Intestinal malrotation

Intestinal malrotation is an abnormality that can happen early in pregnancy when a baby’s intestines don’t form into a coil in the abdomen. Malrotation means that the intestines (or bowel) are twisting, which can cause obstruction (blockage). Some children with intestinal malrotation never have problems and the condition isn’t diagnosed. But most develop symptoms and are diagnosed by 1 year of age. Intestinal malrotation most often isn’t a problem by itself. But it makes a child more likely to have a volvulus (twisted intestine). A volvulus can be very dangerous. That’s why intestinal malrotation needs to be treated, even if your child has no symptoms. Although surgery is needed to repair malrotation, most kids will go on to grow and develop normally after treatment.

Intestinal malrotation occurs in between 1 in 200 and 1 in 500 live births ¹⁾. However, most patients with malrotation are asymptomatic, with symptomatic malrotation occurring in only 1 in 6000 live births ²⁾. Symptoms and diagnosis may occur at any age, with some reports of prenatal diagnosis of intestinal malrotation ³⁾. Male predominance is observed in neonatal presentations at a male-to-female ratio of 2:1. No sexual predilection is observed in patients older than 1 year.

Malrotation may occur as an isolated anomaly or in association with other congenital anomalies; 30-62% of children with malrotation have an associated congenital anomaly. All children with diaphragmatic hernia, gastroschisis, and omphalocele have intestinal malrotation by definition. Additionally, malrotation is seen in approximately 17% of patients with duodenal atresia and 33% of patients with jejunoileal atresia ⁴⁾.

While a baby is still in the womb, its intestines (bowels) form. During normal abdominal development, the 3 divisions of the gastrointestinal tract (i.e., foregut, midgut, hindgut) herniate out from the abdominal cavity, where they then undergo a 270º counterclockwise rotation around the superior mesenteric vessels ⁵⁾. Following this rotation, the bowels return to the abdominal cavity, with fixation of the duodenojejunal loop to the left of the midline and the cecum in the right lower quadrant.

Intestinal malrotation, also known as intestinal nonrotation or incomplete rotation, refers to any variation in this rotation and fixation of the gastrointestinal tract during development. Interruption of typical intestinal rotation and fixation during fetal development can occur at a wide range of locations; this leads to various acute and chronic presentations of disease. The intestines may bend the wrong way. Or, parts of the intestine may end up in the wrong part of the abdomen. Bands of tissue called Ladd bands can grow between the intestines and body wall. These secure the intestines in the wrong place. Ladd bands can also block part of the intestine, causing digestive problems. The most common type found in pediatric patients is incomplete rotation predisposing to midgut volvulus, requiring emergent operative intervention ⁶⁾.

Malrotation can lead to these complications:

• In a condition called volvulus, the bowel twists on itself, cutting off the blood flow to the tissue and causing the tissue to die. Symptoms of volvulus, including pain and cramping, are often what lead to the diagnosis of malrotation.
• Bands of tissue called Ladd’s bands may form, obstructing the first part of the small intestine (the duodenum).
• Obstruction caused by volvulus or Ladd’s bands is a potentially life-threatening problem. The bowel can stop working and intestinal tissue can die from lack of blood supply if an obstruction isn’t recognized and treated. Volvulus, especially, is a medical emergency, with the entire small intestine in jeopardy.

If you suspect any kind of intestinal obstruction because your child has bilious (yellow or green) vomiting, a swollen abdomen, or bloody stools, see your doctor immediately, and take your child to the emergency room right away.

• If the child has only intestinal malrotation, surgery is done. During surgery, any Ladd bands present are cut. The intestines are then moved to where they will be least likely to twist. If the child still has his or her appendix, it will be removed during the surgery.
• If the child has intestinal malrotation with a volvulus, surgery is done right away. The intestine is carefully untwisted. If a portion of intestine has died due to lack of blood flow, this portion must be removed. The healthy ends of the intestine are then reattached. If a long length of intestine is removed, a small opening (stoma) may need to be made in the child’s abdomen. This provides a new way for waste to leave the body. If your child needs a stoma, the doctor will tell you more.

Intestinal malrotation causes

Intestinal malrotation occurs due to disruption of the normal embryologic development of the bowel. The intestines are the longest part of the digestive system. If stretched out to their full length, they would measure more than 20 feet long by adulthood, but because they’re folded up, they fit into the relatively small space inside the abdomen.

When a fetus develops in the womb, the intestines start out as a small, straight tube between the stomach and the rectum. As this tube develops into separate organs, the intestines move into the umbilical cord, which supplies nutrients to the developing embryo.

Near the end of the first trimester of pregnancy, the intestines move from the umbilical cord into the abdomen. If they don’t properly turn after moving into the abdomen, malrotation occurs. It happens in 1 out of every 500 births in the United States and the exact cause is unknown.

Some children with intestinal malrotation are born with other associated conditions, including:

• other defects of the digestive system
• heart defects
• abnormalities of other organs, including the spleen or liver

Intestinal malrotation symptoms

An intestinal blockage can prevent the proper passage of food. So one of the earliest signs of malrotation and volvulus is abdominal pain and cramping, which happen when the bowel can’t push food past the blockage.

A baby with cramping might:

• pull up the legs and cry
• stop crying suddenly
• behave normally for 15 to 30 minutes
• repeat this behavior when the next cramp happens

Infants also may be fussy, lethargic, or have trouble pooping.

Vomiting is another symptom of malrotation, and it can help the doctor determine where the obstruction is. Vomiting that happens soon after the baby starts to cry often means the blockage is in the small intestine; delayed vomiting usually means it’s in the large intestine. The vomit may contain bile (which is yellow or green) or may resemble feces.

Other symptoms of malrotation and volvulus can include:

• a swollen abdomen that’s tender to the touch
• diarrhea and/or bloody poop (or sometimes no poop at all)
• fussiness or crying in pain, with nothing seeming to help
• rapid heart rate and breathing
• little or no pee because of fluid loss
• fever

Intestinal malrotation diagnosis

If volvulus or another intestinal blockage is suspected, the doctor will examine your child and then may order X-rays, a computed tomography (CT) scan, or an abdominal ultrasound.

The doctor may use barium or another liquid contrast agent to see the X-ray or scan more clearly. The contrast can show if the bowel has a malformation and can usually find where the blockage is.

Adults and older kids usually drink barium in a liquid form. Infants may need to be given barium through a tube inserted from the nose into the stomach, or sometimes are given a barium enema, in which the liquid barium is inserted through the rectum.

Intestinal malrotation tests may include:

• Blood tests. Tests to check electrolytes.
• Stool guaiac. A test to detect blood in stool samples.
• Computed tomography scan (CT or CAT scan). A diagnostic imaging procedure using a combination of X-rays and computer technology to produce horizontal, or axial, images (often called slices) of the body. A CT scan shows detailed images of any part of the body, including the bones, muscles, fat, and organs. CT scans are more detailed than general X-rays.
• Abdominal X-ray. A diagnostic test which may show intestinal obstructions.
• Barium swallow/upper GI test. A procedure done to examine the intestine for abnormalities. A fluid called barium (a metallic, chemical, chalky, liquid used to coat the inside of organs so that they will show up on an X-ray) is swallowed. An X-ray of the abdomen may show an abnormal location for the small intestine, obstructions (blockages), and other problems. The upper GI series generally looks at the small intestine while the lower GI series looks at the large intestine.
• Barium enema. A procedure done to examine the intestine for abnormalities. A fluid called barium (a metallic, chemical, chalky, liquid used to coat the inside of organs so that they will show up on an X-ray) is given into the rectum as an enema. An X-ray of the abdomen may show that the large intestine is not in the normal location.
• Flexible sigmoidoscopy. This test, usually only done for volvulus, looks at the lower part of the GI tract, rectum, and colon. It can be used to diagnose the volvulus.

Intestinal malrotation treatment

Treating significant malrotation almost always requires surgery. The timing and urgency will depend on the child’s condition. If there is already a volvulus, surgery must be done right away to prevent damage to the bowel.

Any child with bowel obstruction will need to be hospitalized. A tube called a nasogastric (NG) tube is usually inserted through the nose and down into the stomach to remove the contents of the stomach and upper intestines. This keeps fluid and gas from building up in the abdomen. The child may also be given intravenous (IV) fluids to help prevent dehydration and antibiotics to prevent infection.

During the surgery, which is called a Ladd procedure, the intestine is straightened out, the Ladd’s bands are divided, the small intestine is folded into the right side of the abdomen, and the colon is placed on the left side.

Because the appendix is usually found on the left side of the abdomen when there is malrotation (normally, the appendix is found on the right), it is removed. Otherwise, should the child ever develop appendicitis, it could complicate diagnosis and treatment.

If it appears that blood may still not be flowing properly to the intestines, the doctor may do a second surgery within 48 hours of the first. If the bowel still looks unhealthy at this time, the damaged portion might be removed.

If the child is seriously ill at the time of surgery, an ileostomy or colostomy usually will be done. In this procedure, the diseased bowel is completely removed, and the end of the normal, healthy intestine is brought out through an opening on the skin of the abdomen (called a stoma). Fecal matter (poop) passes through this opening and into a bag that is taped or attached with adhesive to the child’s belly.

In young children, depending on how much bowel was removed, the ileostomy or colostomy is often a temporary condition that can later be reversed with another operation.

Most of these surgeries are successful, although some kids have recurring problems after surgery. Recurrent volvulus is rare, but a second bowel obstruction due to adhesions (scar tissue build-up after any type of abdominal surgery) could happen later.

Children who had a large portion of the small intestine removed can have too little bowel to maintain adequate nutrition (a condition known as short bowel syndrome). They might need intravenous (IV) nutrition for a time after surgery (or even permanently if too little intestine remains) and may require a special diet afterward.

Most kids in whom the volvulus and malrotation are found and treated early, before permanent injury to the bowel happens, do well and develop normally.

Long-term management of growth and nutrition

Patients with short-bowel syndrome are at high risk for failure to thrive. These infants require frequent monitoring of growth parameters during the immediate postoperative period to ensure adequate weight, length, and head circumference gains.

Patients may develop iron, folate, and vitamin B-12 deficiencies due to malabsorption depending on how much bowel is resected.

Outpatient care should be individualized, depending on each patient’s operative and postoperative course.

Development considerations

Children with prolonged hospitalization may experience developmental delays and require aggressive physical, occupational, and speech therapy.

Infants can develop poor truncal control due to prolonged periods in the supine position while hospitalized, additionally they may develop contractures in the extremities, or feeding aversion due to prolonged periods with nasogastric tubes in place and taking nothing by mouth.

Developmental delays should be monitored in both inpatient and outpatient settings and should be intervened upon as early as possible ⁷⁾.

Intestinal malrotation complications

Complications include the following:

Short-bowel syndrome

Short-bowel syndrome is the most common complication of midgut volvulus. These patients have longer delays to recovery of bowel motility and function. They are at high risk for malabsorption and can require long-term parenteral nutrition. Furthermore, these patients have more complications from treatment and longer hospital stays than patients with malrotation without volvulus.

Infection

Wound infections and sepsis can occur in the immediate postoperative period, requiring extended treatment with intravenous antibiotics. Additionally, central venous catheters have the potential to become infected causing bacteremia and/or sepsis

Surgical complications

Postoperative and surgical complications are more likely to occur in those patients with acute symptoms than those with chronic symptoms ⁸⁾. One review reported an overall complication rate of 8.7% (14 of 161) following Ladd procedure ⁹⁾. Complications reported include adhesive small bowel obstruction in 6% with 5 requiring reoperation (3%), and 1 patient developed recurrent volvulus (1%). A second review showed comparable rates of recurrent volvulus (2%, 1 of 57) and reoperation for adhesive small bowel obstruction (2%, 1 of 57) ¹⁰⁾. Other series have reported lower rates of recurrent volvulus, 0.4% in one series of 441 patients, and 0.6% in a series of 159 patients who underwent Ladd’s procedure ¹¹⁾.

Persistent gastrointestinal symptoms

In the same series of 57 patients, 13 had persistent (>6 months) gastrointestinal symptoms, including constipation (6), intractable diarrhea (1), abdominal pain (2), vomiting (3), and feeding difficulties (1) following Ladd procedure ¹²⁾.

Mortality

Death occurs due to peritonitis, late nutritional complications, or catheter-related sepsis. Rates are increased among children younger than one year. Following Ladd procedure, mortality rates reported in the literature are as low as 2% ¹³⁾. However, if more than 75% of the bowel is necrotic, mortality is as high as 65% ¹⁴⁾.

Intestinal malrotation prognosis

Prognosis is dependent on the presence of ischemic or necrotic bowel, the amount of bowel resected, and the age of the child. In general, older children have improved morbidity and mortality compared to infants. The presence of midgut volvulus is associated with prolonged hospital length of stay. Long-term prognosis is dependent on how much bowel is resected and the development of short-bowel syndrome.

What is hepatoblastoma

Hepatoblastoma is a very rare type of liver cancer that occurs in infants and children accounting for 80% of malignant liver tumors in childhood ¹⁾. Hepatoblastoma typically striking children within the first 3 years of their young lives ²⁾. Hepatoblastoma preferentially affects boys and occurs in infants or very young children at a median age at diagnosis of 16 months ³⁾. Hepatoblastoma incidence is estimated at 1.2–1.5 million children per year, comprising about 1% of all pediatric cancers ⁴⁾. Over the last 3 decades, advances in chemotherapy and newer surgical techniques have improved survival in patients with localized hepatoblastoma, unfortunately, for the 25% of patients with metastasis (hepatoblastoma stage 4), the overall survival remains poor. The treatment has advanced with neo-adjuvant chemotherapy now the standard of care for most cases. Neo-adjuvant chemotherapy and surgical resection produce a cure rate of approximately 70%, a vast improvement over the dismal 30% cure rate in the 1970s ⁵⁾. Prognosis is based on many factors including alpha-fetoprotein (AFP) levels, age at the time of diagnosis, completeness of resection, and clinical stage of the disease ⁶⁾.

What causes hepatoblastoma?

