deficiency.",
" </li>",
" <li>",
" Other transcription factors — In addition to",
" POU1F1/Pit-1",
" </span>",
" and Prop-1, other transcription factors participate in the differentiation
of anterior pituitary cells, including LHX3, LHX4, TBX19 (TPIT), SOX3, SOX2, and
HESX1 [",
" 16",
" </a>",
" ]. Mutations in these genes also cause congenital deficiencies of multiple
pituitary hormones, with variable phenotypes.",
" </li>",
" <li>",
" GHRH receptor gene defects — Children with GHRH receptor gene defects
have undetectable GH release during standard provocative tests and after exogenous
GHRH administration, but they respond to GH treatment.",
" </li>",
" <li>",
" Deletions and mutations of GH-1 — GH-1 is the gene encoding GH,
located on chromosome 17. Gene deletions, frameshift mutations, and nonsense
mutations of the GH-1 gene have been described as causes of familial GHD [",
" 17",
" </a>",
" ].",
" </li>",
" <li>",
" Syndrome of bioinactive GH — A diagnosis of the syndrome of
bioinactive GH has been proposed for short children with a phenotype that resembles
that of isolated GHD, with normal or slightly elevated basal GH levels in
combination with low IGF-I concentrations that increase after treatment with
exogenous GH. True molecular abnormalities involving a mutant GH molecule have
rarely been reported [",
" 18,19",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Other mutations can cause growth hormone insensitivity (GHI). The clinical
phenotype of GHI is similar to that of GHD, but the mechanisms, laboratory
findings, and treatment are different. (See",
" \"Growth hormone insensitivity syndromes\", section on 'Introduction'",
" </a>",
" .)",
" </p>",
" CLINICAL PRESENTATION",
" </span>",
" — Growth hormone deficiency (GHD) can be divided into
congenital and acquired forms. The single most important clinical manifestation of
GHD is growth failure, and careful documentation of growth rate is critical to
making the correct diagnosis. In some cases of congenital GHD or hypopituitarism,
the growth failure may not be manifested until late infancy, as noted below.",
" </p>",
" Congenital",
" </span>",
" — Patients with congenital, severe GHD have only a slightly
reduced birth length and may not immediately show growth failure. There is a higher
frequency of breech presentation and perinatal asphyxia. Neonatal morbidity may
include hypoglycemia and prolonged jaundice.",
" </p>",
" <p>",
" When GHD is combined with deficiency of Adrenocorticotropic hormone (ACTH),
hypoglycemia may be severe. The combination of GHD with gonadotropin deficiency can
cause microphallus, cryptorchidism, and hypoplasia of the scrotum. (See",
" \"Undescended testes (cryptorchidism) in children and adolescents\"",
" </a>",
" .)",
" </p>",
" <p>",
" Postnatal growth is abnormal, and growth failure can occur during the first
months of life [",
" 20-23",
" </a>",
" ], but may not be obvious until 6 to 12 months of age, by which time the
growth rate is definitely slow and deviates from the normal growth curve, with
length measurements often significantly below the mean. Bone age becomes delayed
but is similar to height age, unless there is concurrent hypothyroidism.",
" </p>",
" Acquired",
" </span>",
" — Children with acquired GHD present with severe growth
failure, delayed bone age,",
" weight/height",
" </span>",
" ratios increased, fat distribution often \"infantile,\" \"doll-like,\"
or \"angel-like\" (cherubic) in pattern, and immature face with underdeveloped
nasal bridge and frontal bossing. The voice is infantile, and hair growth is sparse
and thin. The penis may be small, and puberty is usually delayed.",
" </p>",
" WHICH CHILDREN REQUIRE EVALUATION?",
" </span>",
" — Children with short stature should be evaluated with
careful serial measurements of length or height and compared to reference
standards. (See",
" 'Auxology'",
" </a>",
" above.)",
" </p>",
" <p>",
" Any of the following growth patterns, without alternative explanations, are
appropriate indications for evaluation for growth hormone deficiency (GHD) [",
" 24",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" Marked short stature, more than 2.5 SD below the mean (corresponds
approximately to <0.5 percentile) for chronological age, sex, and ethnic
background. The SD (Z-scores) can be determined from length or height percentiles,
or from calculators for boys (",
" calculator 1",
" </a>",
" ) or for girls (",
" calculator 2",
" </a>",
" ). Note that virtually all of these patients also have growth failure.",
" </li>",
" <li>",
" Growth failure, defined as height velocity less than the 25",
" <sup>",
" th",
" </sup>",
" percentile (",
href=\"UTD.htm?32/1/32792\">",
" figure 3A-B",
" </a>",
" ), whether or not short stature is present. Children with severe growth
failure (eg, height velocity <10",
" <sup>",
" th",
" </sup>",
" percentile) are most likely to have a pathological cause, so it is important
to evaluate such patients promptly.",
" </li>",
" <li>",
" Less severe short stature (2 SD to 2.5 SD below the mean [approximately 0.5
through 3",
" <sup>",
" rd",
" </sup>",
" percentiles]) for chronological age, sex and ethnic background, combined
with growth failure, in the absence of an alternative explanation. ",
" </li>",
" <li>",
" Evidence suggesting hypothalamic-pituitary dysfunction (eg, hypoglycemia,
microphallus, cryptorchidism, optic nerve hypoplasia, intracranial tumor, or
history of cranial irradiation), with decelerating growth, even if the child's
height is within the normal range [",
" 5",
" </a>",
" ].",
" </li>",
" <li>",
" Evidence for deficits in other hypothalamic-pituitary hormones, either
congenital or acquired. ",
" </li>",
" </ul>",
" </p>",
" DIAGNOSTIC APPROACH",
" </span>",
" — Once the decision to evaluate a short child has been made,
a variety of different tests can be performed.",
" </p>",
" <p>",
" The first step is to evaluate for other causes of growth failure, including
chronic systemic disease, hypothyroidism, Turner syndrome (in girls), and skeletal
disorders. This is accomplished through a thorough medical history and physical
examination. Laboratory evaluation should be performed when appropriate, including
screens for systemic disease, undernutrition, inflammation, and thyroid function,
and a karyotype in girls to rule out Turner syndrome. (See",
" \"Diagnostic approach to short stature\", section on 'Laboratory studies'",
" </a>",
" .)",
" </p>",
" <p>",
" If there is no evidence of these disorders, then the possibility of growth
hormone deficiency (GHD) can be investigated with the following tests:",
" </p>",
" <p>",
" <li>",
" Insulin-like growth factor-1 (IGF-I)",
" </li>",
" <li>",
" Insulin-like growth factor binding protein-3 (IGFBP-3)",
" </li>",
" <li>",
" Bone age",
" </li>",
" </ul>",
" </p>",
" <p>",
" GHD is effectively excluded in children with a normal bone age and height
velocity. In this case, provocative testing for GHD is not required.",
" </p>",
" <p>",
" When GHD is congenital and near-complete, the diagnosis is relatively easy to
confirm, as affected children present with severe growth failure, delayed bone age,
and very low serum concentrations of growth hormone, IGF-I, and IGFBP-3 [",
" 5",
" </a>",
" ].",
