Case 3.

[Alon]

This 12-year-old girl is a rare visitor to your office. But today she's here, accompanied by her mother, with a complaint of headache and vomiting. The symptoms developed two weeks earlier, she reports, and have occurred intermittently since. Pain is localized to the occipital region but is occasionally bilateral frontal, occurs more often in the afternoon, and persists severely for five to 15 minutes and then dully thereafter. She doesn't complain of photophobia but does describe halos around objects, and tells you that colors "look weird" during headaches.

The patient had three episodes of vomiting on one day when the headache was present, two episodes on another. The vomiting was not self-induced, she insists, and was not associated with abdominal pain. She has not been awakened during the night or early morning by headache or vomiting; in fact, she reports, sleep relieves the headaches.

The girl cannot identify any triggers for the headaches, although her mother confesses to significant—but unspecified—family stress. Acetaminophen, the only medication that the girl takes, does not provide relief. She reports having had her first menstrual period two months earlier but not having one since.

The girl's medical history is vague. The mother recounts evaluation for rapid head growth in infancy, including a computed tomographic (CT) scan of the brain. There was a question of hydrocephalus at the time, but she was never treated surgically; the family was eventually reassured that follow-up was unnecessary. You perform a quick check of her head circumference: it's at the 98th percentile.

The family history reveals some interesting, perhaps relevant, information. Her mother has a history of migraine headache since 17 years of age, although symptoms subsided as she grew older. The mother's second pregnancy was complicated by birth defects, including hydrocephalus, and resulted in spontaneous abortion. The girl's father had congenital hydrocephalus that required placement of a shunt.

The physical examination shows you a well-appearing teenaged girl. Vital signs are normal, as is her general exam. No focal neurologic abnormalities are detected, and fundi show sharp disk margins.
Proceeding lacking clear direction

You consider the need for further work-up. Certainly, headache is a common complaint in children and adolescents, but rarely one that signals serious disease; clinical laboratory testing, electroencephalography, and brain imaging are usually uninformative. Are there features in this patient that prompt specific concerns? The visual aura, vomiting, and family history in the mother support classic migraine headache, although the occipital location and short duration are less typical. Recent stress could be the trigger for migraine or tension headache. You are most concerned about headache caused by intracranial pathology, however. It is reassuring to note that her headaches are marked by afternoon (as opposed to early morning) onset, that she has symptom-free intervals, and that the neurologic and funduscopic exams are normal.

Still, her uncertain history and strong family history of hydrocephalus create lingering doubt. Could macrocephaly in infancy be related to her current symptoms? You decide that brain imaging is indicated and order a CT scan of the head.

The patient and her mother—and you—are relieved to learn that the cranial CT is unremarkable. Confident that the headaches must be related to recent stress, they decline a trial of antimigraine medication. They agree to keep a headache diary and to return for follow-up in one month.
Two heads may not be better than one

At the next visit, you detect significant discrepancy between the history provided by the patient and her mother's account of her illness. Having failed to maintain a headache diary, the girl can only report that the headaches continue at a rate of least three times a week. Her mother disagrees: They're much less frequent. The patient insists that the pain is still severe (she rates most headaches at 8, on a scale of 1 to 10). General features of the headache are unchanged, although vomiting has completely resolved. But her mother disputes her, again, on the intensity of the headaches; she says she is sympathetic to her daughter's situation but is concerned that the girl is seeking secondary gain with her ongoing complaint. The mother's perception is that the headaches aren't incapacitating, occur at school only very rarely, and may allow her daughter to "escape" some of the conflict at home. You discuss this possibility further with mother and daughter, and all agree that counseling, with attention to stress management, should be initiated as soon as possible.
Milking the history

A long time passes before you see this patient again. She fails to keep several appointments. In a telephone conversation with you, her mother attributes the missed appointments to continued family stressors but reports that her daughter has generally been well.

Fifteen months later, the girl returns for a routine physical examination. Review of the time since her last visit reveals that the headaches have continued but are more easily tolerated. She does, however, have a new concern: Her first menses—reported longer than one year ago now—was the only one she experienced. She recalls that the vaginal blood flow on that occasion was scant and lasted only two days. She admits that she just assumed that her body "wasn't ready" to start menstruation, but now wonders aloud to you whether such a pattern—really, no pattern at all—is normal.