Most cases of hepatoblastoma have unknown cause, but one-third of cases occur in association with specific predisposition syndromes in the setting of normal liver function ⁷⁾. Hepatoblastoma is strongly associated with premature birth, particularly among low birth weight neonates that weigh < 1,000 g ⁸⁾. Hepatoblastoma occurs in children from families affected by familial adenomatous polyposis (FAP), which is associated with an inherited germ line mutation of the adenomatous polyposis coli (APC) gene ⁹⁾. This mutation is also seen in association with Beckwith-Wiedemann syndrome, with which the relative risk of hepatoblastoma is estimated to be 2,280 ¹⁰⁾. Hepatoblastoma has also been observed in patients with Li-Fraumeni syndrome, Edward syndrome (trisomy 18), nephroblastoma, and Down syndrome (trisomy 21) ¹¹⁾. Evidence has also shown an association with preeclampsia and parental tobacco smoking before and during pregnancy ¹²⁾. Other factors thought to play a role in pathogenesis include oxygen therapy, certain medication (furosemide), radiation, plasticizers, and total parenteral nutrition (TPN) ¹³⁾.

The most common genetic mutation involves the Wnt signaling pathway which results in the accumulation of beta-catenin; these mutations are present in a higher proportion of the sporadic cases ¹⁴⁾. By immunohistochemistry, beta-catenin usually shows a membranous staining pattern in the more differentiated fetal types and nuclear staining pattern in the less differentiated histologic types ¹⁵⁾. In aggressive cases, activation of TERT (human telomerase reverse transcriptase) and MYC signaling has been shown ¹⁶⁾.

An American Association for Cancer Research publication suggested that all children with more than a 1% risk of developing hepatoblastoma be screened ¹⁷⁾. This includes patients with Beckwith-Wiedemann, hemihyperplasia, Simpson-Golabi-Behmel, and trisomy 18 syndromes. Screening is by abdominal ultrasound and alpha-fetoprotein determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children ¹⁸⁾.

Risk factors for hepatoblastoma

Conditions associated with an increased risk of hepatoblastoma are described in Table 1.

Table 1. Conditions associated with hepatoblastoma

Associated Disorder	Clinical Findings
Aicardi syndrome 19)	Refer to the Aicardi syndrome section of this summary for more information.
Beckwith-Wiedemann syndrome 20)	Refer to the Beckwith-Wiedemann syndrome and hemihyperplasia section of this summary for more information.
Familial adenomatous polyposis 21)	Refer to the Familial adenomatous polyposis section of this summary for more information.
Glycogen storage diseases I–IV 22)	Symptoms vary by individual disorder.
Low-birth-weight infants 23)	Preterm and small-for-gestation-age neonates.
Simpson-Golabi-Behmel syndrome 24)	Macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of Wilms tumor.
Trisomy 18, other trisomies 25)	Trisomy 18: Microcephaly and micrognathia, clenched fists with overlapping fingers, and failure to thrive. Most patients (>90%) die in the first year of life.

[Source ²⁶⁾ ]

Aicardi syndrome

Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found ²⁷⁾.

Beckwith-Wiedemann syndrome and hemihyperplasia

The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome ²⁸⁾. The risk of hepatoblastoma is also increased in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal ²⁹⁾.

Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma ³⁰⁾. The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome ³¹⁾. When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2 ³²⁾. The genetics of tumors in children with hemihyperplasia have not been clearly defined.

To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasonography ³³⁾. Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children ³⁴⁾. Because the hepatoblastomas that are discovered early are small, it has been suggested to minimize the use of adjuvant therapy after surgery ³⁵⁾. However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C mutation ³⁶⁾. The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.

Familial adenomatous polyposis

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial ³⁷⁾. However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline mutations ³⁸⁾.

Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5′ region of the gene, but some patients had mutations closer to the 3′ region ³⁹⁾. This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.

In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, hepatoblastomas frequently have mutations in the beta-catenin gene, the function of which is closely related to APC ⁴⁰⁾.

Hepatoblastoma histopathology

The cells of hepatoblastoma are similar to fetal liver cells. The histologic types are subdivided into 2 broad categories: epithelial type and mixed type ⁴¹⁾. Hepatoblastomas originate from primitive hepatic stem cells that give rise to the epithelial components of the liver. Classically, these tumors are divided into 2 broad categories: epithelial type (E-HB) and mixed epithelial and mesenchymal type (MEM-HB). Revision of this original classification system resulted in the pathology consensus of the pediatric hepatoblastoma classification system, which retained the subdivision of the histologic types into 2 broad categories, as described above. The epithelial type is subdivided into fetal, embryonal, macrotrabecular small cell undifferentiated and cholangioblastic variants, while the mixed type is subdivided into stromal derivatives and teratoid variants.

The fetal subtype is further stratified into 4 categories: well-differentiated; crowded or mitotically active; pleomorphic, poorly differentiated; and anaplastic. The well-differentiated variant is characterized by a low power view demonstrating alternating light and dark areas due to variable cytoplasmic glycogen content. Assessment at higher power reveals a uniform population of hepatocytes arranged in trabeculae that are 2to 3 cells thick. Extramedullary hematopoiesis is a typical finding, and mitotic rate is low. Description of the other variants is beyond the scope of this article.

The embryonal subtype is the most commonly encountered subtype and consists of basophilic cells with scant cytoplasm and increased mitotic rate that is arranged in nests, trabeculae, acini, pseudorosettes, or sheets. The macrotrabecular subtype is arranged in trabeculae that are more than ten cells thick. The SCU subtype consists of dyscohesive, uniform round cells arranged in sheets with increased mitotic activity. Some cases of SCU have a loss of INI1, suggesting a possible association with primary rhabdoid tumors of the liver. The cholangioblastic variant has bile ducts, typically located at the periphery of the epithelial sheets.

The mixed subtype contains a variable combination of epithelial and mesenchymal components. Most commonly, the epithelial component is fetal or embryonal, and the mesenchymal component is osteoid. Stromal derivatives include spindle cells, osteoid, skeletal muscle, and cartilage. Teratoid features include primitive endoderm, neural derivatives, melanin, squamous and glandular elements ⁴²⁾.

Hepatoblastoma symptoms

Hepatoblastomas usually present with as a single, mildly painful, rapidly enlarging abdominal mass that arises in the right lobe of the liver in 55% to 60% of cases ⁴³⁾. Rapid enlargement of these tumors rarely results in tumor rupture and hemorrhage. Hepatoblastoma tumors may reach up to 25 cm in size. Most tumors are solitary; however, up to 15% of tumors are multifocal. Some cases are associated with non-specific symptoms such as weight loss, failure to thrive or anorexia ⁴⁴⁾. Significant elevations of alpha-fetoprotein (AFP) are observed in 90% of patients, and rarely, a paraneoplastic syndrome can occur.

Hepatoblastoma complications

Hepatoblastoma complications include:

• Intraperitoneal tumor rupture
• Complications related to chemotherapy
• Post-transplant complications
• Psychosocial effects of treatment and painful procedures

Hepatoblastoma diagnosis

Ultrasound and either computed tomography (CT) or magnetic resonance imaging (MRI) are the imaging modalities used to define the extent of tumor involvement of the liver and aid in pre-surgical planning. A chest CT can help detect lung metastasis as up to 20% of cases present with metastases; the lung is the most common location of metastases ⁴⁵⁾. After imaging, a biopsy, alpha-fetoprotein (AFP) level, liver function tests, and a hepatitis panel are performed as needed.

Biopsy

A biopsy of a pediatric liver tumor is always indicated to secure the diagnosis of a liver tumor, with the exception of the following circumstances:

• Infantile hepatic hemangioma. Biopsy is not indicated in infantile hemangioma of the liver with classic findings on magnetic resonance imaging (MRI). If the diagnosis is in doubt after high-quality imaging, a confirmatory biopsy is done.
• Focal nodular hyperplasia. Biopsy may not be indicated or may be delayed in focal nodular hyperplasia with classic features on MRI using hepatocyte-specific contrast agent. If the diagnosis is in doubt, a confirmatory biopsy is done.
• Children’s Oncology Group (COG) surgical guidelines ⁴⁶⁾ recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRE-Treatment EXTent of disease (PRETEXT) group I tumors and PRETEXT group II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Therefore, biopsy is not usually recommended in this circumstance.
• Infantile hepatic choriocarcinoma. In infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG), chemotherapy without biopsy is often indicated ⁴⁷⁾.

Tumor markers

The AFP and beta-hCG tumor markers are very helpful in the diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancy, it is not pathognomonic for a malignant liver tumor ⁴⁸⁾. The AFP level can be elevated with either a benign tumor or a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL ⁴⁹⁾.

Hepatoblastoma staging

The Children’s Hepatic Tumors International Collaboration constructed a staging and risk stratification system intended to standardize the assessment of hepatoblastoma cancer across the globe. This new staging system is called the Children’s Hepatic Tumors International Collaboration – Hepatoblastoma Stratification and incorporates confirmed prognostic factors from prior risk stratification systems with new additional factors to stratify patients into 4 risk groups.

Found to be most predictive are alpha-fetoprotein (AFP) levels, patient age, Pretreatment Extent of Disease (PRETEXT) group (I, II, III, or IV), the presence of metastases, and PRETEXT annotation factor. PRETEXT group is based on the extent of the tumor in the liver. PRETEXT annotation factor is determined to be positive if at least 1 of the following 5 factors are present: involvement of the vena cava or all 3 hepatic veins, or both (V); involvement of portal bifurcation or both right and left portal veins, or both (P); extrahepatic contiguous tumor extension (E); multifocal liver tumor (F); tumor rupture at diagnosis (R). Gender, low birth weight, prematurity, and Beckwith-Wiedemann syndrome were not found to be significant. Of note, the histologic type was not included in this risk stratification system but may be incorporated at a future date. Validation of these risk groups is in progress ⁵⁰⁾.

Table 2. Definitions of PRETEXT/POST-TEXT group (I, II, II, IV) and PRETEXT grouping system annotations V,P,E,M,C,F,N,R.

PRETEXT/POST-text group	Definition
I	One liver section involved
	Three adjoining sections are tumor free
II	One or two liver sections involved
	Two adjoining sections are tumor free
III	Two or three liver sections involved
	One adjoining section is tumor free
IV	Four liver sections involved
Annotation:
V	Venous involvement, V, denotes vascular involvement of the retrohepatic vena cava or involvement of ALL THREE major hepatic veins (right, middle, and left)
P	Portal involvement, P, denotes vascular involvement of the main portal vein and/or BOTH right and left portal veins
E	Extrahepatic involvement of a contiguous structure such as the diaphragm, abdominal wall, stomach, colon, etc.
M	Distant metastatic disease (usually lungs, occasionally bone or brain)
C	Caudate lobe
F	Multifocal tumor nodules
N	Lymph node involvement
R	Tumor rupture

[Source ⁵¹⁾ ]

Hepatoblastoma prognostic factors

Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy ⁵²⁾. A collaborative group consisting of four study groups (International Childhood Liver Tumors Strategy Group [SIOPEL], Children’s Oncology Group, Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH], and Japanese Study Group for Pediatric Liver Tumor [JPLT]), termed Childhood Hepatic tumor International Collaboration (CHIC), have retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. The CHIC published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS) ⁵³⁾. The analysis confirmed many of the findings described below. The statistically significant adverse factors included the following ⁵⁴⁾:

• Higher PRETEXT group.
• Positive PRETEXT annotation factors:
  • V: Involvement all three hepatic veins and/or intrahepatic inferior vena cava.
  • P: Involvement of both left and right portal veins.
  • E: Contiguous extrahepatic tumor extensions (e.g., diaphragm, adjacent organs).
  • F: Multifocal tumors.
  • R: Tumor rupture.
  • M: Distant metastases, usually lung.
• Low AFP level (<100 ng/mL or 100–1,000 ng/mL to account for infants with elevated AFP levels) ⁵⁵⁾.
• Older age. Patients aged 3 to 7 years have a worse outcome in the PRETEXT IV group ⁵⁶⁾. Patients aged 8 years and older have a worse outcome than do younger patients in all PRETEXT groups.
  In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT, annotation factors, and outcomes similar to that of older children undergoing the same treatment ⁵⁷⁾.

In contrast, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on event-free survival ⁵⁸⁾.

A multivariate analysis of these prognostic factors has been published to help develop a new risk group classification for hepatoblastoma ⁵⁹⁾. This classification was used to generate a risk stratification schema to be used in international clinical trials.

Other studies of factors affecting prognosis observed the following:

• PRETEXT group: In SIOPEL studies, having a low PRETEXT group at diagnosis (PRETEXT I, II, and III tumors) is a good prognostic factor, whereas PRETEXT IV is a poor prognostic factor.[42] (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information.)
• Tumor stage: In Children’s Oncology Group studies, stage I tumors that were resected at diagnosis and tumors with well-differentiated fetal histology have a good prognosis. These tumors are treated differently than tumors of other stages and histologies ⁶⁰⁾.
• Treatment-related factors:
  • Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[45-49] Favorable response of the primary tumor to chemotherapy, defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels, predicted the resectability of the tumor; in turn, this favorable response predicted overall survival among all CHIC risk groups treated with neoadjuvant chemotherapy on the JPLT-2 Japanese national clinical trial.[50][Level of evidence: 2A]
  • Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, most patients survive, but because of vascular or other involvement, less than one-third of patients have lesions amenable to complete resection at diagnosis ⁶¹⁾. Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon; the surgeon should be experienced in the techniques of extreme liver resection with vascular reconstruction and have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the rate of overall survival ⁶²⁾. Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy ⁶³⁾; however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome ⁶⁴⁾. This may be due to the additional courses of chemotherapy that are administered before or after resection ⁶⁵⁾.
• Tumor marker–related factors: Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy ⁶⁶⁾. Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[42] Some of these variants do not express INI1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of INI1 expression by immunohistochemistry ⁶⁷⁾. Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys ⁶⁸⁾.
• Tumor histology.

Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted event-free survival ⁶⁹⁾. In an analysis of the intergroup U.S. study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV ⁷⁰⁾.