" </p>",
" <p>",
" Milder degrees of growth failure and decreases in IGF-I and IGFBP-3 levels are
consistent with GHD, but are also consistent with other causes of growth failure,
including poor nutrition. (See",
" 'IGF-I and IGFBP-3'",
" </a>",
" below.)",
" </p>",
" <p>",
" Abnormal results of IGF-I",
" and/or",
" </span>",
" IGFBP-3 levels should be confirmed by provocative growth hormone (GH) testing
if not explicable on the basis of undernutrition. In addition, an MRI of the
hypothalamic-pituitary region is recommended for children with suspected GHD [",
" 25",
" </a>",
" ]. (See",
" 'GH stimulation tests'",
" </a>",
" below and",
" 'Imaging'",
" </a>",
" below.)",
" </p>",
" TESTING FOR GROWTH HORMONE DEFICIENCY",
" </span>",
" — Assessment of pituitary growth hormone (GH) production is
difficult because GH secretion is pulsatile, with the most consistent surges during
stages 3 and 4 of sleep. The regulation of GH secretion involves at least two well-
studied hypothalamic factors, growth hormone releasing hormone (GHRH) (stimulatory)
and somatostatin (inhibitory). In addition, GH secretion is influenced by multiple
other peptides and neurotransmitters, including ghrelin (stimulatory) produced both
in the hypothalamus and in the stomach, which causes stimulation of GHRH [",
" 26",
" </a>",
" ].",
" </p>",
" <p>",
" Between normal pulses of GH secretion, serum GH levels are often low, below
the limits of sensitivity of most conventional assays. Thus, measurement of a
random serum GH level is not helpful in diagnosing growth hormone deficiency (GHD),
and is used only to exclude the possibility of growth hormone insensitivity.",
" </p>",
" <p>",
" Because of these issues, the diagnosis of GHD is made with a combination of
clinical assessment and auxology, IGF-I and IGFBP-3 levels, and GH stimulation
tests.",
" </p>",
" IGF-I and IGFBP-3",
" </span>",
" — The determination of IGF-I and IGFBP-3 levels has become a
widely used tool in the diagnostic evaluation of growth disorders. IGF-I is the
mediator of the majority of the growth-promoting actions of GH. (See",
" \"Physiology of insulin-like growth factor I\"",
" </a>",
" .)",
" </p>",
" <p>",
" Two benefits of measurement of serum concentrations of IGF-I and IGFBP-3
are:",
" </p>",
" <p>",
" <li>",
" Their concentrations often reflect the integrated concentration of secreted
GH.",
" </li>",
" <li>",
" Unlike the pulsatile secretion of GH, IGF-system peptides are stable during
the day (serum half-lives of 12 to 16 hours) [",
" 27",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Despite relatively good correlations with groups of patients between GH
secretion and IGF-I concentrations [",
" 28-31",
" </a>",
" ], the problems in assessing GH status by measurement of IGF-I in individual
patients remain substantial:",
" </p>",
" <p>",
" <li>",
" IGF-I values are quite low early in life, and the normal range overlaps with
the range for GHD.",
" </li>",
" <li>",
" Inadequate nutrition lowers IGF-I despite normal or even elevated levels of
GH.",
" </li>",
" <li>",
" Serum IGF-I levels may be low in conditions other than GHD, such as GHI,
hypothyroidism [",
" 32",
" </a>",
" ], diabetes [",
" 33",
" </a>",
" ], and renal failure [",
" 32,34",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Of the six IGFBPs, IGFBP-3 is the major serum carrier protein for IGF-I [",
" 35-37",
" </a>",
" ] and the most GH dependent [",
" 38",
" </a>",
" ]. IGFBP-3 levels are less nutritionally dependent, and are more
discriminatory than those of IGF-I in the lower end of the normal range. Although
levels of both IGF-I and IGFBP-3 normally increase with age, IGFBP-3 is a better
screening test for GHD than IGF-I in younger children because IGFBP-3 is better
able to distinguish low-normal levels of IGFBP-3 in young children from truly low
levels [",
" 39",
" </a>",
" ]. (See",
" \"Physiology of insulin-like growth factor I\"",
" </a>",
" .)",
" </p>",
" <p>",
" For the patient with unequivocal GHD, IGF-I and IGFBP-3 are invariably
reduced; for patients with milder abnormalities of GH secretion, IGF-system
peptides provide a meaningful measure of functional GH secretion and probably
reflect GH secretion more effectively than does provocative GH testing, which is
described below. The fact that IGF-I and IGFBP-3 do not invariably correlate with
results of provocative GH testing speaks more directly to the inadequacies of our
direct assessment of GH secretion than to limitations of IGF system assays. IGF-I
and IGFBP-3 levels should be interpreted against reference ranges that are
standardized for sex and age (or better, by stage of sexual development, if
available). The range varies with the assay used, and results should be interpreted
against standards provided by the laboratory performing the test [",
" 40",
" </a>",
" ]. Values below the lower limit of normal (eg, more than 2 SD below the mean)
strongly suggest an abnormality in the GH axis if other causes of low IGF have been
excluded. Consideration of norms based on bone age rather than chronological age
has also been recommended.",
" </p>",
" <p>",
" Patients with growth hormone insensitivity have normal or elevated circulating
serum GH levels but low levels of IGF-I and IGFBP-3. (See",
" \"Treatment of growth hormone deficiency in children\", section on 'Growth
hormone insensitivity syndrome'",
" </a>",
" .)",
" </p>",
" GH stimulation tests",
" </span>",
" — Provocative GH testing has a number of limitations (",
7/3/7227\">",
" table 1",
" </a>",
" ) [",
" 5",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" The tests are nonphysiological.",
" </li>",
" <li>",
" The cutoff level of \"normal\" is arbitrary.",
" </li>",
" <li>",
" The tests are age dependent [",
" 41",
" </a>",
" ], and the role of sex steroid administration has not been adequately
defined; however, priming prepubertal and peripubertal subjects with sex steroids
increases the likelihood that a normal child will have a normal response to a
variety of stimuli.",
" </li>",
" <li>",
" The tests rely upon GH assays of variable accuracy.",
" </li>",
" <li>",
" The tests are expensive, uncomfortable, and carry some risks.",
" </li>",
" <li>",
" Test reproducibility has not been adequately documented.",
" </li>",
" <li>",
" The ability of the tests to discriminate between normal short children and
children with partial GHD is limited.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Because of these limitations, it is clear that there is no real \"gold
standard\" for the diagnosis of GHD [",
" 25",
" </a>",
" ]. Nonetheless, GH stimulation tests are a valuable diagnostic tool when
combined with auxological data and measurements of IGF-I and IGFBP-3. Provocative
testing is also a useful predictor of response during the first year of treatment
with GH [",
" 42,43",
" </a>",
" ].",
" </p>",
" <p>",
" Measurement of GH secretory reserve relies upon the use of physiological or
pharmacological stimuli. Physiologic stimuli include sleep [",
" 44,45",
" </a>",
" ], fasting [",
" 46",
" </a>",
" ], and exercise [",
" 47,48",
" </a>",
" ]. Pharmacological stimuli include L-dopa [",
" 49",
" </a>",
" ],",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?13/14/13545?