Breast development began more than three years ago; breasts and pubic hair are now Tanner stage IV. Growth has decelerated slightly (her height is at the 50th percentile for age) and weight has been steady at the 95th percentile. She has no complaint of hirsutism, acne, or galactorrhea. She denies cyclic abdominal pain, cold intolerance, constipation, change in skin or hair texture, decreased energy level, sexual activity, and taking medications or using illicit drugs or alcohol. She has pursued interscholastic sports, but not seriously.

She has no appreciable hirsutism, acne, striae, or acanthosis nigricans. Inspection of the external genitalia shows a normal vulva without clitoromegaly. A digital pelvic exam confirms a patent vaginal canal and palpable cervix. The only other change she notes is difficulty with vision during the past year. Indeed, although a prior vision screening examination yielded 20/20 acuity, her best effort at this visit demonstrates 20/100 acuity. Visual fields by confrontation seem normal.

[dr.Ira]

Я бы послала ее сделать TSH, LH, Prolactine, FSH, GH, эстрадиол, тестостерон. И дальше, в зависимости от результатов. И консультация гинеколога.

[Alon]

The history of amenorrhea in this well-developed girl intrigues you, and you conclude that it deserves attention. A single episode of menses suggests normal anatomy, and you ponder the differential diagnosis of secondary amenorrhea. Is this symptom independent of her earlier complaint of headache, or is it related—somehow?

You order tests of thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone (FSH), prolactin, dehydroepiandrosterone, and testosterone. TSH, gonadotropin, and testosterone levels are normal, but the prolactin level returns markedly elevated at 183 ng/mL (normal, 2.8 to 29.2 ng/mL). Dehydroepiandrosterone is also elevated at 14.8 ng/mL (normal, 1.5 to 7 ng/mL).
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DDx - Expanded

Secondary amenorrhea:
Gynecologic:
• Pregnancy
Endocrine:
Contraceptive related:
• Oral contraceptives
• Depo-Provera
Hypothalamic
(hypogonadotropic hypogonadism):
• Exercise
• Anorexia nervosa
• CNS disease:
» Tumor
» Infarction
• Kallmann’s syndrome
Anovulatory:
• Polycystic ovary syndrome
• Chronic illness:
» Thyroid disease
» Diabetes mellitus
• Obesity
• Stress
• Congenital adrenal hyperplasia
• Tumors
• Ovarium damage/disease:
» Autoimmune
» Radiation
» Chemotherapy
• Androgen insensitivity syndrome
Pituitary related:
• Hypopituitarism
• Infarction (Sheehan’s syndrome)
• Tumor
Drug/Toxin related:
• Antidepressants
• Phenothiazides
• Opiates
Other:
• Malignancy
• Chronic renal failure
• SLE
• IBD
---------------------------
Что делаем дальше?

[dr.Ira]

Ну, теперь надо делать MRI и искать пролактиному.

[Alon]

Magnetic resonance imaging (MRI) of the brain confirms your suspicion. A mass 0.8 x 1.2 cm is visualized within the left pituitary fossa. It does not appear to impinge on the optic chiasm, but does displace the left internal carotid artery and cavernous sinus. Reproductive endocrinologic and neurosurgical consultations are obtained and treatment for prolactinoma is initiated.

A prolactinoma is a benign tumor of the pituitary gland that leads to hypersecretion of the hormone prolactin. The tumor is rare in children compared to its prevalence among adults, although pituitary tumors do constitute approximately 2.7% of supratentorial tumors of childhood.In younger age groups, adrenocorticotropic hormone-secreting tumors are the most common pituitary adenomas, whereas prolactinoma predominates by adolescence.Girls are affected more often—by a ratio as high as 4.5:1—although prolactinomas are usually larger in boys by the time they are identified.