Hepatoblastoma treatment

Treatment options for newly diagnosed hepatoblastoma depend on the following:

• Whether the cancer is resectable at diagnosis.
• The tumor histology.
• How the cancer responds to chemotherapy.
• Whether the cancer has metastasized.

Surgical resection is the mainstay of treatment with resectability of the tumor determining the need for neo-adjuvant or adjuvant chemotherapy. At presentation, approximately 60% of tumors are unresectable ⁷¹⁾. If unresectable and chemotherapy fails to shrink the tumor to a resectable size, a liver transplant can be done and has a good long-term survival rate ⁷²⁾. The benefit of radiation therapy is unclear, with some unresectable cases responding well. Alpha-fetoprotein levels are useful for tracking surgical success and whether the tumor has metastasized ⁷³⁾. An increased risk of post-transplant lymphoproliferative disorder after immunosuppression for liver transplant has been suggested in some publications ⁷⁴⁾.

Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy ⁷⁵⁾.

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 3.

Table 3. Outcomes for Hepatoblastoma Multicenter Trials

Study	Chemotherapy Regimen	Number of Patients	Outcomes
INT0098 (CCG/POG) 1989–1992	C5V vs. CDDP/DOXO	Stage I/II: 50	4-Year Event-Free Survival/Overall Survival:
			I/II = 88%/100% vs. 96%/96%
		Stage III: 83	III = 60%/68% vs. 68%/71%
		Stage IV: 40	IV = 14%/33% vs. 37%/42%
P9645 (COG)b 1999–2002	C5V vs. CDDP/CARBO	Stage I/II: Pending publication	1-Year Event-Free Survival:
			I/II: Pending publication
		Stage III: 38	III/IV: C5V = 51%; CDDP/CARBO = 37%
		Stage IV: 50
HB 94 (GPOH) 1994–1997	I/II: IFOS/CDDP/DOXO	Stage I: 27	4-Year Event-Free Survival/Overall Survival:
			I = 89%/96%
		Stage II: 3	II = 100%/100%
	III/IV: IFOS/CDDP/DOXO + VP/CARBO	Stage III: 25	III = 68%/76%
		Stage IV: 14	IV = 21%/36%
HB 99 (GPOH) 1999–2004	SR: IPA	SR: 58	3-Year Event-Free Survival/Overall Survival:
			SR = 90%/88%
	HR: CARBO/VP16	HR: 42	HR = 52%/55%
SIOPEL-2 1994–1998	SR: PLADO	PRETEXT I: 6	3-Year Event-Free Survival/Overall Survival:
			SR: 73%/91%
		PRETEXT II: 36
		PRETEXT III: 25
	HR: CDDP/CARBO/DOXO	PRETEXT IV: 21	HR: IV = 48%/61%
		Metastases: 25	HR: metastases = 36%/44%
SIOPEL-3 1998–2006	SR: CDDP vs. PLADO	SR: PRETEXT I: 18	3-Year Event-Free Survival/Overall Survival:
			SR: CDDP = 83%/95%; PLADO = 85%/93%
		PRETEXT II: 133
		PRETEXT III: 104
	HR: SUPERPLADO	HR: PRETEXT IV: 74	HR: Overall = 65%/69%
		VPE+: 70
		Metastases: 70	Metastases = 57%/63%
		AFP <100 ng/mL: 12
SIOPEL-4 2005–2009	HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXO	PRETEXT I: 2	3-Year Event-Free Survival/OS:
			All HR = 76%/83%
		PRETEXT II: 17
		PRETEXT III: 27
		PRETEXT IV: 16	HR: IV = 75%/88%
		Metastases: 39	HR: Metastases = 77%/79%
JPLT-1 1991–1999	I/II: CDDP(30)/THP-DOXO	Stage I: 9	5-Year Event-Free Survival/Overall Survival:
			I = NR/100%
		Stage II: 32	II = NR/76%
	III/IV: CDDP(60)/THP-DOXO	Stage IIIa: 48	IIIa = NR/50%
		Stage IIIb: 25	IIIb = NR/64%
		Stage IV: 20	IV = NR/77%
JPLT-2 1999–2010	I: Low-dose CDDP-pirarubicin	PRETEXT I–IV: 212	5-Year Event-Free Survival/Overall Survival:
			I = NR/100%
	II–IV: CITA		II = NR/89%
			III = NR/93%
			IV = NR/63%
	Metastases: High dose chemotherapy + stem cell transplant		Metastases = 32%

Abbreviations: AFP = alpha-fetoprotein; C5V = cisplatin, 5-fluorouracil (5FU), and vincristine; CARBO = carboplatin; CCG = Children’s Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children’s Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; JPLT = Japanese Study Group for Pediatric Liver Tumor; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.

Footnote: (a) Adapted from Czauderna et al. ⁷⁶⁾ and Meyers et al. ⁷⁷⁾; (b) Study closed early because of inferior results in the CDDP/CARBO arm.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. Children’s Oncology Group (COG) surgical guidelines recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery ⁷⁸⁾.

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

1. Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
2. Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant ⁷⁹⁾.
3. Transarterial chemoembolization (TACE). TACE may be used to improve resectability before definitive surgical approaches ⁸⁰⁾.

In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection ⁸¹⁾. Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease ⁸²⁾. In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant ⁸³⁾. In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical ⁸⁴⁾. In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):

1. In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed ⁸⁵⁾.
   • The chemotherapy was well tolerated.
   • Complete resection was obtained in 87% of children.
   • This strategy resulted in an overall survival rate of 75% at 5 years after diagnosis.
2. Identical results were seen in a follow-up international study (SIOPEL-2) ⁸⁶⁾.
3. The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and not involving more than three sectors ⁸⁷⁾.
   • The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
   • The overall survival rates were also similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
4. In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma ⁸⁸⁾.
   • In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year overall survival of this group was 69% (± 11%).
   • Of the 70 patients with metastases enrolled in the trial, the 3-year event-free survival rate was 56% and the overall survival rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
5. SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients whose tumors were resected or whose livers were transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT II (27%), III (44%), and IV (26%) ⁸⁹⁾.
   • Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
   • Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
   • Two patients died postoperatively.
   • There were 37 partial hepatectomies and 16 liver transplants.
   • The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection. The 3-year disease-free survival (DFS) was 76% and the 3-year overall survival was 83%.
   • Of the 16 PRETEXT IV patients, 11 were downstaged after chemotherapy—6 patients to PRETEXT III, 4 patients to PRETEXT II, and 1 patient to PRETEXT I. Twelve tumors became resectable; of these, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease, the 3-year disease-free survival (DFS) was 73% and the 3-year overall survival was 80%.
6. In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free ⁹⁰⁾.
7. A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease ⁹¹⁾.

In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant ⁹²⁾. On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy ⁹³⁾. Some European centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant ⁹⁴⁾.

Chemotherapy followed by transarterial chemoembolization (TACE) followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal ⁹⁵⁾.

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible ⁹⁶⁾. Survival rates at 3 to 5 years range from 20% to 79% ⁹⁷⁾. To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial) ⁹⁸⁾.

Treatment options for hepatoblastoma with metastases at diagnosis include the following:

• Chemotherapy followed by reassessment of surgical resectability.
  • If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection followed by additional chemotherapy.
  • If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant.
  • If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, transarterial chemoembolization (TACE), or radiation therapy.

The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil ⁹⁹⁾ or doxorubicin/cisplatin ¹⁰⁰⁾ followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported.

High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy ¹⁰¹⁾.

Evidence (chemotherapy to treat metastatic disease at diagnosis):

• A subset of 39 patients presenting with metastases were entered on the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients whose tumors were resected or livers transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery ¹⁰²⁾.
  • After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
  • Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient recurred.
  • Two patients with initial metastases eventually recurred.
  • Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
  • For the subset of 39 patients presenting with metastases, the 3-year disease-free survival was 77% and the overall survival was 79%.

In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible ¹⁰³⁾. A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor ¹⁰⁴⁾.

If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed ¹⁰⁵⁾.

The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups ¹⁰⁶⁾, while others have noted high rates of hepatoblastoma recurrence ¹⁰⁷⁾. All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease ¹⁰⁸⁾.

If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:

• Nonstandard chemotherapy agents. Nonstandard chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used ¹⁰⁹⁾.
• Hepatic arterial chemoembolization (HACE) or transarterial chemoembolization (TACE) ¹¹⁰⁾.
• Radiation therapy ¹¹¹⁾.

Treatment options for progressive or recurrent hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following ¹¹²⁾:

• Site of recurrence.
• Previous treatment.
• Individual patient considerations.

Treatment options for progressive or recurrent hepatoblastoma include the following:

1. Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes appropriate chemotherapy, may make extended disease-free survival possible ¹¹³⁾. If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[108] A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year Event-Free Survival was 34%, and the Overall Survival was 43% ¹¹⁴⁾. Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma ¹¹⁵⁾. Enrollment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. Phase I and phase II clinical trials may be appropriate and should be considered.
2. Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil ¹¹⁶⁾. Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the COG study AHEP0731 [NCT00980460]. Combined vincristine/irinotecan and single-agent irinotecan have been used with some success ¹¹⁷⁾. A review of Children’s Oncology Group (COG) phase I and II studies found no promising agents for relapsed hepatoblastoma ¹¹⁸⁾.
3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection ¹¹⁹⁾.
4. Percutaneous ablation. Percutaneous ablation techniques may also be considered for palliation ¹²⁰⁾ or, in some cases, for curative therapy of oligometastatic disease ¹²¹⁾.

Hepatoblastoma prognosis

Prognosis is based on numerous factors including age of diagnosis, PRETEXT group, metastases, alfa fetal protein (AFP) levels, histologic subtype, completeness of resection, and clinical stage of the disease. With certainty, the well-differentiated fetal subtype is associated with a better prognosis compared with small cell undifferentiated and macrotrabecular, which are linked to unfavorable prognosis ¹²²⁾. Alfa-fetoprotein is typically high upon diagnosis, but a significant drop after neo-adjuvant chemotherapy portends a better response to treatment. Younger age of diagnosis has historically been a poor prognostic factor; however, recent studies have called this into question, providing evidence that these younger patients do just as well as older children ¹²³⁾. Specifically, children younger than 1 year of age have a better prognosis and children greater than 6 years of age have a worse prognosis ¹²⁴⁾. Tumor presence at the resection margin, multifocality, and metastases have been shown to be poor prognostic factors. Beta-catenin expression has been shown to be associated with a lower period of event-free survival, while EpCAM expression has been associated with higher tumor viability and a poorer response to neo-adjuvant chemotherapy ¹²⁵⁾.

Hepatoblastoma survival rate

The 5-year overall survival rate for children with hepatoblastoma is 70% ¹²⁶⁾. Neonates with hepatoblastoma have outcomes comparable to older children up to age 5 years ¹²⁷⁾.

Children with MS

MS in children is not that different from MS in adults. Children with MS exclusively have a relapsing-remitting MS. This form of MS is characterized by recurring attacks (relapses) causing new or worsening neurologic symptoms, followed by periods without new symptoms, called remissions. During the periods of remission between attacks, there is no progression of the multiple sclerosis disease. Even though children may experience frequent relapses (possibly more than typically seen in adults), studies have shown that children also seem to have very good recovery that is often more rapid than that of adults ¹⁾.

Multiple sclerosis (MS) is thought to be an autoimmune disease that attacks the central nervous system (CNS), causing episodes of neurologic symptoms. These neurologic symptoms may include weakness, numbness, tingling, difficulty balancing, bowel or bladder problems, or changes to vision.

The central nervous system consists of the brain, spinal cord and optic nerves. MS primarily attacks the coating around nerve cells called myelin. The attacks leave spots (called plaques or lesions) that interfere with nerve conduction and produces the symptoms of MS. Symptoms of multiple sclerosis vary depending on the location of lesions.

Multiple sclerosis affects about 1 in 1,000 people. About 450,000 people in the United States and Canada are living with multiple sclerosis. Less than 5,000 children and teens are living with MS in the United States and less than 10,000 worldwide.

Multiple sclerosis is more common in women than in men. It is more common in Caucasians than in Hispanics or African Americans, and more common in temperate areas of the world away from the Equator. It is rare in Asians and other groups.

Diagnosing MS in children is more challenging than in adults because of other childhood disorders with similar symptoms and characteristics. At the time of a first attack, it is not always clear whether the diagnosis of MS is appropriate since relapsing disease has not yet occurred. New relapses or attacks will confirm your child’s diagnosis and provide insight to help their doctors better manage their care.

Although the peak age of diagnosis is between 20 to 50 years old, approximately 2.7% to 5% of people are diagnosed before the age of 16, with the majority of these cases diagnosed after the age of 10.

The treatment of MS in children and teens, as well as adults, involves several strategies:

• Modifying the disease course
• Managing relapses
• Maximizing lifestyle interventions
• Managing symptoms

There are medications that are effective at preventing relapses and disability accumulation known as disease modifying therapies (DMTs). More than a dozen DMTs are approved by the U.S. Food and Drug Administration (FDA) to treat adults with relapsing forms of MS. In May 2018, the FDA approved the use of the oral MS therapy Gilenya® (fingolimod) for the treatment of children and adolescents 10 years of age or older with relapsing forms of MS.

Many of the medications used for adults with MS have been studied in children with MS. Skilled pediatric MS healthcare providers can adapt the treatments with FDA approval in adults for their younger patients.

What does the future hold for my child with MS?

The course of MS is difficult to predict and varies from person to person, so predicting exactly how it will affect each child is not possible. Most children have relapsing remitting MS, with periods of good, if unpredictable, recovery.

Some children can be more severely affected, but rapid progression is rare. MS is not a terminal illness. Like diabetes, it’s known as a chronic or long-term condition that needs to be managed for life. Most people with MS live a normal life span, with perhaps a five to 10 year reduction in average life expectancy. Of course averages aren’t always helpful and everyone’s MS is different. With recent advances in medicine, the gap in life expectancy appears to be getting smaller.

Multiple sclerosis life expectancy

It is generally very difficult to predict the course of multiple sclerosis. The condition varies greatly in each individual but most people with multiple sclerosis can expect 95% of the normal life expectancy ²⁾.