" clonidine",
" </a>",
" [",
" 50",
" </a>",
" ],",
" propranolol",
" </a>",
" [",
" 49",
" </a>",
" ],",
" glucagon",
" </a>",
" [",
" 51",
" </a>",
" ], arginine [",
" 52",
" </a>",
" ], and insulin-induced hypoglycemia [",
" 53-55",
" </a>",
" ]. The last three tests have the highest specificity, but are still subject to
false-positive results. Therefore, there is general consensus that a diagnosis of
impaired GH secretion can be confirmed only if subnormal GH secretion is observed
during two different GH stimulation tests. In a patient with known pathology of the
central nervous system, other pituitary hormone defects, or a genetic defect, one
test is sufficient to establish the diagnosis [",
" 24,25",
" </a>",
" ].",
" </p>",
" <p>",
" These stimulation tests are performed after an overnight fast. After the
pharmacologic stimulus, serum samples are collected at intervals designed to
capture the peak growth hormone level; the expected time to this peak varies with
the stimulus administered. Most pediatric endocrinologists define a \"normal\"
response by a serum GH concentration of >10",
" mcg/L,",
" </span>",
" although the ideal threshold may vary slightly with the assay used.",
" </p>",
" <p>",
" <li>",
" Clonidine",
" </a>",
" — Clonidine stimulates GH by several mechanisms, including the
stimulation of GHRH. It is administered at a dose of 5",
" mcg/kg",
" </span>",
" (maximum 250 mcg), and peak GH secretion is expected about one hour after
the stimulus [",
" 24",
" </a>",
" ]. Clonidine may cause modest hypotension and hypoglycemia, so patients
should be monitored for these problems during the test. Estimates of this test's
sensitivity and specificity vary considerably [",
" 56,57",
" </a>",
" ].",
" </li>",
" <li>",
" Arginine — An intravenous infusion of 0.5",
" g/kg",
" </span>",
" body weight (to a maximum of 40 g) is given over 30 minutes, and serum
growth hormone is measured at 0, 30, 60, 90, and 120 minutes [",
" 24",
" </a>",
" ]. The maximum GH peak is expected at about 60 minutes. There are no side
effects from this test, but overdoses have been described. Growth hormone secretion
can be enhanced (and therefore false-positive results reduced) by adding a dose of
L-Dopa orally just prior to the administration of arginine [",
" 24",
" </a>",
" ]. However, L-Dopa is not currently available in the United States. L-Dopa
also can be used alone, but is a relatively weak stimulant of GH release.",
" </li>",
" <li>",
" Glucagon",
" </a>",
" — Administration of glucagon causes transient hyperglycemia, which in
turn stimulates endogenous insulin secretion followed by controlled hypoglycemia,
and consequent GH secretion [",
" 24,58",
" </a>",
" ]. It is less risky than insulin-induced hypoglycemia (described below), and
is a good choice for infants and young children. Glucagon is administered
subcutaneously at a dose of 0.03",
" mg/kg",
" </span>",
" (maximum 1 mg), and serum samples are drawn at intervals between one and
three hours after the stimulus. Peak GH secretion occurs between two and three
hours after glucagon administration; side effects are mild and transient, and
include nausea, vomiting, sweating, or headaches.",
" </li>",
" <li>",
" Insulin-induced hypoglycemia — Insulin-induced hypoglycemia is a
potent stimulant of growth hormone release, and is therefore among the most
specific tests for GHD. However, this test is less commonly used in children
because of safety concerns [",
" 25",
" </a>",
" ] (see",
" \"Growth hormone deficiency in adults\", section on 'Insulin-induced
hypoglycemia'",
" </a>",
" ). The performance of other provocative tests is discussed separately.
(See",
" \"Growth hormone deficiency in adults\", section on 'Provocative tests'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" Stimulation testing with GHRH is sometimes used in combination with arginine
to better evaluate patients with multiple pituitary hormone deficiencies to
determine the level of the secretory defect [",
" 24,59",
" </a>",
" ]. However, it is not useful in making a diagnosis of GHD in children with
isolated idiopathic GHD because these children have a defect in hypothalamic
regulation of pituitary GH secretion and are expected to respond normally to GHRH.
GHRH is not currently available in the United States.",
" </p>",
" <p>",
" It is important to remember that if the child is thyroid deficient, the tests
of GH secretion should be postponed until thyroxine is adequately replaced. GH
secretion may be subnormal merely as a result of the hypothyroidism. Thus,
hypothyroidism should be excluded before performing GH stimulation tests. (See",
" 'Diagnostic approach'",
" </a>",
" above.)",
" </p>",
" Imaging",
" </span>",
" — High-quality contrast-enhanced magnetic resonance imaging
(MRI) permits excellent visualization of the hypothalamo-hypophyseal tract. On T1-
weighted imaging, a clear demarcation can be made between the adenohypophysis
(after two months of age) and the neurohypophysis, which appears as hyperintense
[",
" 60",
" </a>",
" ]. (See",
" \"Approach to neuroimaging in children\", section on 'Magnetic resonance
imaging'",
" </a>",
" .)",
" </p>",
" <p>",
" After the clinical and biochemical diagnosis of GHD is made, it is essential
to obtain an MRI of the brain with narrow cuts through the hypothalamic-pituitary
area [",
" 25",
" </a>",
" ]. This imaging is important to exclude the possibility of a pituitary tumor;
it also permits diagnostic characterization by showing the presence or absence of
morphological abnormalities such as anterior pituitary hypoplasia, pituitary stalk
agenesis, and posterior pituitary ectopia.",
" </p>",
" <p>",
" An MRI is helpful in the prediction of permanent GHD. In one study, GH
secretion was reevaluated after completion of GH treatment in young adults with
childhood-onset GHD [",
" 61",
" </a>",
" ]. GHD was permanent in children with congenital hypothalamic-pituitary
abnormalities on MRI scans, while children without hypothalamic-pituitary
abnormalities frequently showed normalization of GH secretion at the completion of
GH treatment.",
" </p>",
" <p>",
" MRI may also provide evidence of severe GHD (GH peak in any stimulation test,
<7",
" mcg/dL)",
" </span>",
" if the diagnosis of pituitary stalk interruption syndrome (PSIS) is made [",
" 61",
" </a>",
" ]. This entity consists of ectopic neurohypophysis, interrupted pituitary
stalk, and hypoplastic adenohypophysis, and has been associated with severe GHD.",
" </p>",
" <p>",
" If an MRI is not available, computerized tomography (CT) of the head is
sufficient to screen for a pituitary tumor.",
" </p>",
" GROWTH HORMONE INSENSITIVITY",
" </span>",
" — Growth hormone insensitivity (GHI) is a group of inherited
disorders where there is a reduction or absence of the biological effects of GH
despite normal or above normal production of growth hormone. GHI should be
suspected in patients with growth failure and low IGF-I and IGFBP3 levels, but
normal or increased circulating levels of growth hormone (GH), and lack of response
to GH.",
" </p>",
" <p>",
" The classic GHI syndrome is also known as Laron syndrome (Laron dwarfism), in
which mutations of the GH receptor cause severe postnatal growth failure. Lesser
degrees of GH resistance may play a role in a small percentage of cases of
idiopathic short stature (see",
" \"Growth hormone treatment for idiopathic short stature\", section on 'Dose
adjustment for IGF-I levels'",
" </a>",
" ). This disorder is discussed in a separate topic review. (See",
" \"Growth hormone insensitivity syndromes\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </span>",
" — UpToDate offers two types of patient education materials,
“The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5",
" <sup>",
" th",
" </sup>",
" to 6",
" <sup>",
" th",
" </sup>",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" <sup>",
" th",
" </sup>",
" to 12",
" <sup>",
" th",
" </sup>",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)",
" </p>",
" <p>",
" <li>",
" Basics topic (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?3/12/3266?
" \"Patient information: My child is short (The Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" </span>",
" </p>",
" <p>",
" <li>",
" Growth hormone deficiency (GHD) is primarily a clinical diagnosis, based
upon auxological features, and confirmed by biochemical testing.",
" </li>",
" <li>",
" GHD can be caused by a variety of genetic mutations (although these are
rare), or by processes affecting hypothalamic or pituitary function. GHD may be
isolated or may occur in association with deficiencies of other pituitary hormones.
(See",
" 'Molecular genetics of growth hormone deficiency'",
" </a>",
" above and",
" 'Clinical presentation'",
" </a>",
" above.)",
" </li>",
" <li>",
" GHD should be suspected in patients with marked short stature (more than 2.5
SD below the mean),",
" and/or",
" </span>",
" marked growth failure (height velocity less than the 25",
" <sup>",
" th",
" </sup>",
" percentile for age), or more moderate degrees of short stature and growth
failure with decelerating growth (without alternative explanation). It should also
be suspected in children with signs or symptoms of hypothalamic-pituitary
dysfunction with decelerating growth. (See",
" 'Which children require evaluation?'",
" </a>",
" above.) ",
" </li>",
" <li>",
" Patients with suspected GHD should be screened with radiographic measurement
of bone age and IGF-I and IGFBP-3 levels. In the majority of short-statured
children, both IGF-I and IGFBP-3 will be in the normal range. If the values are
near or above the 50th percentile, GHD is extremely unlikely, and no further
testing is required. (See",
" 'IGF-I and IGFBP-3'",
" </a>",
" above.)",
" </li>",
" <li>",
" If GHD is congenital and complete, the diagnosis is relatively easy to
confirm. Affected children present with severe growth failure, delayed bone age,
and very low serum concentrations of IGF-I, and its major binding protein, IGFBP-3.