In addition to its lactogenic effect, prolactin may affect the hypothalamic-pituitary-gonadal axis.Presenting symptoms of prolactinoma reflect hyperprolactinemia or mass effect, and often include headache, arrested growth, and delayed puberty. In girls, amenorrhea or galactorrhea may be the initial complaint; boys may rarely demonstrate gynecomastia. Enlargement of the pituitary may cause compression of the optic chiasm, resulting in visual disturbances such as bitemporal hemianopia (tunnel vision).

Under normal circumstances, prolactin is secreted episodically from the pituitary gland and regulated by chronic dopamine inhibition, yielding a serum concentration of 1 to 20 ng/mL. Many physiologic and pathologic factors affect secretion of prolactin; stress, exercise, routine breast examination, a number of medications (phenothiazines, benzodiazepines, cimetidine, and metoclopramide, for example), and illicit drugs may cause a modest elevation. Hormonal changes of pregnancy, hypothyroidism, and polycystic ovary syndrome can also cause hyperprolactinemia. These clinical scenarios typically elevate the prolactin level to 30 to 100 ng/mL. Concomitant rise in dehydroepiandrosterone may occur as a result of prolactin receptors in the adrenal gland. A prolactin level >100 ng/mL suggests a prolactin-secreting tumor and should be further explored by brain imaging.

Because routine head CT may provide suboptimal images of the sellar region or lack the sensitivity to detect very small lesions, pituitary pathology is best defined by MRI. Once a prolactinoma is delineated radiologically, it is classified on the basis of its size as a microadenoma (<1 cm in diameter) or a macroadenoma (>1 cm).Size often correlates with the degree of hyperprolactinemia and may influence the approach to management.

Both microadenomas and macroadenomas must be treated if symptoms are to be relieved, normal menstrual cycles and fertility restored, and the patient protected from further complications. Because a microadenoma does not necessarily progress to a macroadenoma, the decision to treat is based on the clinical scenario.5,6 Direct extension of a macroadenoma poses an ongoing risk of loss of vision, destruction of the pituitary, and hypopituitarism—mandating more urgent need for treatment.In addition, most adolescents with a prolactinoma are estrogen-deficient and therefore suffer significant bone loss if not treated.

Dopamine agonist therapy has replaced surgery as the mainstay of treatment for adolescents with prolactinoma. Bromocriptine, once daily, or cabergoline, twice weekly, decreases the level of circulating prolactin, ultimately shrinking the tumor in most patients. Common side effects—including headache, nausea, and dizziness secondary to postural hypotension—are less likely when using newer, long-acting formulations of these drugs. Duration of therapy depends on the patient's response, although few prolactinomas are self-limited. Despite the striking reduction in the size of the tumor prompted by medication, it is never eliminated and lifelong pharmacotherapy is often required to sustain remission.

When a prolactinoma is refractory to medical management or a patient cannot tolerate dopamine agonist medications, then trans-sphenoidal surgery or, more rarely, radiation therapy may be required. These alternatives are avoided as first-line interventions because they carry a high risk of severe complications, especially in cases of macroadenoma.

It is essential to provide long-term follow-up for patients with prolactinoma. Routine monitoring of clinical status, measurement of the prolactin level, examination for visual field changes, and observation of the appearance of the tumor with MRI should be performed every three to six months during the initial phase of therapy. Especially close surveillance is needed during pregnancy and in the peripartum period. Dopamine agonist therapy is discontinued upon recognition of pregnancy, thereby increasing the risk that a macroadenoma will expand and related complications will develop.

Pituitary adenomas, including prolactinomas, are rarely fatal, but associated endocrinopathy may exert a profound effect on the patient's quality of life. Early evaluation and intervention are necessary to prevent permanent consequences of unrestrained tumor growth, especially during vulnerable periods of rapid sexual and skeletal development.

Pediatricians, and parents, often attribute headache to psychosocial stressors, particularly in adolescents, based on a consistent history and physical exam. This may often be true, but these patients should nevertheless be followed carefully for evolving symptoms or clinical changes that suggest an alternative cause. Before you conclude that the problem is all in the patient's head, consider this: It just might be.

[dr.Ira]

Esh!!!!!