Some studies have shown that people who have few attacks in the first several years after diagnosis; long intervals between attacks; complete recovery from attacks and attacks that are sensory in nature (i.e. numbness or tingling) tend to have better outcomes in the long run.

People who have early symptoms of tremor, difficulty in walking, or who have frequent attacks with incomplete recoveries tend to have a more progressive disease course.

What is neuromyelitis optica (NMO)?

Children may also develop neuromyelitis optica (NMO). In NMO, immune system cells and antibodies attack and destroy myelin in the optic nerves and the spinal cord, causing optic neuritis (resulting in pain in the eye and vision loss) and transverse myelitis (causing weakness, numbness and sometimes paralysis or the arms and legs, as well as bladder and bowel problems).

The discovery of an antibody (NMO-IgG) in the blood of individuals with NMO now makes it possible to distinguish NMO from MS. NMO attacks are more severe than those seen in MS and in early disease are generally confined to optic nerves and the spinal cord.

Types of MS

MS can affect people very differently and one of the most frustrating aspects of the condition is its unpredictability – not knowing what symptoms may arise, when, or how long they will last.

The most common form of multiple sclerosis is known as relapsing-remitting MS ~ 90 percent of cases. When people who have this kind of MS have flare-ups, the symptoms become noticeably worse. Then there is a period of recovery, when symptoms get better or disappear completely for some time. In relapsing-remitting MS, symptom flare-ups may be triggered by an infection, such as the flu. More than 50% of people who have relapsing-remitting MS develop the secondary progressive type in which there are relapses followed by a gradual worsening of the disease. About 15% to 20% of people who have MS have a form known as primary-progressive MS. In primary-progressive MS, the disease gets steadily worse, without any remissions. A fourth type—progressive relapsing MS—is rare, but the pattern follows a worsening of the disease with sudden, clear relapses. Often MS is mild, but some people lose the ability to write, speak or walk.

Relapsing remitting MS

Most people with MS, including almost all children, are first diagnosed with relapsing remitting MS. This means they experience a relapse or flare up of symptoms (also known as an attack or exacerbation) followed by a period of stability between relapses when symptoms settle down or disappear. This period of stability is known as remission. Remissions can last any length of time, even years. No one knows exactly what makes MS go into remission.

A relapse is defined as the appearance of new symptoms, or the return of old symptoms, that last for at least 24hours, and occur at least 30 days since the start of any previous relapse. If your child has a fever caused by an infection, or becomes overheated from exercise or hot weather, his or her symptoms may worsen temporarily. But this flare-up of symptoms is caused by an elevated body temperature, rather than by new MS activity, and the symptoms will fade as your child’s body temperature returns to normal. This is known as a ‘pseudo relapse’.

Relapses can take a few days to develop and can last for days, weeks or months. Symptoms can be mild or severe. Most children recover well from relapses. In the early stages of relapsing remitting MS, symptoms can disappear completely during remissions. However, after several relapses there may be some residual damage to the myelin, meaning that some symptoms may remain. These accumulating symptoms may cause your child difficulty, even if only mild.

Figure 1. Relapsing-remitting MS

Secondary progressive MS

Many people who start out with relapsing remitting MS later develop a form that is known as secondary progressive MS. In secondary progressive MS, people experience fewer relapses, or none at all, and the disease slowly progresses over time.

In general, people who develop MS in childhood have a slower rate of progression than people who are diagnosed with MS in adulthood. It is difficult to give exact figures, and even harder to make accurate predictions for individual children. In the largest study to date looking at progression in childhood- onset MS, 50 per cent of people whose MS started before the age of 16 had developed secondary progressive MS after 28 years.

Figure 2. Secondary progressive MS

Benign MS

People with relapsing remitting MS who only have a small number of relapses, followed by a complete recovery, may be described as having benign MS. It is only possible to make a diagnosis of benign MS once a person has experienced little or no physical or cognitive disability for a period of 20 years.

However, a diagnosis of benign MS does not mean that a person will be totally free of problems; a relapse may occasionally occur after many years in which the MS has been inactive. Perhaps around 10 percent of people with MS will have a benign form of the condition.

Primary progressive MS

Primary progressive MS is rare in children, with less than five percent of children with MS being diagnosed with this form. It tends to be diagnosed in older people, usually in their forties or later. From the outset, those with primary progressive MS experience steadily worsening symptoms and an increase in disability. Symptoms may level off for a time, or may continue to worsen, often with no relapses. Approximately 10 to 15 percent of adults with MS have the primary progressive form.

Figure 3. Primary progressive MS

Multiple sclerosis in children causes

The cause of multiple sclerosis is still unknown. It’s considered an autoimmune disease in which the body’s immune system attacks its own tissues. In the case of MS, this immune system malfunction destroys myelin (the fatty substance that coats and protects nerve fibers in the brain and spinal cord).

Myelin can be compared to the insulation coating on electrical wires. When the protective myelin is damaged and nerve fiber is exposed, the messages that travel along that nerve may be slowed or blocked. The nerve may also become damaged itself.

It isn’t clear why MS develops in some people and not others. A combination of genetics and environmental factors appears to be responsible.

Researchers believe there is a genetic predisposition that is triggered by some environmental factor, such as a viral infection. That means that MS is not genetically passed down from one generation to the next, like hair color or eye color, but a combination of genes can make one person more susceptible to the disease than another person. Subsequently, the average risk of developing multiple sclerosis is 1 in 750, but the risk of a child whose parent has MS is 1 in 40.

Risk factors for multiple sclerosis

These factors may increase your risk of developing multiple sclerosis:

• Age. MS can occur at any age, but most commonly affects people between the ages of 15 and 60.
• Sex. Women are about twice as likely as men are to develop MS.
• Family history. If one of your parents or siblings has had MS, you are at higher risk of developing the disease.
• Certain infections. A variety of viruses have been linked to MS, including Epstein-Barr, the virus that causes infectious mononucleosis.
• Race. White people, particularly those of Northern European descent, are at highest risk of developing MS. People of Asian, African or Native American descent have the lowest risk.
• Climate. MS is far more common in countries with temperate climates, including Canada, the northern United States, New Zealand, southeastern Australia and Europe.
• Certain autoimmune diseases. You have a slightly higher risk of developing MS if you have thyroid disease, type 1 diabetes or inflammatory bowel disease.
• Smoking. Smokers who experience an initial event of symptoms that may signal MS are more likely than nonsmokers to develop a second event that confirms relapsing-remitting MS.

Pediatric MS symptoms

Multiple sclerosis signs and symptoms in children include:

• Fatigue (an overwhelming sense of tiredness making physical or mental activity difficult)
• Changes in vision (blurred or double vision, temporary loss of sight in one eye or both)
• Weakness (loss of muscle strength and dexterity)
• Numbness or tingling: commonly in the hands or feet
• Pain sometimes mild, sometimes severe
• Balance problems and dizziness: walking difficulties, problems with coordination
• Stiffness and spasms: tightening or rigidity in particular muscle groups
• Problems with bowel/bladder
• Emotional changes (including depression, anxiety or mood swings)
• Mood changes: depression, anxiety, irritability
• Speech problems: slurring, slowing of speech, or changes in pitch or tone
• Problems with thinking and memory

Complications of multiple sclerosis

People with multiple sclerosis also may develop:

• Muscle stiffness or spasms
• Paralysis, typically in the legs
• Problems with bladder, bowel or sexual function
• Mental changes, such as forgetfulness or mood swings
• Depression
• Epilepsy

Pediatric MS diagnosis

Diagnosing MS can be difficult, both in children and adults, due to its complexity and variety of symptoms. There is no single diagnostic test for MS. In most cases, MS is diagnosed with a combination of methods. A neurologist – a doctor who specializes in conditions of the central nervous system – is the best person to evaluate your child and determine whether he or she has MS. Your child’s neurologist is likely to start with a thorough medical history and examination. Your child’s neurologist may then order tests that may include:

• Blood tests, to help rule out other diseases with symptoms similar to MS. Tests to check for specific biomarkers associated with MS are currently under development and may also aid in diagnosing the disease.
• Lumbar puncture (spinal tap), in which a small sample of the cerebral spinal fluid is removed from your spinal canal for laboratory analysis. This sample can show abnormalities in antibodies that are associated with MS. Spinal tap can also help rule out infections and other conditions with symptoms similar to MS.
• MRI, which can reveal areas of MS (lesions) on your brain and spinal cord. You may receive an intravenous injection of a contrast material to highlight lesions that indicate your disease is in an active phase.
• Evoked potential tests, which record the electrical signals produced by your nervous system in response to stimuli. An evoked potential test may use visual stimuli or electrical stimuli, in which you watch a moving visual pattern, or short electrical impulses are applied to nerves in your legs or arms. Electrodes measure how quickly the information travels down your nerve pathways.

In some patients, the first MRI scan shows multiple lesions that are so consistent with MS that an MS diagnosis may be given after only one clinical attack has happened. While not as common, early diagnosis can offer an important opportunity for early treatment.

In most people with relapsing-remitting MS, the diagnosis is fairly straightforward and based on a pattern of symptoms consistent with the disease and confirmed by brain imaging scans, such as MRI.

Diagnosing MS can be more difficult in persons with unusual symptoms or progressive disease. In these cases, further testing with spinal fluid analysis, evoked potentials and additional imaging may be needed.

To confirm a diagnosis of MS, there needs to be evidence of MS activity in two or more parts of the central nervous system (brain, spinal cord and optic nerves) that occurred at different points in time. If your child has experienced a single episode of symptoms, the diagnosis of MS cannot be confirmed.

You may have been told that your child has ‘ADEM’ (acute disseminated encephalomyelitis), ‘optic neuritis’ or has had a ‘clinically isolated syndrome’. These can all have the same symptoms as MS, but might happen only once and not return. If further episodes do occur, then MS might be diagnosed.

Table 1. Conditions potentially confused with Multiple Sclerosis

Disease		Examples
Central and peripheral nervous system disease
	Degenerative disease	Amyotrophic lateral sclerosis, Huntington disease
	Demyelinating disease	Chronic inflammatory demyelinating polyneuropathy, progressive multifocal leukoencephalopathy
	Infection	Human immunodeficiency virus infection, Lyme disease, mycoplasma, syphilis
	Inflammatory disease	Behçet syndrome, sarcoidosis, Sjögren syndrome, systemic lupus erythematosus
	Structural disease	Arteriovenous malformation, herniated disk, neoplasm
	Vascular disease	Cerebrovascular accident, diabetes mellitus, hypertensive disease, migraine, vasculitis
Genetic disorder		Leukodystrophy, mitochondrial disease
Medication and illicit drug effects		Alcohol, cocaine, isoniazid, lithium, penicillin, phenytoin (Dilantin)
Nutritional deficiency		Folate deficiency, vitamin B12 deficiency, vitamin E deficiency
Psychiatric disease		Anxiety, conversion disorder, somatization

[Source ³⁾]

Diagnostic Criteria to Multiple Sclerosis

MS is a clinical diagnosis. Two neurologic deficits (e.g., focal weakness, sensory disturbances) separated in time and space, in the absence of fever, infection, or competing etiologies, are considered diagnostic ⁴⁾, ⁵⁾. Attacks may be patient-reported or objectively observed, and must last for a minimum of 24 hours. Corroborating magnetic resonance imaging (MRI) is the diagnostic standard (Figure 5) ⁶⁾.

Figure 2. Diagnostic Criteria to Multiple Sclerosis

Abbreviations: MRI = magnetic resonance imaging; MS = multiple sclerosis.

[Source ⁷⁾]

Childhood MS treatment

There is no cure for multiple sclerosis. Treatment is focused on managing symptoms during attacks, as well as slowing the disease progression to prevent relapses and limit formation of new lesions in the brain or spine.

Your child’s care team will determine the best treatment based on your child’s symptoms and condition.

Treatment of MS relapses

Corticosteroid therapy

Steroids (corticosteroids, prednisone, or methylprednisolone), most commonly IV methylprednisolone, are used to treat an attack of neurological symptoms –either the first episode or later relapses. IV methylprednisolone is given only for a few days. If needed, oral prednisone may be prescribed for a further one to two weeks. Although they do not alter the course of the condition, steroids can reduce the inflammation in the central nervous system and speed up recovery from the relapse.

Steroids do not affect the level of recovery from an attack, so if some symptoms remain several months later, steroids will have no impact on them. And although they often speed up recovery, their effectiveness can vary from one person to another and from one relapse to another for a given individual.

Neurologists specializing in MS will generally choose intravenous methylprednisolone as the steroid to treat severe MS relapses. Large doses are usually given over 3-5 days via a drip that goes into a vein (intravenous). This method may require admission to hospital, particularly for disabling relapses. Oral methylprednisolone may be prescribed instead of intravenous methylprednisolone.

All medications can have unwanted effects, and steroids are no exception. Steroids are given only for short periods of time and only for relapses that are causing a significant disruption in a person’s life.

Serious side effects are possible, but they are not common when treatment is short. Less serious side effects are common, however, and these include irritability and difficulty sleeping. Giving the steroids in the morning reduces the impact on sleep. Upset stomach is common and medications that reduce stomach acid are typically given to prevent this. High blood sugar levels may also be a side effect that resolves when the steroids are stopped.

Continuous, long-term use of steroids is known to increase a person’s risk of osteoporosis, cataracts and diabetes.

Possible short-term side effects of steroids include:

• a metallic taste in the mouth
• increased heart rate
• hot flushes or a red face
• sleeping problems
• an increased need to urinate, particularly at night
• weight gain

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is an IV medication that is made up of antibodies from healthy blood donors. These help decrease the unwanted immune response that occurs in MS. The most common side effect is headache, but other side effects include muscle or joint pain and low-grade fever. IVIG is not usually the first treatment used for an MS relapse, but may be used in certain situations.

Plasma exchange

Plasma exchange, also called plasmapheresis or PLEX, is used when neurologic symptoms are difficult to treat. It is a process where the blood is removed from the body and washed to remove disease-causing substances, such as antibodies from the plasma (the liquid component of blood). The blood cells are then returned to the body. Multiple treatments are required, given over a couple of weeks. Plasma exchange requires the surgical placement of a special line for IV access. Risks include changes in blood pressure and fluid balance as well as infection of the access site.