(See",
" 'Diagnostic approach'",
" </a>",
" above.)",
" </li>",
" <li>",
" If IGF-I and IGFB-3 are moderately reduced (eg, <10th percentile) and
bone age is delayed, the possibility of GHD should be explored by provocative
growth hormone (GH) testing. For children with isolated GHD, testing with two
different provocative tests is recommended to establish the diagnosis;",
" clonidine",
" </a>",
" , arginine, and",
" glucagon",
" </a>",
" are common choices in children. Hypothyroidism should be excluded first by
performing thyroid function tests. (See",
" 'GH stimulation tests'",
" </a>",
" above.)",
" </li>",
" <li>",
" For children with GHD, magnetic resonance imaging (MRI) of the hypothalamic-
pituitary area is recommended to investigate to rule out tumors, investigate for
structural causes of GHD, and to evaluate the severity and prognosis of the
deficiency. (See",
" 'Imaging'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
" REFERENCES",
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" Li S, Crenshaw EB 3rd, Rawson EJ, et al. Dwarf locus mutants lacking three
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" Cohen LE, Wondisford FE, Salvatoni A, et al. A \"hot spot\" in the Pit-1
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" </a>",
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" Pellegrini-Bouiller I, Bélicar P, Barlier A, et al. A new mutation of
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" Wu W, Cogan JD, Pfäffle RW, et al. Mutations in PROP1 cause familial
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" Zygmunt-Górska A, Starzyk J, Adamek D, et al. Pituitary enlargement
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" Besson A, Salemi S, Deladoëy J, et al. Short stature caused by a
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" Wit JM, van Unen H. Growth of infants with neonatal growth hormone
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" Gluckman PD, Gunn AJ, Wray A, et al. Congenital idiopathic growth hormone
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" De Luca F, Bernasconi S, Blandino A, et al. Auxological, clinical and
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Acta Paediatr 1995; 84:561.",
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" Pena-Almazan S, Buchlis J, Miller S, et al. Linear growth characteristics of
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" Richmond EJ, Rogol AD. Growth hormone deficiency in children. Pituitary
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" Growth Hormone Research Society. Consensus guidelines for the diagnosis and
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2000; 85:3990.",
" </a>",
" </li>",
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" Osterstock G, Escobar P, Mitutsova V, et al. Ghrelin stimulation of growth
hormone-releasing hormone neurons is direct in the arcuate nucleus. PLoS One 2010;
5:e9159.",
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" Martha PM Jr, Rogol AD, Veldhuis JD, et al. Alterations in the pulsatile
properties of circulating growth hormone concentrations during puberty in boys. J
Clin Endocrinol Metab 1989; 69:563.",
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" </li>",
" <li>",
" Rosenfeld RG. Biochemical diagnostic strategies in the evaluation of short
stature: the diagnosis of insulin-like growth factor deficiency. Horm Res 1996;
46:170.",
" </a>",
" </li>",
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" Underwood LE. Clinical uses of IGF-1 and IGF binding protein assays. In: The
IGF System: Molecular Biology, Physiology, and Clinical Applications, Rosenfeld RG,
Roberts CT (Eds), Human Press Inc., New Jersey 1999. p.617.",
" </li>",
" <li>",
" Hasegawa Y, Hasegawa T, Aso T, et al. Comparison between insulin-like growth
factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) measurement in the diagnosis
of growth hormone deficiency. Endocr J 1993; 40:185.",
" </a>",
" </li>",
" <li>",
" Nunez SB, Municchi G, Barnes KM, Rose SR. Insulin-like growth factor I (IGF-
I) and IGF-binding protein-3 concentrations compared to stimulated and night growth
hormone in the evaluation of short children--a clinical research center study. J
Clin Endocrinol Metab 1996; 81:1927.",
" </a>",
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" <li>",
" Baxter RC, Brown AS, Turtle JR. Radioimmunoassay for somatomedin C:
comparison with radioreceptor assay in patients with growth-hormone disorders,
hypothyroidism, and renal failure. Clin Chem 1982; 28:488.",
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" Tamborlane WV, Hintz RL, Bergman M, et al. Insulin-infusion-pump treatment
of diabetes: influence of improved metabolic control on plasma somatomedin levels.
N Engl J Med 1981; 305:303.",
" </a>",
" </li>",
" <li>",
" Powell DR, Rosenfeld RG, Baker BK, et al. Serum somatomedin levels in adults
with chronic renal failure: the importance of measuring insulin-like growth factor
I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab
1986; 63:1186.",
" </a>",
" </li>",
" <li>",
" Rosenfeld RG, Lamson G, Pham H, et al. Insulinlike growth factor-binding
proteins. Recent Prog Horm Res 1990; 46:99.",
" </a>",
" </li>",
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" Lamson G, Giudice LC, Rosenfeld RG. Insulin-like growth factor binding
proteins: structural and molecular relationships. Growth Factors 1991; 5:19.",
" </a>",
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" Baxter RC, Martin JL. Binding proteins for the insulin-like growth factors:
structure, regulation and function. Prog Growth Factor Res 1989; 1:49.",
" </a>",
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" Baxter RC, Martin JL. Radioimmunoassay of growth hormone-dependent
insulinlike growth factor binding protein in human plasma. J Clin Invest 1986;
78:1504.",
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" Bhala A, Harris MC, Zirin S, et al. Insulin-like growth factor axis
parameters in sick hospitalized neonates. J Pediatr Endocrinol Metab 1998;
11:451.",
" </a>",
" </li>",
" <li>",
" Examples of reference ranges from commonly used laboratories are available in
the Interpretive Guide from Quest (www.questdiagnostics.com/hcp/index.html), or the
Expected Values manual from Esoterix
(www.esoterix.com/prodserv/test_menu/endocrinology.asp)
www.questdiagnostics.com/hcp/index.html;
www.esoterix.com/prodserv/test_menu/endocrinology.asp (Accessed on October 15,
2008).",
" </li>",
" <li>",
" Price DA. GH testing in KIGS: The clinical reality. In: Growth Hormone
Therapy in KIGS-10 Years' Experience, Ranke MB, Wilton P (Eds), Huthig GmbH,
Heidelberg-Leipzig, Germany 1999. p.73.",
" </li>",
" <li>",
" Cole TJ, Hindmarsh PC, Dunger DB. Growth hormone (GH) provocation tests and
the response to GH treatment in GH deficiency. Arch Dis Child 2004; 89:1024.",
" </a>",
" </li>",
" <li>",
" Cohen P, Rogol AD, Howard CP, et al. Insulin growth factor-based dosing of
growth hormone therapy in children: a randomized, controlled study. J Clin
" </a>",
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" <li>",
" Takahashi Y, Kipnis DM, Daughaday WH. Growth hormone secretion during sleep.
J Clin Invest 1968; 47:2079.",
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" <li>",
" Underwood LE, Azumi K, Voina SJ, Van Wyk JJ. Growth hormone levels during
sleep in normal and growth hormone deficient children. Pediatrics 1971; 48:946.",
" </a>",
" </li>",
" <li>",
" GREENWOOD FC, HUNTER WM, MARRIAN VJ. GROWTH-HORMONE LEVELS IN CHILDREN AND
ADOLESCENTS. Br Med J 1964; 1:25.",
" </a>",
" </li>",
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" Buckler JM. Plasma growth hormone response to exercise as diagnostic aid.