Treatments to modify progression of multiple sclerosis

The goal of disease-modifying therapy is to forestall disease, preserve function, and sustain healthy immune function while suppressing the T-cell autoimmune cascade thought to be responsible for demyelination and axonal damage. Early treatment at or before the diagnosis of clinically confirmed MS may delay damage to the central nervous system ⁸⁾. The U.S. Food and Drug Administration (FDA) has approved seven agents for the treatment of MS: interferon beta, glatiramer (Copaxone), fingolimod (Gilenya), teriflunomide (Aubagio), dimethyl fumarate (Tecfidera), natalizumab (Tysabri), and mitoxantrone (Table 2). Because of the chronic nature and evolving treatment of MS, disease-modifying treatment is typically managed by a neurologist with expertise in prescribing these potentially toxic agents.

Table 2. Disease-Modifying Agents for Relapsing Remitting Multiple Sclerosis

Agent		Dosage	Cost (yearly)*	Evidence (95% confidence interval)	Adverse effects
Interferon beta			$62,000 to $67,000	Decrease in relapses: RR = 0.80	Injection site reactions (e.g., edema, inflammation, pain); influenza-like symptoms; leukopenia; elevated liver enzyme levels; depression and suicidal thoughts (increased with preexisting depression, neutralizing antibodies)
	Interferon beta-1a IM (Avonex)	Intramuscular, weekly		Decrease in progression: RR = 0.69
	Interferon beta-1a SC (Rebif)	Subcutaneous, three times per week
	Interferon beta-1b (Betaseron)	Subcutaneous, every other day
Glatiramer (Copaxone)		Subcutaneous, daily	$70,000	Decrease in relapses: MD = 0.51	Injection site reactions, facial flushing, chest tightness, palpitations
				Decrease in disability at two years: MD = 0.33
Fingolimod (Gilenya)		Oral, daily	$67,000	Annualized relapse rate vs. placebo: 0.18 vs. 0.40	Bradycardia (contraindicated in recent heart disease or arrhythmia); elevated liver enzyme levels
				Decrease in progression at two years: HR = 0.70	Melanoma, macular edema, herpes encephalitis (only occurs at higher doses)
Teriflunomide (Aubagio)		Oral, daily	$63,000	Annualized relapse rate vs. placebo: 0.37 vs. 0.54	Alopecia, diarrhea, nausea, decreased white blood cell count, elevated liver enzyme levels, peripheral neuropathy
				Decrease in progression: HR = 0.76
Dimethyl fumarate (Tecfidera)		Oral, daily	$68,000	Annualized relapse rate vs. placebo: 0.17 vs. 0.36	Flushing, abdominal pain, lymphocytopenia, elevated liver enzyme levels
				Decrease in progression: HR = 0.62
Natalizumab (Tysabri)		Intravenous, once per month	$61,000	Decrease in relapses: RR = 0.57	Infusion reactions, headache, fatigue, progressive multifocal leukoencephalopathy
				Decrease in progression at two years: RR = 0.74
Mitoxantrone		Intravenous, every three months	$900	Decrease in relapses: MD = 0.85	Myelosuppression, elevated liver enzyme levels, decreased cardiac function, leukemia
				Decrease in progression: OR = 0.30

Footnote:*—Estimated retail price of treatment for one year based on information obtained at http://www.goodrx.com. All prices are for brand name drugs except for mitoxantrone, which is available only as generic.

Abbreviations: HR = hazard ratio; MD = mean difference; OR = odds ratio; RR = relative risk

[Source ⁹⁾]

For primary-progressive MS, ocrelizumab (Ocrevus) is the only FDA-approved disease-modifying therapy. It slows worsening of disability in people with this type of MS.

For relapsing-remitting MS, several disease-modifying therapies are available.

Much of the immune response associated with MS occurs in the early stages of the disease. Aggressive treatment with these medications as early as possible can lower the relapse rate and slow the formation of new lesions.

Many of the disease-modifying therapies used to treat MS carry significant health risks. Selecting the right therapy for you will depend on careful consideration of many factors, including duration and severity of disease, effectiveness of previous MS treatments, other health issues, cost, and child-bearing status.

Treatment options for relapsing-remitting MS include:

Beta interferons. These medications are among the most commonly prescribed medications to treat MS. They are injected under the skin or into muscle and can reduce the frequency and severity of relapses.

Side effects of beta interferons may include flu-like symptoms and injection-site reactions.

You’ll need blood tests to monitor your liver enzymes because liver damage is a possible side effect of interferon use. People taking interferons may develop neutralizing antibodies that can reduce drug effectiveness.

Ocrelizumab (Ocrevus). This humanized immunoglobulin antibody medication is the only DMT approved by the FDA to treat both the relapse-remitting and primary progressive forms of MS. Clinical trials showed it reduced relapse rate in relapsing disease and slowed worsening of disability in both forms of the disease.

Ocrevus is given via an intravenous infusion by a medical professional. Side effects may infusion-related reactions including irritation at the injection site, low blood pressure, fever, and nausea among others. Ocrevus may also increase the risk of some types of cancer, particularly breast cancer.

Glatiramer acetate (Copaxone). This medication may help block your immune system’s attack on myelin and must be injected beneath the skin. Side effects may include skin irritation at the injection site.

Dimethyl fumarate (Tecfidera). This twice-daily oral medication can reduce relapses. Side effects may include flushing, diarrhea, nausea and lowered white blood cell count.

Fingolimod (Gilenya). This once-daily oral medication reduces relapse rate.

You’ll need to have your heart rate monitored for six hours after the first dose because your heartbeat may be slowed. Other side effects include headache, high blood pressure and blurred vision.

Teriflunomide (Aubagio). This once-daily medication can reduce relapse rate. Teriflunomide can cause liver damage, hair loss and other side effects. It is harmful to a developing fetus and should not be used by women who may become pregnant and are not using appropriate contraception, or their male partner.

Natalizumab (Tysabri). This medication is designed to block the movement of potentially damaging immune cells from your bloodstream to your brain and spinal cord. It may be considered a first line treatment for some people with severe MS or as a second line treatment in others. This medication increases the risk of a viral infection of the brain called progressive multifocal leukoencephalopathy in some people.

Alemtuzumab (Lemtrada). This drug helps reduce relapses of MS by targeting a protein on the surface of immune cells and depleting white blood cells. This effect can limit potential nerve damage caused by the white blood cells, but it also increases the risk of infections and autoimmune disorders.

Treatment with alemtuzumab involves five consecutive days of drug infusions followed by another three days of infusions a year later. Infusion reactions are common with alemtuzumab. The drug is only available from registered providers, and people treated with the drug must be registered in a special drug safety monitoring program.

Mitoxantrone. This immunosuppressant drug can be harmful to the heart and is associated with development of blood cancers. As a result, its use in treating MS is extremely limited. Mitoxantrone is usually used only to treat severe, advanced MS.

Medicines to prevent relapses and progression of MS

Treatments to prevent relapses and progression of MS may include the following categories of disease-modifying agents. Decisions about the best disease-modifying therapy can be complicated and are always made while considering other health conditions and what is best for each individual patient.

Disease modifying drugs can affect the course of MS. They are not a cure but they can reduce the number and severity of MS relapses. No controlled clinical trials of the disease modifying drugs have been completed in children and as yet, none are specifically approved for use in children under the age of 18. However pediatric clinical trials of several disease modifying drugs are currently underway.

Injectable medications

• Interferons (Avonex®, Rebif®, Betaseron®, Plegridy®): These medications mimic the effects of some proteins that your body can make to change how your immune system works. They are used to decrease the number of relapses and new lesions on MRI. Common side effects include flu-like symptoms shortly after the injection and injection site pain. Regular blood tests are required to monitor the medication. The type and frequency of injection is different with each of these medications.
• Glatiramer acetate (Copaxone®): This medicine is given by subcutaneous injection (just under the skin). This medication looks like one of the proteins that makes up myelin in the brain and spinal cord. The injection is given daily or three days a week. Common side effects include injection site reactions and, rarely, a reaction with chest pain. Regular blood tests are not required.

Oral medications

While there are several oral medications used in the treatment of MS, only fingolimod (Gilenya®) is currently under widespread use in the treatment of children with MS.

This medicine is taken daily and decreases relapses by trapping certain white blood cell in the lymph nodes to decrease immune system reactions. Blood testing is required before starting fingolimod and during treatment because it is associated with an increased risk of infection. Fingolimod also requires close monitoring with an eye doctor as it may cause an eye problem called macular edema.

The first dose of fingolimod is administered in a hospital or medical office setting because it can lower your heart rate. If you stop and then restart fingolimod, you will have to be monitored again when you restart it.

Infused medications

Infused medications such as Rituximab®, Tysabri® or Ocrevus® are given by IV infusion in a hospital setting. They are associated with increased risks of infection and require blood tests before starting as well as close monitoring and blood testing during treatment. These medications are most often used when injectable or oral medications have not been effective, but may be used in other settings as well.

Other treatments for MS

In addition to medication, certain lifestyle factors can help decrease relapses and manage MS symptoms.

• Taking vitamin D if needed. Having enough vitamin D decreases MS disease activity. We will check vitamin D levels and may recommend taking vitamin D3. Vitamin D may also decrease the risk of disease in other family members.
• Avoiding cigarette smoking. Researchers know that exposure to cigarette smoke increases the risk of MS. Please don’t smoke, and avoid exposure to second-hand smoke. Family members who smoke should smoke outside and change clothes when they come inside.
• Eating a healthy diet and exercising. It is extra important for people with MS to be sure that they are making healthy choices. A healthy diet, regular exercise, and plenty of sleep are all essential. Maintaining a healthy weight is important.

Home remedies for multiple sclerosis

To help relieve the signs and symptoms of MS, try to:

• Get plenty of rest.
• Exercise. If you have mild to moderate MS, regular exercise can help improve your strength, muscle tone, balance and coordination. Swimming or other water exercises are good options if you’re bothered by heat. Other types of mild to moderate exercise recommended for people with MS include walking, stretching, low-impact aerobics, stationary bicycling, yoga and tai chi.
• Cool down. MS symptoms often worsen when your body temperature rises. Avoiding exposure to heat and using devices such as cooling scarves or vests can be helpful.
• Eat a balanced diet. Results of small studies suggest that a diet low in saturated fat but high in omega-3 fatty acids, such as those found in olive and fish oils, may be beneficial. But further research is needed. Studies also suggest that vitamin D may have potential benefit for people with MS.
• Relieve stress. Stress may trigger or worsen your signs and symptoms. Yoga, tai chi, massage, meditation or deep breathing may help.

Many people with MS use a variety of alternative or complementary treatments or both to help manage their symptoms, such as fatigue and muscle pain.

Activities such as exercise, meditation, yoga, massage, eating a healthier diet, acupuncture and relaxation techniques may help boost overall mental and physical well-being, but there are few studies to back up their use in managing symptoms of MS.

Guidelines from the American Academy of Neurology recommend the use of oral cannabis extract for muscle spasticity and pain, but do not recommend cannabis in any other form for other MS symptoms due to a lack of evidence.

The guidelines also do not recommend the use of herbal supplements such as Ginkgo biloba and bee venom or magnetic therapy for MS symptoms.

Pediatric multiple sclerosis prognosis

MS is a chronic condition that needs to be managed throughout life. The course of the disease is difficult to predict and varies from person to person. Some have long periods of remission while others have more frequent attacks.

Appendicitis in kids

Appendicitis is an infection or inflammation of the appendix, a pinky-sized, tube-like structure part of the large intestine in children. The appendix is located in the right lower section of the abdomen in most children. Doctors are not really sure what the appendix does, but removing it is not harmful.

Appendicitis can be an emergency situation. Appendicitis is the most common childhood surgical emergency, but the diagnosis can be challenging, especially in children, often leading to either unnecessary surgery in children without appendicitis, or a ruptured appendix and serious complications when the condition is missed.

Appendicitis affects 1 in 1,000 people living in the U.S. Most cases of appendicitis occur between the ages of 10 and 30 years.

Since an infected appendix can rupture and be a life-threatening problem, call your health care provider or go to the emergency room immediately if your child has these symptoms:

• sudden, pronounced pain around the belly button area
• in a short period of time, the pain moves to the lower right-hand part of the abdomen and your child may have a difficult time breathing.

Symptoms of appendicitis may resemble other conditions or medical problems. Consult your health care provider for a diagnosis.

Figure 1. Appendix

Why is appendicitis in children a concern?

An irritated appendix can rapidly turn into an infected and ruptured appendix, sometimes within hours. A ruptured appendix can be life-threatening. When the appendix ruptures, bacteria infect the organs inside the abdominal cavity, causing peritonitis. The bacterial infection can spread very quickly and be difficult to treat if diagnosis is delayed.

Is immediate surgery always necessary if a child has appendicitis?

Health care providers may recommend non-operative treatment of a ruptured appendix if there is a contained abscess and the child is stable. In some cases in which the appendix has ruptured and formed a localized abscess, a health care provider may recommend that the appendix not be removed right away. Instead, your child may receive treatment with intravenous antibiotics given through an intravenous catheter (called a peripherally inserted central catheter or PICC line) for about 10 to 14 days. This may be done along with CT or ultrasound-guided drainage of the abscess. This allows the infection and inflammatory process to resolve. Your child will then undergo an elective (planned) interval appendectomy 6 to 8 weeks later.

A child whose appendix ruptured will have to stay in the hospital longer than the child whose appendix was removed before it ruptured. Some children will need to take antibiotics by mouth for a period of time specified by the health care provider after they go home.

Appendicitis in children causes

Appendicitis is the result of a blockage of the appendix caused by hard mucus or stool, or swelling caused by a virus. The blockage causes the appendix to swell and become inflamed. If the swelling and infection are left untreated, the appendix can burst (perforate), causing the contents of the appendix to be released into the abdomen, spreading the infection.

Pediatric appendicitis is the most common cause of emergency abdominal surgery in children. Though it can happen at any age, appendicitis occurs more frequently in school-aged children, and rarely occurs under the age of 1.

Appendicitis signs and symptoms in children

The signs and symptoms of appendicitis can vary from child to child. The most common symptoms of appendicitis in children are:

• Abdominal pain that begins around the belly button and moves to the right lower side of the abdomen. The pain typically increases when walking, jumping or coughing, and usually worsens as time goes on.
• Low fever, beginning after other symptoms
• Nausea and/or vomiting
• Loss of appetite
• Diarrhea
• Constipation
• Gas pain
• Tenderness in the right lower abdomen
• Abdominal swelling
• Elevated white blood cell count
• Appetite loss

The distinctive symptom should be treated very seriously; should the appendix rupture, it may infect the double-layer peritoneal membrane that lines the abdominal cavity. The medical term for this is peritonitis. Notify your child’s doctor at once or contact a local hospital emergency department. While you wait to see the doctor, instruct your child to lie down and be still. Any kind of movement, including coughing or taking a deep breath, can exacerbate the pain. Don’t offer water, food, laxatives, aspirin or a heating pad.

Appendicitis in kids diagnosis

Appendicitis can be difficult to diagnose definitely. Appendicitis in kids is diagnosed with a thorough health history and physical examination. Your child may need to have an imaging study completed, such as an ultrasound, MRI or CT scan, to see the appendix. Your child may also have laboratory studies completed, such as a complete blood count (CBC), to determine the extent of the infection.

Appendicitis in children treatment

Immediately following diagnosis, patients with appendicitis will receive antibiotics to treat the infection.

Ultimately, the treatment for appendicitis is a surgery to remove the appendix, called an appendectomy. Your child’s surgeon will help determine the best treatment for your child. Conventional “open” surgery usually requires a two day hospital stay, barring complications, and leaves youngsters with a small scar, but completely cured.

The appendix may be removed in two ways:

1. Open method. Under anesthesia, an incision is made in the lower right-hand side of the abdomen. The surgeon finds the appendix and removes it. If the appendix has ruptured, a small drainage tube may be placed to allow pus and other fluids that are in the abdomen to drain out. The tube will be removed in a few days, when the surgeon feels the abdominal infection has subsided.
2. Laparoscopic method. This procedure uses several small incisions and a camera called a laparoscope to look inside the abdomen during the operation. Under anesthesia, the instruments the surgeon uses to remove the appendix are placed through the small incisions, and the laparoscope is placed through another incision. This method is not usually performed if the appendix has ruptured.

After surgery, children are not allowed to eat or drink anything for a specified period of time so the intestine can heal. Fluids are given into the bloodstream through small plastic tubes called IVs until your child is allowed to begin drinking liquids. Your child will also receive antibiotics and medications through the IV to help her feel comfortable. Eventually, children will be allowed to drink clear liquids (such as water, sports drinks or apple juice), and then gradually advance to solid foods.

What happens after my child leaves the hospital?

Your physician will generally recommend that your child not do any heavy lifting, play contact sports or “rough-house” for several weeks after the operation.

If a drain is still in place when your child goes home, she should not take a tub bath or go swimming until the drain is removed. Your child may need to take antibiotics at home to help fight the infection in the abdomen. You will be given a prescription for pain medication for your child to take at home to help her feel comfortable. Some pain medications can make your child constipated, so ask your physician or pharmacist about any side effects the medication might have.

Moving around after surgery rather than lying in bed can help prevent constipation. Drinking fruit juices and eating fruits, whole grain cereals and breads and vegetables after being advanced to solid foods can help with constipation as well. Most children who have their appendix removed will have no long-term problems.

Meconium ileus

Meconium ileus is obstruction of the terminal ileum by abnormally thicker and stickier meconium; it most often occurs in neonates with cystic fibrosis. Meconium is the first stool (bowel movement) that a newborn has. This stool is very thick and sticky consisting of succus entericus (bile salts, bile acids, and debris from the intestinal mucosa) and is normally evacuated within 6 hours of birth (or earlier). Meconium ileus accounts for up to 33% of neonatal small-bowel obstructions. Symptoms include vomiting that may be bilious (green), abdominal distention, and failure to pass meconium in the first several days of life. Diagnosis is based on clinical presentation and x-rays. Treatment is enemas with dilute contrast under fluoroscopy and surgery if enemas fail.

Meconium ileus is most often an early manifestation of cystic fibrosis, which causes gastrointestinal secretions to be extremely viscid and adherent to the intestinal mucosa. Meconium ileus is the presenting clinical manifestation of cystic fibrosis in 10 to 20% of cases. Of infants with meconium ileus, 80 to 90% have cystic fibrosis.

Although meconium ileus is usually understood as synonymous with cystic fibrosis until proven otherwise, it may also be seen with pancreatic atresia or stenosis of the pancreatic duct.

Only rarely does meconium ileus occur without cystic fibrosis or pancreatic abnormality, and is thought to be related to gut immaturity (more favourable outcome).

Meconium ileus is classified as either uncomplicated or complicated ¹⁾. Uncomplicated meconium ileus is characterized by a distended abdomen often noted at birth and is caused by inspissated meconium in the distal ileum. This is one of the only two causes of neonatal intestinal obstruction that may manifest immediately at birth prior to infant ingestion of air (Figure 1). The other possible cause for such obstruction is in-utero perforation with meconium cyst, which may or may not be caused by meconium ileus. Additional features of the presentation of simple meconium ileus include bilious emesis and the failure to pass meconium. Complicated meconium ileus consists of neonatal bowel obstruction with evidence of necrosis or perforation, and may include intra-abdominal calcification, redness of the abdominal wall, and abdominal tenderness.

Obstruction occurs at the level of the terminal ileum (unlike the colonic obstruction caused by meconium plug syndrome) and may be diagnosed by prenatal ultrasonography. Distal to the obstruction, the colon is narrow and empty or contains small amounts of desiccated meconium pellets. The relatively empty, small-caliber colon is called a microcolon and is secondary to disuse.

In about 50% of meconium ileus cases, complications such as ileal atresia or stenosis, ileal perforation, meconium peritonitis, and malrotation with or without pseudocyst formation can occur in association with meconium ileus ²⁾. The distended loops of small bowel may twist to form a volvulus in utero. If the intestine loses its vascular supply and infarcts, sterile meconium peritonitis can result. The infarcted intestinal loop may be resorbed, leaving an area or areas of intestinal atresia. Infants with meconium ileus are also at increased risk of developing cholestasis.

Figure 1. Meconium ileus

Footnote: Meconium ileus. Newborn with dilated loops of small bowel and a “doughy” abdomen.

[Source ³⁾ ]

Meconium ileus causes

Meconium ileus is estimated to occur in 15% of infants with cystic fibrosis. Cystic fibrosis is one of the most common inheritable diseases among Caucasians with an incidence of 1 in 2,500 live births ⁴⁾. Incidence varies according to race with 93% of cases in the United States occurring among Whites, while only 3.6 and 0.4% cases occur in Blacks and Asian Americans, respectively ⁵⁾. In the state of California, the overall birth prevalence has been estimated at 19.9 per 100,000 births with 38.8 per 100,000 births for Whites, 37.2 per 100,000 births for Native Americans, and 17.1 per 100,000 births for Blacks ⁶⁾. Median age of survival for patients with cystic fibrosis has been estimated to be 50 years ⁷⁾. There does not appear to be a difference in mortality by gender ⁸⁾.

The pathophysiology of cystic fibrosis is based on an autosomal recessive defect in the gene on the long arm of Chromosome 7. This gene codes for the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel on epithelial surfaces. Defects in this receptor cause decreased chloride secretion and increased sodium resorption. Thousands of mutations of the CFTR gene have been identified, but the most common is known as delta F508 ⁹⁾. The CFTR regulates epithelial sodium channels known as ENaCs, so the defect in CFTR results in unregulated ENaCs and increased sodium resorption. In both the pulmonary and gastrointestinal systems, increased sodium resorption is accompanied by water resorption resulting in dehydrated mucus in the lungs and luminal contents of the small bowel ¹⁰⁾. Meconium ileus is characterized by intestinal obstruction from the impaction of thickened, protein-rich, meconium inspissated in the distal ileum, possibly related to a deficiency in pancreatic enzymes and abnormal mucin production ¹¹⁾.

Meconium ileus symptoms

After birth, unlike normal neonates, infants with meconium ileus fail to pass meconium in the first 12 to 24 hours. They have signs of intestinal obstruction, including emesis that may be bilious and abdominal distention. Loops of distended small bowel sometimes can be palpated through the abdominal wall and may feel characteristically doughy. Meconium peritonitis with respiratory distress and ascites can occur secondary to perforation.

Simple meconium ileus

Simple meconium ileus is defined as the failure to pass meconium within 48 hours of birth without additional complications ¹²⁾. Typical management includes an attempted contrast enema and if unsuccessful, celiotomy. Historically, meconium ileus was often treated with an ostomy and postoperative irrigations to break up and evacuate the inspissated meconium. In some cases, these various types of ostomies may still be appropriate. Options for creation of an ostomy include the Bishop-Koop, a distal stoma with a proximal end-to-side anastomosis; Santulli enterostomy, a proximal stoma with a side-to-end distal anastomosis; or Mikulicz, double barrel enterostomy (Figure 3) ¹³⁾. Current trends in operative management include enterotomy for irrigation with saline or N-acetylcystine. Irrigation may be completed either intraoperatively via the appendix or an enterotomy, or postoperatively through one of the ostomies mentioned previously. Use of a T-tube placed within the intestinal lumen has also been described for postoperative irrigations ¹⁴⁾. The T-tube may be removed once the meconium has cleared with spontaneous closure of the fistula ¹⁵⁾. Alternatively, an appendicostomy may be created for ongoing irrigations ¹⁶⁾. In some cases, a limited bowel resection with primary anastomosis may be necessary after the inspissated meconium has been evacuated.

Complicated meconium ileus

Complicated meconium ileus is characterized by the addition of atresia, volvulus, and perforation, which may result in meconium cyst with peritonitis or gangrene ¹⁷⁾. An ultrasound may demonstrate free intraperitoneal fluid with echogenic particles, single or multiple pseudocysts, hepatic or splenic calcifications, and collapsed bowel loops or obstruction ¹⁸⁾.

There are four typical presentations of complicated meconium ileus including ¹⁹⁾:

1. meconium pseudocyst with a calcified fibrous wall and bowel loops peripheral and usually posterior to the cyst,
2. dense vascular adhesions with scattered calcifications,
3. meconium ascites, and
4. infected meconium ascites.

Again, creation of an ostomy is usually necessary to relieve the obstruction and for ongoing irrigation postoperatively. In some of these cases such as meconium cyst, the bowel may be very difficult to find and may be hidden posterior to the cyst rind. To find the bowel, it is necessary to make the abdominal incision laterally and attempt to get behind the cyst rind from the side. Because the bowel may be difficult to discern, an ostomy is usually the best option with later reoperation for establishing intestinal continuity once the inflammation has resolved.

Meconium ileus diagnosis

Diagnosis of meconium ileus is suspected in a neonate with signs of intestinal obstruction, particularly if a family history of cystic fibrosis exists. The earliest signs of meconium ileus are abdominal distention (a swollen belly), bilious (green) vomit and no passage of meconium. Your child’s doctor will order an X-ray of your child’s abdomen to find out if she has meconium in her intestines. A “soap bubble” or “ground glass” appearance due to small air bubbles mixed with the meconium is diagnostic of meconium ileus. If meconium peritonitis is present, calcified meconium flecks may line the peritoneal surfaces and even the scrotum. A water-soluble contrast enema reveals a microcolon with an obstruction in the terminal ileum.

Patients diagnosed with meconium ileus should be tested for cystic fibrosis.

Prenatal ultrasonography can detect changes in utero suggestive of cystic fibrosis and meconium ileus (eg, dilated bowel, polyhydramnios), but these changes are not specific.

Figure 2. Meconium ileus abdominal X-ray

Footnote: Premature child with failure to pass meconium, abdominal distension and vomiting. There is marked dilatation of small bowel loops. Contrast enema reveals small entire colon with radiolucent filling defects representing meconium seen scattered at right colon and distal ileum.

Meconium ileus treatment

If a doctor suspects that your child has a meconium ileus, she won’t be given anything to eat or drink and will be fed through an intravenous (IV) line, a small tube that’s inserted into a vein. A small tube called a nasogastric (NG) tube will also be placed through your child’s nose and passed into her stomach to help remove excess air and fluid.

The medical team may try to break up the meconium blockage with medicines given to your child through an enema. Obstruction may be relieved in uncomplicated cases (ie, without perforation, volvulus, or atresia) by giving ≥ 1 enema with a dilute radiographic contrast medium plus N-acetylcysteine under fluoroscopy; hypertonic contrast material may cause large gastrointestinal water losses requiring IV rehydration.

If the enema does not relieve the obstruction, a laparotomy is required. If your baby needs surgery for meconium ileus, she’ll have a bowel resection and ileostomy placement. A double-barreled ileostomy with repeated N-acetylcysteine lavage of the proximal and distal loops is usually required to liquefy and remove the abnormal meconium.

Nonoperative management

Nonoperative management consists of a hypertonic enema such as Gastrograffin or other contrast enema performed under fluoroscopic guidance. Gastrograffin is a hyperosmolar (1900 mOsm/L), water-soluble, radiopaque solution that contains 0.1% polysorbate 80 and 37% organically bound iodine. 13 14 Prior to initiation of contrast, the patient must undergo fluid resuscitation because the hypertonicity of the enema can lead to significant fluid shifts and cardiovascular collapse in the neonate. It may be acceptable to attempt more than one enema if progress, defined as the passing of contrast more proximally with each enema, is noted on each study. Contrast must be noted passing into the dilated loops of bowel to differentiate meconium ileus from intestinal or colonic atresia. The enema is considered failed if the meconium cannot be evacuated or contrast does not enter the dilated bowel. If a contrast enema is unsuccessful, operative intervention must follow. 13 14

Bowel resection surgery

Your child may need a bowel resection, a surgical procedure that brings part of the small intestine out to the surface of the abdominal wall. This creates an ileostomy, which is temporary. The bowel can be reconnected once your child’s ileus is gone.