Arch Dis Child 1973; 48:565.",
" </a>",
" </li>",
" <li>",
" Lacey KA, Hewison A, Parkin JM. Exercise as a screening test for growth
hormone deficiency in children. Arch Dis Child 1973; 48:508.",
" </a>",
" </li>",
" <li>",
" Stimulation of growth hormone secretion by levodopa-propranolol in children
and adolescents. Pediatrics 1975; 56:262.",
" </a>",
" </li>",
" <li>",
" Lanes R, Hurtado E. Oral clonidine-an effective growth hormone-releasing
agent in prepubertal subjects. J Pediatr 1982; 100:710.",
" </a>",
" </li>",
" <li>",
" Mitchell ML, Byrne MJ, Sanchez Y, Sawin CT. Detecon of growth-hormone
deficiency. N Engl J Med 1970; 282:539.",
" </a>",
" </li>",
" <li>",
" Merimee TJ, Rabinowtitz D, Fineberg SE. Arginine-initiated release of human
growth hormone. Factors modifying the response in normal man. N Engl J Med 1969;
280:1434.",
" </a>",
" </li>",
" <li>",
" Kaplan SL, Abrams CA, Bell JJ, et al. Growth and growth hormone. I. Changes
in serum level of growth hormone following hypoglycemia in 134 children with growth
retardation. Pediatr Res 1968; 2:43.",
" </a>",
" </li>",
" <li>",
" Root AW, Rosenfield RL, Bongiovanni AM, Eberlein WR. The plasma growth
hormone response to insulin-induced hypoglycemia in children with retardation of
growth. Pediatrics 1967; 39:844.",
" </a>",
" </li>",
" <li>",
" Raiti S, Davis WT, Blizzard RM. A comparison of the effects of insulin
hypoglycaemia and arginine infusion on release of human growth hormone. Lancet
1967; 2:1182.",
" </a>",
" </li>",
" <li>",
" Fraser NC, Seth J, Brown NS. Clonidine is a better test for growth hormone
deficiency than insulin hypoglycaemia. Arch Dis Child 1983; 58:355.",
" </a>",
" </li>",
" <li>",
" Obara-Moszy��ska M, Kedzia A, Korman E, Niedziela M. Usefulness of growth
hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency
diagnosis. J Pediatr Endocrinol Metab 2008; 21:569.",
" </a>",
" </li>",
" <li>",
" Leong KS, Walker AB, Martin I, et al. An audit of 500 subcutaneous glucagon
stimulation tests to assess growth hormone and ACTH secretion in patients with
hypothalamic-pituitary disease. Clin Endocrinol (Oxf) 2001; 54:463.",
" </a>",
" </li>",
" <li>",
" Maghnie M, Salati B, Bianchi S, et al. Relationship between the
morphological evaluation of the pituitary and the growth hormone (GH) response to
GH-releasing hormone Plus arginine in children and adults with congenital
hypopituitarism. J Clin Endocrinol Metab 2001; 86:1574.",
" </a>",
" </li>",
" <li>",
" Dietrich RB, Lis LE, Greensite FS, Pitt D. Normal MR appearance of the
pituitary gland in the first 2 years of life. AJNR Am J Neuroradiol 1995;
16:1413.",
" </a>",
" </li>",
" <li>",
" Maghnie M, Strigazzi C, Tinelli C, et al. Growth hormone (GH) deficiency
(GHD) of childhood onset: reassessment of GH status and evaluation of the
predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab
1999; 84:1324.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0504-60.18.131.125-10F4DE3033-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY & RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" AUXOLOGY",
" </a>",
" </li>",
" MOLECULAR GENETICS OF GROWTH HORMONE DEFICIENCY",
" </a>",
" </li>",
" CLINICAL PRESENTATION",
" </a>",
" </li>",
" Congenital",
" </a>",
" </li>",
" Acquired",
" </a>",
" </li>",
" WHICH CHILDREN REQUIRE EVALUATION?",
" </a>",
" </li>",
" DIAGNOSTIC APPROACH",
" </a>",
" </li>",
" TESTING FOR GROWTH HORMONE DEFICIENCY",
" </a>",
" </li>",
" IGF-I and IGFBP-3",
" </a>",
" </li>",
" GH stimulation tests",
" </a>",
" </li>",
" Imaging",
" </a>",
" </li>",
" GROWTH HORMONE INSENSITIVITY",
" </a>",
" </li>",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </a>",
" </li>",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/5842\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/5842|FIG\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
title=\"figure 1A\">",
" WHO length for age boys 0 to 24 months",
" </a>",
" </li>",
title=\"figure 1B\">",
" WHO length for age girls 0 to 24 months",
" </a>",
" </li>",
title=\"figure 2A\">",
" CDC stature for age boys 2 to 20 years",
" </a>",
" </li>",
" CDC stature for age girls 2 to 20 years",
" </a>",
" </li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?4/37/4692\" title=\"figure
3A\">",
" Height velocity in boys",
" </a>",
" </li>",
" Height velocity in girls",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/5842|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
" </a>",
" </div>",
" </li>",
1\">",
" Limitations of provocative testing for GH deficiency",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" CALCULATORS",
" </h1>",
" <div id=\"relatedCalculators\">",
" <ul>",
source=related_link\" title=\"calculator 1\">",
" Calculator: CDC height for age percentiles for boys (2 to 20 years)",
" </a>",
" </li>",
source=related_link\" title=\"calculator 2\">",
" Calculator: CDC height for age percentiles for girls (2 to 20 years)",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Approach to neuroimaging in children",
" </a>",
" </li>",
" Causes of hypopituitarism",
" </a>",
" </li>",
" Diagnostic approach to short stature",
" </a>",
" </li>",
" Growth hormone deficiency in adults",
" </a>",
" </li>",
" Growth hormone insensitivity syndromes",
" </a>",
" </li>",
" Growth hormone treatment for idiopathic short stature",
" </a>",
" </li>",
" Measurement of growth in children",
" </a>",
" </li>",
" Patient information: My child is short (The Basics)",
" </a>",
" </li>",
" Physiology of insulin-like growth factor I",
" </a>",
" </li>",
" Treatment of growth hormone deficiency in children",
" </a>",
" </li>",
" Undescended testes (cryptorchidism) in children and adolescents",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
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ov8P1d7mU604ScYuyR//9k=);\">",
" </div>",
" <div class=\"lgnd\">",
" Endomyocardial biopsy obtained one year after biopsy-proven acute myocarditis.
There is now considerable fibrosis with disruption of the normal myocardial
architecture.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Walter Abelmann, MD.",
" </div>",
" </div>",
" </div>",
" Normal endomyocardial byopsy",
" </div>",
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dOlFFFvdXqcUasnKSfRGDfKyw3FvEr/JGVQOcsyYJx/ePHt0z2ooormrrYyk+Zn//2Q==);\">",
" </div>",
" Light microscopy from a normal endomyocardial biopsy.",
" </div>",
" Courtesy of Helmut Rennke, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var outline_f0_5_83=null;
var title_f0_5_84="ECG in evolving anterior MI";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=CARD%2F81914%7ECARD
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=CARD%2F81914%7ECARD
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Electrocardiogram (ECG) in an evolving anterior myocardial infarction",
" </div>",
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F+cLtByoHbiisZyUndHv5XhJ4PDqlUtfy2/JH/2Q==);\">",
" </div>",
" Electrocardiogram shows findings typical of an evolving Q-wave anterior MI:
loss of R waves in leads V1 to V3, ST segment elevations in V2 to V4, and T wave
inversions in leads I, aVL, and V2 to V5. Sinus bradycardia (55 beats/min) is
present due to concurrent therapy with a beta blocker.",
" </div>",
" Courtesy of Ary Goldberger, MD.",
" </div>",
" </div>",
" </div>",
" Normal ECG",
" </div>",
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\">",
" </div>",
" Normal electrocardiogram showing normal sinus rhythm at a rate of 75
beats/min, a PR interval of 0.14 sec, a QRS interval of 0.10 sec, and a QRS axis of
approximately 75°.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Electrocardiogram (ECG) late in the evolution of an anterior myocardial
infarction",
" </div>",
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" </div>",
" Later stage in the evolution of an acute anterior myocardial infarction. There
is a QS pattern in leads V1 to V3 and T wave inversion in leads V2 to V4. The ST
segment elevations in these leads have almost disappeared.",
" </div>",
" </div>",
" </div>",
" </div>",
" Normal ECG",
" </div>",
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KACiiigAooooAKKKKACiiigAooooAKKKKACiiigAooooAKKKKACiiigAooooAKKKKACiiigAooooA/9k=);
\">",
" </div>",
" Normal electrocardiogram showing normal sinus rhythm at a rate of 75
beats/min, a PR interval of 0.14 sec, a QRS interval of 0.10 sec, and a QRS axis of
approximately 75°.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_85="Two Item Conjoint Screen";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=PC
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PC
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" TICS (Two-item Conjoint Screen)",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tr>",
" <td>",
" Have you used drugs more than you meant to?",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Have you wanted or needed to cut down on your drug use?",
" </td>",
" </tr>",
" </table>",
" </div>",
" An affirmative answer to any question suggests the need for further
evaluation.",
" </div>",
" Data from: Brown, RL, Leonard, T, Saunders, LA, Papasouliotis, O. A two-item
conjoint screen for an alcohol and other drug problems. J AM Board Fam Pract 2001;
14:95.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_86="ICAR-MEDCOM hypothermia scale";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=EM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=EM
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" ICAR-MEDCOM hypothermia (HT) scale",
" </div>",
" <tbody>",
" <tr>",
" <td class=\"subtitle1\" colspan=\"3\">",
" International Commission for Mountain Emergency Medicine hypothermia
scale",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle2\">",
" Hypothermia (HT) stage",
" </td>",
" Clinical assessment",
" </td>",
" Expected core temperature, C° (F°)*",
" </td>",
" </tr>",
" <tr>",
" <td class=\"centered\">",
" HT I",
" </td>",
" <td>",
" Clear consciousness with shivering",
" </td>",
" 35-32 (95-89.6)",
" </td>",
" </tr>",
" <tr>",
" HT II",
" </td>",
" <td>",
" Impaired consciousness without shivering",
" </td>",
" 32-28 (89.6-82.4)",
" </td>",
" </tr>",
" <tr>",
" HT III",
" </td>",
" <td>",
" Unconsciousness (circulation present)",
" </td>",
" 28-24 (82.4-75.2)",
" </td>",
" </tr>",
" <tr>",
" HT IV",
" </td>",
" <td>",
" Apparent death (circulation absent)",
" </td>",
" <24-13.7 (<75.2-56.7)",
" <sup>",
" •",
" </sup>",
" </td>",
" </tr>",
" <tr>",
" HT V",
" </td>",
" <td>",
" Death due to irreversible hypothermia",
" </td>",
" <13.7-9 (56.7-48.2)",
" <sup>",
" •",
" </sup>",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" * Clinical assessment may be used alone to stage hypothermia when core
temperature measurement in the field is not available.",
" <br>",
" <font class=\"bullet\">",
" •",
" </font>",
" The core temperature at which irreversible hypothermia with death occurs is
not well defined. Please see the UpToDate topics on hypotherma for discussions
regarding prehospital declaration of death and withdrawal of resuscitation.",
" </br>",
" </div>",
" Modified with permission from: Durrer B, Brugger H, Syme D, and the
International Commission for Mountain Emergency Medicine. The medical on-site
treatment of hypothermia: ICAR-MEDCOM recommendation. High Alt Med Biol 2003; 4:99.
Copyright © 2003 Mary Ann Liebert, Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_87="Documenting decline for hospice";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=PALC
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PALC
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Medical guidelines for determining appropriateness of hospice referral:
Documenting decline",
" </div>",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" A patient will be considered to have a life expectancy of six months or
less if he/she meets the following criteria for decline in clinical status, when
they are not considered to be reversible:",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1_start\">",
" 1. Progression of disease as documented by worsening clinical status,
symptoms, signs, and laboratory results",
" </td>",
" </tr>",
" <tr>",
" A. Clinical status",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent2\">",
" 1) Recurrent or intractable infections such as pneumonia, sepsis, or upper
urinary tract infection",
" <br/>",
" 2) Progressive inanition as documented by weight loss of at least 10
percent not due to reversible causes (depression, diuretics), decreasing
anthropomorphic measurements (mid-arm circumference, abdominal girth), decreasing
serum albumin or cholesterol, dysphagia leading to recurrent aspiration and/or
inadequate oral intake documented by decreased food portion consumption",
" </td>",
" </tr>",
" <tr>",
" B. Symptoms",
" </td>",
" </tr>",
" <tr>",
" 1) Dyspnea with increased respiratory rate",
" <br/>",
" 2) Cough, intractable",
" <br/>",
" 3) Nausea/vomiting poorly responsive to treatment",
" <br/>",
" 4) Diarrhea, intractable",
" <br/>",
" 5) Pain, requiring increasing doses of analgesia",
" </td>",
" </tr>",
" <tr>",
" C. Signs",
" </td>",
" </tr>",
" <tr>",
" 1) Decline in systolic blood pressure below 90 or progressive postural
hypotension",
" <br/>",
" 2) Ascites",
" <br/>",
" 3) Venous, arterial, or lymphatic obstruction due to local progression of
metastatic disease",
" <br/>",
" 4) Edema",
" <br/>",
" 5) Pleural/pericardial effusion",
" <br/>",
" 6) Weakness",
" <br/>",
" 7) Change in level of consciousness",
" </td>",
" </tr>",
" <tr>",
" D. Laboratory (when available, lab testing not required to establish
hospice eligibility)",
" </td>",
" </tr>",
" <tr>",
" 1) Increasing PaCO2 or decreasing PaO2, or decreased SaO2",
" <br/>",
" 2) Increasing calcium, creatinine, liver function",
" <br/>",
" 3) Increasing tumor markers (CEA, PSA)",
" <br/>",
" 4) Progressively decreasing or increasing sodium or increasing serum
potassium",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 2. Decline in Karnofsky Performance Status (KPS) or Palliative Performance
Status from 70 percent, due to progression of disease",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 3. Increasing emergency room visits, hospitalizations, or physicians'
visits related to hospice primary diagnosis",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 4. Progressive decline in Functional Assessment Staging (FAST) for
dementia",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 5. Progression to dependence of assistance with additional activities of
daily living",
" </td>",
" </tr>",
" <tr>",
" <td>",
" 6. Progressive stage 3 to 4 pressure ulcers despite optimal care",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" CEA: carcinoembryonic antigen; PSA: prostate specific antigen.",
" </div>",
" Source: Centers for Medicare & Medicaid Services. Local Coverage
Determination (LCD) for Hospice Determining Terminal Status (L32015)",
" <a href=\"file://www.cms.gov/medicare-coverage-
database/shared/handlers/highwire.ashx?url=file://www.cms.gov/medicare-coverage-
database/details/lcd-details.aspx@@@LCDId$$$32015***ContrId$$$236***ver$$
$11***ContrVer$$$2***CntrctrSelected$$$236*2***Cntrctr$$$236***name$$
$CGS+Administrators,+LLC+(15004,+HHH+MAC)***LCntrctr$$$236*2***bc$$
$AgACAAIAQAAA***&session=a2qgjyiqqk1bgt454ny2dr55&kq=1056876468\"
" file://www.cms.gov",
" </a>",
" (Accessed on January 10, 2013).",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_88="Headache and vomiting in stroke";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=NEURO
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=NEURO
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Headache and vomiting in stroke subtypes",
" </div>",
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8iDAEAOw==);\">",
" </div>",
" The frequency of sentinel headache, onset headache, and vomiting in three
subtypes of stroke: subarachnoid hemorrhage (SAH), intraparenchymal (intracerebral)
hemorrhage (IPH), and ischemic stroke (IS). Onset headache was present in virtually
all patients with SAH and about one-half of those with IPH; all of these symptoms
were infrequent in patients with IS.",
" </div>",
" Data from: Gorelick PB, Hier DB, Caplan LR, et al, Neurology 1986; 36:1445.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_89="Carotid endarterectomy stroke";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=CARD
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=CARD
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Carotid endarterectomy in severe carotid stenosis",
" </div>",
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Pdmmfdmqvdmu/dmzPdm3fdsAJCAA7);\">",
" </div>",
" Top panel: Among 588 patients with a symptomatic 80 to 99 percent carotid
stenosis, carotid endarterectomy reduced the incidence of a major stroke (p",
" </div>",
" Data from European Carotid Surgery Trialists' Collaborative Group. Lancet
1998; 351:1379.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_90="Morphea and lichen sclerosus";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=DERM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=DERM
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Morphea and lichen sclerosus",
" </div>",
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;\">",
" </div>",
" Sclerotic lesions of morphea with overlying hypopigmented, finely wrinkled
skin are present.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_91="Algorithm Syst Rx desmoids";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=ONC
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ONC
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Systemic therapy algorithm for desmoid tumors at MD Anderson Cancer Center",
" </div>",
url(data:image/gif;base64,R0lGODlhDwLNAtUAAP///
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vrwAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
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" </div>",
" DOXO: doxorubicin; DTIC: dacarbazine; MTX: methotrexate; VBL: vinblastine;
RT: radiation therapy; SD: stable disease; PR: partial response; CR: complete
response; PD: progressive disease; NSAID: non-steroidal anti-inflammatory drug.",
" <br/>",
" * Response may take >6 months to appear.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_92="Patient information: Heart transplant (The Basics)";
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" <br>",
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" ©2013 UpToDate",
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here to print\">",
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" <dl>",
" <dt class=\"basics\">",
" The Basics",
" </dt>",
" <dd>",
" <a href=\"UTD.htm?6/21/6483\">",
" Patient information: Reducing the costs of medicines (The Basics)",
" </a>",
" </dd>",
" <dt class=\"beyondthebasics\">",
" Beyond the Basics",
" </dt>",
" <dd>",
" <a href=\"UTD.htm?25/36/26179\">",
" Patient information: Heart transplantation (Beyond the Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?31/61/32726\">",
" Patient information: Reducing the costs of medicines (Beyond the
Basics)",
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" Patient information: Heart transplant (The Basics)",
" </div>",
" <span class=\"view\">",
" View in",
" <a class=\"lang\" href=\"./es-419/heart-transplant-the-basics?