Figure 3. Ileostomy

Figure 4. Double-barreled ileostomy

Follow-up care

After the operation, your child will go to the Neonatal Intensive Care Unit (NICU). Your child will have a small incision on her abdomen, which will be covered with a gauze dressing. She’ll also have an NG tube to help empty her stomach. Your child may have an ileostomy. You will learn how to care for the ileostomy before leaving the hospital.

Your baby’s healthcare team will give her pain medication, as needed. When your child first comes back to her room after surgery, she’ll need narcotic medications, such as morphine or Versed, which she’ll get through her IV. After a few days, acetaminophen (paracetamol) should relieve her pain.

Your child will also receive antibiotics after surgery to prevent infection.

Once the bowel has been cleared of meconium, oral feeds with pancreatic enzyme supplementation may be initiated. An evaluation of a cystic fibrosis database from 1990 to 2010 identified 75 neonates with meconium ileus of which 92% underwent laparotomy and 72% received ostomies ²⁰⁾. In this series as well as in others, those who required an ostomy or had complicated meconium ileus had a longer length of stay ²¹⁾.

Your child will be ready to go home when her incisions are healing nicely, she doesn’t have a fever, and is able to drink, urinate and have a bowel movement. This is usually in one to two weeks.

Once your baby is home, she may drink formula or breast milk. You can give her acetaminophen v — according to her doctor’s instructions — to relieve any pain she’s experiencing. The thin tapes over the incision (called STERI-STRIPS) will fall off on their own.

Your child can have a tub bath one week after surgery.

Meconium ileus prognosis

Several retrospective cohort studies have examined the association between initial presentation with meconium ileus and later morbidity and mortality. Four retrospective cohort studies that compared pulmonary function and nutritional status for patients diagnosed with cystic fibrosis with meconium ileus versus controls that were diagnosed as a result of other symptoms found no long-term differences between the groups ²²⁾. Two earlier studies compared children presenting with meconium ileus with those diagnosed with screening for cystic fibrosis. Both of these studies found diminished pulmonary function and shorter survival for patients with meconium ileus compared with those diagnosed with prenatal screening ²³⁾. It is possible that studies comparing patients presenting with meconium ileus and those diagnosed later with symptomatic disease found no difference in long-term outcomes because those with meconium ileus may have more severe disease but benefit from early diagnosis, while those diagnosed later have the disadvantage of delayed diagnosis but the benefit of less severe disease. The study by Lai et al ²⁴⁾ found that those patients with meconium ileus and those diagnosed later with symptomatic disease both had significantly shorter survival than those diagnosed with prenatal or neonatal screening. Alternatively, those patients whose disease was detected with screening may have been biased by less severe phenotypes. Additionally, it appears that the differences may equilibrate with long-term analysis.

Long-term complications

Distal intestinal obstruction syndrome

Previously referred to as meconium ileus equivalent, distal intestinal obstruction syndrome has two presentations: complete and incomplete. Incomplete distal intestinal obstruction syndrome, also known as impending distal intestinal obstruction syndrome, is defined as intestinal obstruction accompanied by a fecal mass in the ileo-cecum and abdominal pain or distension. Complete distal intestinal obstruction syndrome includes all of the previous symptoms with the addition of bilious emesis or air–fluid levels on abdominal radiograph ²⁵⁾. Distal intestinal obstruction syndrome is more prevalent in adults than children with cystic fibrosis and has an estimated prevalence of 15 to 20% of patients with cystic fibrosis ²⁶⁾. Nearly 50% of patients with distal intestinal obstruction syndrome have a history of meconium ileus ²⁷⁾.

The cause of distal intestinal obstruction syndrome is thought to be related to a delayed transit of thickened secretions in the lumen of the gastrointestinal tract ²⁸⁾. It has been proposed that pancreatic insufficiency leads to high fecal fat, which increases stool viscosity and activates the ileal break, delaying transit of intraluminal contents ²⁹⁾. The ileal break is a feedback loop that is activated by fat in the ileum and slows jejunal motility, delays gastric emptying, and reduces small intestinal transit of solid and liquid intraluminal contents ³⁰⁾. This hypothesis has been contradicted by the observation of distal intestinal obstruction syndrome in patients with cystic fibrosis without exocrine pancreatic dysfuntion ³¹⁾. In the terminal ileum, bile salts normally trigger increased secretion with a mechanism that is dependent on CFTR. A defect in CFTR causes decreased bile acid-stimulated secretion in the terminal ileum, which has been proposed as a part of the mechanism for distal intestinal obstruction syndrome. Malfunction of CFTR also causes increased sodium and water reabsorption through the epithelial sodium channels (ENaCs) in the terminal ileum. 36 Distinct from constipation ,which consists of diffuse stool impaction in the colon, distal intestinal obstruction syndrome is characterized by fecal material causing obstruction at the terminal ileum and in the small bowel ³²⁾. Risk factors for distal intestinal obstruction syndrome include a previous history of meconium ileus, pancreatic insufficiency, genotype associated with a severe phenotype, previous history of distal intestinal obstruction syndrome, fat malabsorption, dehydration, and transplantation ³³⁾.

Treatment of distal intestinal obstruction syndrome is primarily medical. If the obstruction is incomplete, the patient should receive oral rehydration, stool softeners, and laxatives such as polyethylene glycol ³⁴⁾. If the obstruction is complete without bilious emesis, the patient may be rehydrated and given polyethylene glycol. If the patient presents with complete obstruction and severe bilious emesis, hospitalization with intravenous fluid, nasogastric decompression, and Gastrograffin enemas are required ³⁵⁾. Operative intervention is seldom required with aggressive medical management. However, if the patient fails medical management, celiotomy with enterotomy and possible resection may be necessary ³⁶⁾.

Rectal prolapse

Cystic fibrosis only accounts for approximately 11% of rectal prolapse in pediatric patients; however, 23% of patients with cystic fibrosis will be diagnosed with rectal prolapse ³⁷⁾. Prior to widespread newborn screening, rectal prolapse preceded the diagnosis of cystic fibrosis in more than 40% of cases ³⁸⁾. Since rectal prolapse may be a presenting symptom of undiagnosed cystic fibrosis, testing should be performed in all pediatric patients who present with this finding. 23 40 41 Rectal prolapse has a similar incidence in male and female patients with cystic fibrosis ³⁹⁾. Among patients with cystic fibrosis, those presenting with rectal prolapse have a young average age at diagnosis ranging from 1 to 2.5 years in one series 42 and 3.7 years in another ⁴⁰⁾. It has been proposed that the higher incidence of rectal prolapse in children younger than 4 years is related to anatomical factors such as the straight course of the rectum, low position of the rectum relative to other pelvic organs, mobility of the sigmoid colon, and weakness of the levator ani muscle ⁴¹⁾. In addition, there is only a loose attachment of the mucosa to the underlying muscularis and absence of Houston’s valves in 75% of children under 1 year of age ⁴²⁾. Many of these anatomic factors resolve in early childhood, diminishing the possibility of rectal prolapse. The proposed etiology of rectal prolapse among patients with cystic fibrosis is the presence of large voluminous stool and malnutrition in combination with increased intra-abdominal pressure from chronic coughing ⁴³⁾. It was also noted by Stern et al ⁴⁴⁾ that of the 29 patients diagnosed with cystic fibrosis who had recurrent rectal prolapse, the problem resolved completely in 72% of patients after pancreatic enzyme supplementation was initiated. In contrast, if patients were already taking supplemental enzymes prior to presentation with rectal prolapse, manipulation of the dosages had a little effect on the rectal prolapse ⁴⁵⁾.

Typical management of rectal prolapse in children with cystic fibrosis includes manual reduction, which is successful in almost all cases. Occasionally, a patient may experience multiple episodes that are either painful or intolerable ⁴⁶⁾. In these cases, sclerotherapy, a subcutaneous perianal suture or a sling procedure may be necessary ⁴⁷⁾. Injection of a sclerosing agent into the rectal submucosa has success rates as high as 90 to 100% ⁴⁸⁾. A variety of surgical methods have been proposed and the favored technique appears to be institution dependent, and is discussed in greater detail in this edition in the chapter on “rectal prolapse.”

Fibrosing colonopathy

Fibrosing colonopathy is a complication of cystic fibrosis that was first reported in 1994 by Smyth et al and is characterized by concentric rings of fibrosis deep to the submucosa, most frequently in the ascending colon, though it may involve the entire colon. It also involves hypertrophy of the muscularis mucosa as well as inflammation and fibrosis of the submucosa ⁴⁹⁾. The cause of fibrosing colonopathy was originally thought to be associated with high dosages of enzyme supplementation. This is according to a 1997 study that found a relative risk of fibrosing colonopathy that was double for those on high enzyme doses ⁵⁰⁾. However, the occurrence of this complication appears to be multifactorial, as there have been cases documented in patients who had never received pancreatic enzyme supplementation ⁵¹⁾. It has been hypothesized that increased IgG in response to pancreatic enzymes occurred after ingestion, with a peak elevation at 7 to 9 months following initiation. This timing coincided with the development of fibrosing colonopathy ⁵²⁾. Treatment of fibrosing colonopathy in general includes subtotal versus total colectomy depending on the extent of disease ⁵³⁾. Ostomy may be necessary for rectal strictures though pull-through operations have been described. 29 There are small case reports of using steroids that have allowed strictures to resolve ⁵⁴⁾.

Periventricular leukomalacia

Periventricular leukomalacia (PVL) is characterized by the death of the white matter of the brain due to softening of the brain tissue. Periventricular leukomalacia represent small “holes” in the brain due to the death of small areas of brain tissue around the normal fluid-filled cavities of the brain. Periventricular leukomalacia can affect fetuses or newborns; premature babies are at the greatest risk of periventricular leukomalacia. Periventricular leukomalacia is caused by a lack of oxygen or blood flow to the periventricular area of the brain, which results in the death or loss of brain tissue. The periventricular area-the area around the spaces in the brain called ventricles-contains nerve fibers that carry messages from the brain to the body’s muscles. Although babies with periventricular leukomalacia generally have no outward signs or symptoms of the disorder, they are at risk for motor disorders, delayed mental development, coordination problems, and vision and hearing impairments. Periventricular leukomalacia may be accompanied by a hemorrhage or bleeding in the periventricular-intraventricular area (the area around and inside the ventricles), and can lead to cerebral palsy. Periventricular leukomalacia is diagnosed by ultrasound of the head.

There is no specific treatment for periventricular leukomalacia. Treatment is symptomatic and supportive. Children with periventricular leukomalacia should receive regular medical screenings to determine appropriate interventions.

Figure 1. Periventricular leukomalacia MRI scan

Footnote: This child had a history of a perinatal insult and had significant developmental delay. The lateral ventricles are enlarged with wavy lateral contours demonstrating increase in volume with associated white matter tissue loss typical of moderate to severe periventricular leukomalacia.

Figure 2. Ventricles of the brain

Can periventricular leukomalacia cause migraines?

Migraines or headaches are not specifically described as a feature of periventricular leukomalacia. However, there are two case reports of headaches in individuals with periventricular leukomalacia. Two different studies ¹⁾, ²⁾ of children with recurrent headaches each reported one individual with periventricular leukomalacia diagnosed after brain imaging. It is difficult to determine if headaches can be caused by periventricular leukomalacia because there are few reported cases. It is important to keep in mind that although there are often symptoms that are documented in case reports, they are based on the specific individuals that are studied and may differ from one affected person to another.

Periventricular leukomalacia causes

Periventricular leukomalacia is most common in premature infants (less than 34 weeks gestational age with a median gestational age of 30 weeks and <1500 grams at birth) than in full-term infants. A major cause is thought to be changes in blood flow to the area around the ventricles of the brain. This area is fragile and prone to injury, especially before 32 weeks of gestation. Premature babies who have intraventricular hemorrhage are also at increased risk for developing periventricular leukomalacia.

The incidence of periventricular leukomalacia ranges from 4-26% in premature infants in neonatal intensive care units (NICUs). The incidence of periventricular leukomalacia is much higher in reports from autopsy studies of premature infants. As many as 75% of premature infants have evidence of periventricular leukomalacia on postmortem examination.

Periventricular leukomalacia likely occurs as a result of hypoxic-ischemic lesions resulting from impaired perfusion at the watershed areas, which in premature infants are located in a periventricular location. It is likely that infection or vasculitis also play a role in pathogenesis.

• Early: periventricular white matter necrosis
• Subacute: cyst formation
• Late: parenchymal loss and enlargement of the ventricles

Infection around the time of delivery may also play a role in causing periventricular leukomalacia. The risk for periventricular leukomalacia is higher for babies who are more premature and more unstable at birth.

Maternal infection, placental inflammation, and vasculitis are also important in the pathogenesis of periventricular leukomalacia. A link between maternal infection, preterm birth, and central nervous system (CNS) injury has been established by epidemiological studies ³⁾. A role for infection and cytokine-induced injury in periventricular leukomalacia is strengthened by studies that demonstrate the presence of tumor necrosis factor in periventricular leukomalacia lesions ⁴⁾ and in the cerebrospinal fluid (CSF) of infants with cerebral white matter injury ⁵⁾.

After the initial insult, either ischemia or inflammation, injury to the immature premyelinating oligodendrocytes occurs by either free radical attack or by excitotoxicity. The preterm infant is particularly sensitive to oxygen free radical attack because of delayed development of superoxide dismutase and catalase ⁶⁾.

In a 2014 report, Inomata et al suggested that combined elevations in serum levels of interleukin (IL) 6 and C-reactive protein (CRP) at birth are predictive of white matter injury in preterm infants with a fetal inflammatory response ⁷⁾.

Injury to the premyelinating oligodendrocytes results in astrogliosis and microgliosis. This results in a deficit of mature, myelin-producing oligodendrocytes, which leads to cerebral hypomyelination ⁸⁾.

Premature infants on mechanical ventilation may develop hypocarbia. Several studies have linked hypocarbia, particularly in the first few days of life, with the development of periventricular leukomalacia ⁹⁾. Cumulative exposure during the first 7 days of life has been shown to independently increase the risk of periventricular leukomalacia in low birth weight infants ¹⁰⁾.