source=topic_page\">",
" Spanish",
" </a>",
" </span>",
" <a class=\"contributor contributor_credentials\" href=\"./authors-and-
editors/patient-information\">",
" Written by the doctors and editors at UpToDate",
" </a>",
" What is a heart transplant?",
" </span>",
" — A heart transplant is a type of surgery in which a doctor
replaces your diseased heart with a healthy heart.",
" </p>",
" Why might I need a heart transplant?",
" </span>",
" — You might need a heart transplant if you have severe
heart failure. Heart failure is a condition in which the heart doesn’t pump
as well as it should. It can cause symptoms such as trouble breathing, feeling
tired, or swelling in the feet, legs, or belly.",
" </p>",
" <p>",
" Before you have a heart transplant, your doctor will try all other
treatments first. Your doctor will only recommend a heart transplant if all other
treatments fail.",
" </p>",
" What happens before I can get a heart transplant?",
" </span>",
" — Before you can get a heart transplant, you need to go
through a number of steps.",
" </p>",
" <p>",
" Your doctor will send you to a heart transplant center. At the heart
transplant center, you will have exams and blood tests, and talk with different
doctors. The doctors will ask about your:",
" </p>",
" <p>",
" <li>",
" Other medical conditions and medicines you take",
" </li>",
" <li>",
" Lifestyle (for example, smoking, alcohol, or drug use)",
" </li>",
" <li>",
" Family and other support system",
" </li>",
" </ul>",
" </p>",
" <p>",
" Not everyone who is sent to a heart transplant center will get a transplant.
To be considered for a heart transplant, you need to meet certain conditions. For
example, you need to:",
" </p>",
" <p>",
" <li>",
" Have severe heart failure that hasn’t gotten better with other
treatments",
" </li>",
" <li>",
" Not currently have certain other medical conditions, such as cancer",
" </li>",
" <li>",
" Agree not to smoke, drink, or use drugs — Doing these things can
harm your new heart.",
" </li>",
" <li>",
" Be willing to take medicines for the rest of your life after surgery",
" </li>",
" </ul>",
" </p>",
" <p>",
" If you meet all of these conditions, your doctors will send your information
to an organization called “UNOS.” UNOS keeps a list of every person in
the country who is waiting for a heart transplant. When a new heart becomes
available, UNOS decides who is next on the list to get it.",
" </p>",
" <p>",
" While you are waiting for your heart transplant, your doctors will follow
your health closely. If your condition changes, they will let UNOS know.",
" </p>",
" <p>",
" Sometimes, people get other medical problems while they are waiting for
their heart transplant. If you get other problems, you might need to wait longer
while your doctor treats those problems.",
" </p>",
" What happens when a heart becomes available?",
" </span>",
" — When a heart becomes available, UNOS chooses the person
who is the best match for that heart. People who are waiting for a heart need to
carry a cell phone or pager at all times so that they can be reached quickly.",
" </p>",
" <p>",
" When you get called for your heart transplant, you will need to get to the
hospital quickly.",
" </p>",
" What happens after a heart transplant?",
" </span>",
" — After surgery, most people stay in the hospital for a few
weeks before going home. In the hospital and at home, your doctors will follow you
and do tests to make sure that your new heart is working correctly.",
" </p>",
" <p>",
" After a heart transplant, people need to take medicines for the rest of
their life. These medicines are called “anti-rejection medicines.” They
help the body’s infection-fighting system accept the new heart. Normally, the
infection-fighting system helps people stay healthy by attacking objects in the
body that came in from the outside (“foreign objects”). Anti-rejection
medicines help keep the body from attacking the new heart.",
" </p>",
" What problems can people have after a heart transplant?",
" </span>",
" — In most cases, people do well after surgery. They can go
to work and be active. But some people have problems after a heart transplant.
These problems can happen right after the surgery or a few years later. They
include:",
" </p>",
" <p>",
" <li>",
" Rejection of the new heart — Even though people take anti-rejection
medicines, their body might still reject and attack the new heart.",
" </li>",
" <li>",
" Narrowing of the blood vessels in the new heart",
" </li>",
" <li>",
" Side effects from the anti-rejection medicines — These medicines
have short-term side effects. For example, they increase a person’s chance of
getting infections. They also have long-term side effects. For example, they can
increase a person’s chance of getting certain types of cancer.",
" </li>",
" </ul>",
" </p>",
" More on this topic",
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" <a class=\"medical medical_patient\" href=\"UTD.htm?31/61/32726?
" Patient information: Reducing the costs of medicines (Beyond the Basics)",
" </a>",
" </p>",
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" <a class=\"policy policy_editorialpolicy\" href=\"/home/editorial-
policy\">",
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" is complete.",
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" This topic retrieved from UpToDate on:",
" </span>",
" Apr 20, 2013.",
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"</div>"].join("\n");
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" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" What is a heart transplant?",
" </a>",
" </li>",
" Why might I need a heart transplant?",
" </a>",
" </li>",
" What happens before I can get a heart transplant?",
" </a>",
" </li>",
" What happens when a heart becomes available?",
" </a>",
" </li>",
" What happens after a heart transplant?",
" </a>",
" </li>",
" What problems can people have after a heart transplant?",
" </a>",
" </li>",
" More on this topic",
" </a>",
" </li>",
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" <h1>",
" RELATED TOPICS",
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" </li>",
" Patient information: Reducing the costs of medicines (Beyond the Basics)",
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var title_f0_5_93="Hemodialysis PI";
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" Hemodialysis",
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" </div>",
" This drawing shows a person getting hemodialysis. Two needles are put into
an \"access\" in the person's arm. Blood flows from the body to the hemodialysis
machine, where it is filtered. Then the blood is returned to the body. The whole
process takes about 3 to 5 hours and must be repeated 3 to 7 times a week.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f0_5_94="Trifluridine: Patient drug information";
" </div>",
" </noscript>",
" </img>",
" </div>",
" <sup>",
" ®",
" </sup>",
" </a>",
" <br>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" </a>",
" ©2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Trifluridine: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <p>",
" (For additional information",
" see \"Trifluridine: Drug information\"",
" </a>",
" and",
" see \"Trifluridine: Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F231119\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Viroptic®",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F231120\"
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Sandoz-Trifluridine;",
" </li>",
" <li>",
" Viroptic®",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10014073\"
" What is this drug used for?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" •",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691501",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to stop or treat eye infections.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10014072\"
" What do I need to tell my doctor before I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2703081",
" </span>",
" </span>",
" If you have an allergy to trifluridine or any other part of this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10014077\"
" What are some things I need to know or do while I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" Tell your doctor if you are pregnant or plan on getting pregnant. You will
need to talk about the benefits and risks of using this drug while you are
pregnant.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10014078\"
" What are some side effects of this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698045",
" </span>",
" </span>",
" Eye irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697926",
" </span>",
" </span>",
" Bright lights may bother you. Wear sunglasses.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10014080\"
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699086",
" </span>",
" </span>",
" Sudden change in eyesight, eye pain, or irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" Any rash.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10014075\"
" How is this drug best taken?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2694913",
" </span>",
" </span>",
" For the eye only.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696257",
" </span>",
" </span>",
" Wash your hands before and after use.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2695783",
" </span>",
" </span>",
" Take out contact lenses before using this drug. Lenses may be put back in
15 minutes after this drug is given. Do not put contacts back in if your eyes are
irritated or infected.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694779",
" </span>",
" </span>",
" Do not touch the container tip to the eye, lid, or other skin.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696124",
" </span>",
" </span>",
" Tilt your head back and drop drug into the eye.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694401",
" </span>",
" </span>",
" After use, keep your eyes closed. Put pressure on the inside corner of the
eye. Do this for 1 to 2 minutes. This keeps the drug in your eye.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2695617",
" </span>",
" </span>",
" Space each eye drug by 10 minutes.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10014076\"
" What do I do if I miss a dose?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696583",
" </span>",
" </span>",
" Use a missed dose as soon as you think about it.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696496",
" </span>",
" </span>",
" If it is close to the time for your next dose, skip the missed dose and go
back to your normal time.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696485",
" </span>",
" </span>",
" Do not use 2 doses or extra doses.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyi-os drugH1Div\" id=\"F10014081\"
" How do I store and/or throw out this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699391",
" </span>",
" </span>",
" Store in a refrigerator. Do not freeze.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699166",
" </span>",
" </span>",
" Do not use if solution changes color.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10014082\"
" General drug facts",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699675",
" </span>",
" </span>",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699673",
" </span>",
" </span>",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699678",
" </span>",
" </span>",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699709",
" </span>",
" </span>",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s3302581",
" </span>",
" </span>",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699671",
" </span>",
" </span>",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699683",
" </span>",
" </span>",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.3 - C21.34",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [1103-200.150.3.100-7D04F74F15-S473950.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <a class=\"outlineLink\" href=\"#F231119\">",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Trifluridine: Drug information",
" </a>",
" </li>",
" Trifluridine: Pediatric drug information",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f0_5_95="Metronidazole (topical): Patient drug information";
" </div>",
" </noscript>",
" </img>",
" </div>",
" <sup>",
" ®",
" </sup>",
" </a>",
" <br>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" </a>",
" ©2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Metronidazole (topical): Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <p>",
" (For additional information",
" see \"Metronidazole (topical): Drug information\"",
" </a>",
" and",
" see \"Metronidazole (topical): Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F8770975\"
" </span>",
" <ul>",
" <li>",
" MetroCream®;",
" </li>",
" <li>",
" MetroGel-Vaginal®;",
" </li>",
" <li>",
" MetroGel®;",
" </li>",
" <li>",
" MetroLotion®;",
" </li>",
" <li>",
" Noritate®;",
" </li>",
" <li>",
" Rosadan®;",
" </li>",
" <li>",
" Vandazole®",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F8770976\"
" </span>",
" <ul>",
" <li>",
" MetroCream®;",
" </li>",
" <li>",
" Metrogel®;",
" </li>",
" <li>",
" MetroLotion®;",
" </li>",
" <li>",
" Nidagel™;",
" </li>",
" <li>",
" Noritate®;",
" </li>",
" <li>",
" Rosasol®",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10024336\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2691692",
" </span>",
" </span>",
" It is used to treat acne rosacea. It may take 2 months to see the full
effect.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2692122",
" </span>",
" </span>",
" It is used to treat vaginal infections.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10024335\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2702519",
" </span>",
" </span>",
" If you have an allergy to metronidazole or any other part of this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2701047",
" </span>",
" </span>",
" If you are breast-feeding.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10024340\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697340",
" </span>",
" </span>",
" If you have seizures, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696622",
" </span>",
" </span>",
" Avoid beer, wine, or mixed drinks. Do not take alcohol for at least 24
hours after the last dose. Drinking alcohol or products that have alcohol, such as
cough syrup, may cause cramps, upset stomach, headaches, and flushing.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696708",
" </span>",
" </span>",
" Birth control pills and other hormone-based birth control may not work to
stop pregnancy. Use 2 kinds of birth control while taking this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" Tell your doctor if you are pregnant or plan on getting pregnant. You will
need to talk about the benefits and risks of using this drug while you are
pregnant.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10024341\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698272",
" </span>",
" </span>",
" Upset stomach or throwing up. Many small meals, good mouth care, sucking
hard, sugar-free candy, or chewing sugar-free gum may help.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698119",
" </span>",
" </span>",
" Headache.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696432",
" </span>",
" </span>",
" Bad taste in your mouth. This most often goes back to normal.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698344",
" </span>",
" </span>",
" Skin irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698385",
" </span>",
" </span>",
" Vaginal irritation.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10024343\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699049",
" </span>",
" </span>",
" Very bad skin irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699053",
" </span>",
" </span>",
" Very bad vaginal irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699018",
" </span>",
" </span>",
" Very loose stools (diarrhea), even after drug is stopped.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698988",
" </span>",
" </span>",
" Numbness or tingling in your hands or feet.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" Any rash.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10024338\"
" </span>",
" urn:lims:b498:s2705324",
" </span>",
" </span>",
" <b>",
" <span style=\"text-decoration: underline\">",
" All products:",
" </span>",
" </b>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696130",
" </span>",
" </span>",
" To gain the most benefit, do not miss doses.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696185",
" </span>",
" </span>",
" Use as you have been told, even if you are feeling better.",
" </span>",
" </li>",
" urn:lims:b498:s2705551",
" </span>",
" </span>",
" <b>",
" Skin:",
" </span>",
" </b>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694772",
" </span>",
" </span>",
" Do not take this drug by mouth. Use on your skin only. Keep out of your
mouth, nose, and eyes (may burn).",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696257",
" </span>",
" </span>",
" Wash your hands before and after use.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694623",
" </span>",
" </span>",
" Clean affected part before use. Make sure to dry well.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694440",
" </span>",
" </span>",
" Put a thin layer on the affected skin and rub in gently.",
" </span>",
" </li>",
" urn:lims:b498:s2705579",
" </span>",
" </span>",
" <b>",
" Vaginal:",
" </span>",
" </b>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696174",
" </span>",
" </span>",
" Use gel vaginally.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2694720",
" </span>",
" </span>",
" Do not have sex while using this drug.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10024339\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696441",
" </span>",
" </span>",
" Put on a missed dose as soon as you think about it.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696496",
" </span>",
" </span>",
" If it is close to the time for your next dose, skip the missed dose and go
back to your normal time.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696452",
" </span>",
" </span>",
" Do not put on 2 doses or extra doses.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyi-os drugH1Div\" id=\"F10024344\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699336",
" </span>",
" </span>",
" Store at room temperature.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10024345\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699675",
" </span>",
" </span>",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699673",
" </span>",
" </span>",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699678",
" </span>",
" </span>",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699709",
" </span>",
" </span>",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s3302581",
" </span>",
" </span>",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699671",
" </span>",
" </span>",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699683",
" </span>",
" </span>",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.3 - C21.34",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [1103-125.39.66.146-3A500C5829-S473950.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Metronidazole (systemic): Drug information",
" </a>",
" </li>",
" <a class=\"drug drug_patient\" href=\"UTD.htm?18/48/19205?
" Metronidazole (systemic): Patient drug information",
" </a>",
" </li>",
" Metronidazole (systemic): Pediatric drug information",
" </a>",
" </li>",
" Metronidazole (topical): Drug information",
" </a>",
" </li>",
" Metronidazole (topical): Pediatric drug information",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");

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var title_f0_5_80="Episcleritis";

var content_f0_5_80=[" <noscript>",

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