Periventricular leukomalacia symptoms

Periventricular leukomalacia (PVL) occurs most commonly in premature infants born at less than 32 weeks’ gestation who have a birth weight of less than 1500 g. Many of these infants have a history of maternal chorioamnionitis.

Most affected infants experience cardiorespiratory problems, such as respiratory distress syndrome or pneumonia, in association with hypotension or patent ductus arteriosus during their first days of life. Bacterial infection at birth also appears to be a risk factor.

Some children exhibit fairly mild symptoms, while others have significant deficits and disabilities. Periventricular leukomalacia may manifest as cerebral palsy (>50% in the setting of cystic periventricular leukomalacia), intellectual disability or visual disturbance.

Initially, most premature infants are asymptomatic. If symptoms occur, they are usually subtle. Symptoms may include the following:

• Decreased tone in lower extremities
• Increased tone in neck extensors
• Apnea and bradycardia events
• Irritability
• Pseudobulbar palsy with poor feeding
• Clinical seizures (may occur in 10-30% of infants)

Periventricular leukomalacia diagnosis

Tests used to diagnose periventricular leukomalacia include ultrasound and MRI of the head. The traditional diagnostic hallmarks of periventricular leukomalacia are periventricular echodensities or cysts detected by cranial ultrasonography. More recently MRI studies have demonstrated a relatively common diffuse non-cystic form of periventricular leukomalacia in premature infants. Diagnosing periventricular leukomalacia is important because a significant percentage of surviving premature infants develop cerebral palsy (CP), intellectual impairment, or visual disturbances.

Ultrasound

Cranial ultrasound provides a convenient, non-invasive, relatively low-cost screening examination of the haemodynamically-unstable neonate at the bedside. The examination also imparts no radiation exposure. Sonography is sensitive for the detection of hemorrhage, periventricular leukomalacia, and hydrocephalus.

On ultrasound, hyperechoic areas are firstly identified in a distinctive fashion in the periventricular area, more often at the peritrigonal area and in an area anterior and lateral to the frontal horns (periventricular white matter should be less echogenic than the choroid plexus).

These are watershed areas that are sensitive to ischemic injury. Follow-up scans in the more severely affected patients may reveal the development of cysts in these areas, known as cystic periventricular leukomalacia (when cystic periventricular leukomalacia is present, it is considered the most predictive sonographic marker for cerebral palsy).

Periventricular leukomalacia classification

One of the methods used for grading of periventricular leukomalacia based on sonographic appearances is as ¹¹⁾:

• Grade 1: areas of increased periventricular echogenicity without any cyst formation persisting for more than 7 days
• Grade 2: the echogenicity has resolved into small periventricular cysts
• Grade 3: areas of increased periventricular echogenicity, that develop into extensive periventricular cysts in the occipital and frontoparietal region
• Grade 4: areas of increased periventricular echogenicity in the deep white matter developing into extensive subcortical cysts

Periventricular leukomalacia treatment

There is no treatment for periventricular leukomalacia. Premature babies’ heart, lung, intestine, and kidney functions are watched closely and treated in the newborn intensive care unit (NICU). This helps reduce the risk of developing periventricular leukomalacia.

Infants with periventricular leukomalacia require close neurodevelopmental follow-up after discharge from the hospital. Potential consultants include pediatricians, developmental specialists, neurologists, and occupational and physical therapists.

Developmental follow-up

Premature infants with evidence of periventricular leukomalacia (PVL) require close developmental follow-up because of the high association with cerebral palsy (CP).

Early intervention strategies carried out by occupational therapists or physical therapists may decrease symptoms and may increase the infant’s motor function.

Periventricular leukomalacia prognosis

The prognosis for individuals with periventricular leukomalacia depends upon the severity of the brain damage. Periventricular leukomalacia often leads to nervous system and developmental problems in growing babies. These problems most often occur during the first to second year of life. It may cause cerebral palsy (CP), especially tightness or increased muscle tone (spasticity) in the legs.

Mild periventricular leukomalacia is often associated with spastic diplegia. Severe periventricular leukomalacia is associated with quadriplegia. Severe periventricular leukomalacia is also associated with a higher incidence of intelligence deficiencies and visual disturbances.

Babies with periventricular leukomalacia are at risk for major nervous system problems. These are likely to include movements such as sitting, crawling, walking, and moving the arms. Fixation difficulties, nystagmus, strabismus, and blindness have also been associated with periventricular leukomalacia. These babies may need physical therapy. Extremely premature babies may have more problems with learning than with movement.

Some cases of visual dysfunction in association with periventricular leukomalacia occur in the absence of retinopathy of prematurity, suggesting damage to optic radiations as causation.

A baby who is diagnosed with periventricular leukomalacia should be monitored by a developmental pediatrician or a pediatric neurologist. The child should see the regular pediatrician for scheduled exams.

Femoral anteversion

Femoral anteversion also known as excessive femoral torsion, pigeon toe or parrot toe, is an inward twisting of the thigh bone, also known as the femur (the bone that connects the hip to the knee). Femoral anteversion causes the child’s knees and feet to turn inward, or have what is also known as a “pigeon-toed” appearance. Femoral anteversion is typically detected when the child is 4 years to 6 years old. Children with femoral anteversion often sit in the “W” position, with their knees bent and their feet flared out behind them. Intoeing is also often noticed by parents when their child begins to walk, but it may be present in different aged children for different reasons.

When the child is first learning how to walk, femoral anteversion can create an intoeing appearance. As the knees and feet turn in, the legs look like they are bowed. The bowed leg stance actually helps the child achieve greater balance as they stand. Balance is not as steady when they try to stand and walk with their feet close together or with their feet turned out. This may cause them to trip and fall.

Femoral anteversion usually spontaneously improves in almost all children as they grow older. Femoral anteversion does not increase the risk of arthritis of the hip. Spontaneous improvement in the anatomic position can occur up to the age of 8 years, and further correction can be achieved by improving the gait through conscious effort until adolescence. The natural history of femoral torsion is to resolve by the time the patient is aged 8-9 years. Beyond this age, all remodeling will have occurred, and any further correction is due to a conscious modification of posture. In severe cases, braces may help with the problems related to femoral anteversion. Studies have found that special shoes, braces, and exercises do not help.

Surgery is usually not considered unless the child is older than 9 or 10 years and has a severe deformity that causes tripping and an unsightly gait. When indicated, surgery for femoral anteversion involves cutting the femur and rotating it into proper alignment.

What is normal femoral anteversion?

Normal femoral anteversion is 40º in the newborn and decreases to 10º by the age of 8 years ¹⁾. The acetabulum is angled forward 15º.

Femoral anteversion causes

Femoral anteversion can be the result of stiff hip muscles due to the position of the baby in the uterus. Femoral anteversion is also brought about by increased intrauterine pressures, causing undue pressure in areas of growth. In these cases, the neck of the femur is rotated inwards, which rotates the greater trochanter posteriorly. The resulting in-toeing becomes more evident with age, as there is a physiologic external rotation of the hip during toddler development ²⁾.

Femoral anteversion also has a tendency to run in families. Typically, a child’s walking style looks like that of his or her parents.

Femoral anteversion symptoms

The turned femur causes both the knees and feet to turn inward, creating an appearance that’s often described as “pigeon-toed”. It may make walking and balancing difficult and cause falls.

Femoral anteversion diagnosis

The diagnosis of femoral anteversion is made by a history and physical examination by your child’s doctor. During the examination, the doctor obtains a complete prenatal and birth history of the child and asks if other family members are known to have femoral anteversion. Generally, no X-rays are necessary.

Femoral anteversion treatment

Specific treatment for femoral anteversion will be determined by your child’s doctor based on:

• Your child’s age, overall health, and medical history
• The extent of the condition
• Your child’s tolerance for specific medications, procedures, or therapies
• Expectations for the course of the condition
• Your opinion or preference

The twisting in of the thigh bone usually improves with time. As the child grows, normal walking patterns typically resume by 8 years to 10 years of age.

Occasionally braces or special shoes are prescribed by the doctor, but most studies have not found these treatments to help.

Femoral anteversion prognosis

Long-term outlook for a child with femoral anteversion is very good. Many cases correct themselves as the child grows. On rare occasions, femoral anteversion can be severe and surgery may be required to straighten the thigh bone.

It is important to know that femoral anteversion typically does not lead to arthritis or any other future health problems.

Micrognathia

Micrognathia is the medical term for an undersized jaw, small lower jaw, small mandible or mandibular hypoplasia. Micrognathia can occur in isolation, but it may also be present along with other birth defects in numerous syndromes, including cleft lip, cleft palate, Pierre Robin sequence or syndrome, Stickler’s syndrome, Beckwith-Wiedemann syndrome, hemifacial microsomia, Treacher Collins syndrome and others ¹⁾. Retrognathia is a mandible that is displaced posteriorly (although not necessarily small) with respect to the maxilla. Most fetuses who are diagnosed with micrognathia by prenatal ultrasound imaging have a combination of these two disorders ²⁾. Agnathia (otocephaly) is complete or almost complete agenesis of the mandible, with the temporal bones rotating medially; this results in the ears being horizontal and adjacent to each other or even fused in the expected location of the mandible. This extreme form of micrognathia is very rare ³⁾.

Sometimes babies are born with micrognathia. Micrognathia may interfere with an infant’s feeding and breathing. For example, infants with micrognathia may need special nipples and positioning in order to feed properly. Outcomes for children with micrognathia are generally good, but can vary depending on the severity of the condition.

Symptoms of micrognathia can vary from child to child but may include:

• Apneic spells (a temporary stop in breathing)
• Feeding difficulties including prolonged feeding, inability to feed, and poor weight gain
• Noisy breathing
• Poor ability to sleep

In rare case, parents will report that their child turns blue (cyanosis) when feeding or sleeping due to breathing difficulties.

Micrognathia can be caused by certain inherited disorders and syndromes.

Micrognathia can cause the teeth not to align properly ⁴⁾. This can be seen in the way the teeth close. Often there will not be enough room for the teeth to grow.

Children with micrognathia should see an orthodontist when the adult teeth come in. Because children may outgrow micrognathia, it often makes sense to delay treatment until a child is older.

Micrognathia often corrects itself during growth. The lower jaw may grow a lot during puberty.

Micrognathia causes

Micrognathia can appear in infants by itself or as part of a syndrome (where more than one body system is involved) such as cleft lip or cleft palate. The cause of micrognathia is often unknown but can be caused by an underlying genetic condition especially if the child has other anomalies.

Micrognathia may be part of other genetic syndromes, including:

• Cri du chat syndrome
• Hallerman-Streiff syndrome
• Marfan syndrome
• Pierre Robin syndrome or Pierre Robin sequence
• Progeria
• Russell-Silver syndrome
• Seckel syndrome
• Smith-Lemli-Opitz syndrome
• Treacher-Collins syndrome
• Trisomy 13
• Trisomy 18
• XO syndrome (Turner syndrome)

A syndrome may be inherited (passed down from the parents) or come about spontaneously.

Micrognathia symptoms

Along with a small jaw, infants may have trouble feeding, poor weight gain, failure to thrive (when children begin to fall off their growth curve), difficulty breathing and short periods of temporarily “ stopping to breathe (apnea)” during sleeping. This is called obstructive sleep apnea.

The airway is at the most risk for blockage at night when all the muscles are relaxed. When a child’s tongue is in a backward position due to a small jaw, his or her attempts to breath when sleeping can be met with partial or complete blockage. It occurs in about 2% of children.

Obstructive sleep apnea causes decreases in the blood’s ability to carry oxygen to the developing organs, so it can interfere with development. In children with obstructive sleep apnea and micrognathia, surgical treatment of the airway can be an emergency.

Symptoms of micrognathia can vary from child to child but may include:

• Apneic spells (a temporary stop in breathing)
• Feeding difficulties including prolonged feeding, inability to feed, and poor weight gain
• Noisy breathing
• Poor ability to sleep

In rare case, parents will report that their child turns blue (cyanosis) when feeding or sleeping due to breathing difficulties.

Micrognathia diagnosis

Your baby’s doctor will do a physical exam and may ask questions about the problem. Some of these may include:

• When did you first notice that the jaw was small?
• How severe is it?
• Does the child have trouble eating?
• What other symptoms are present?

During the physical exam, doctors look at:

• The relationship between your child’s tongue and lower jaw
• If your child has a cleft palate
• If your child has any facial asymmetries
• The relationship of your child’s upper jaw to their lower jaw
• Presence of a tongue tie (lingual frenulum)
• The overall health of your child

The following tests may be performed ⁵⁾:

• Dental x-rays
• Skull x-rays
• If the child can tolerate it, a sleep study (polysomnogram) is done to see how bad his or her airway is obstructed. Polysomnogram measures your child’s breathing, brain stimulation, heart function, and oxygenation levels during sleep. If the results are severe, then a formal airway evaluation by the pediatric ENT is done in the operating room to assess the anatomy of the upper airway.

Depending on the symptoms, a child may need to be tested for an inherited condition that may be the source of the problem. The child may need surgery or devices to correct tooth position.

Genetic evaluation

Diagnostic testing with chromosomal microarray analysis should be offered when significant micrognathia is detected, particularly if there are additional features that are suggestive of a syndromic diagnosis. If a common aneuploidy syndrome is suspected, karyotype analysis or fluorescence in situ hybridization, with reflex to chromosomal microarray analysis, is a reasonable approach. Micrognathia can be inherited; however, a de novo variant is common with severe micrognathia. If there are additional anomalies, consanguinity, or a family history of a specific condition, gene panel testing or exome sequencing is sometimes useful because chromosomal microarray analysis does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued, appropriate pretest and posttest genetic counseling by a provider who is experienced in the complexities of genomic sequencing is recommended ⁶⁾. After appropriate counseling, cell-free DNA screening is a reasonable option for patients who decline diagnostic evaluation if a common aneuploidy syndrome is suspected. If micrognathia is isolated, evaluation of both parents is indicated because mild micrognathia can be a constitutionally inherited variant ⁷⁾.

Micrognathia treatment

Early diagnosis and ongoing monitoring help with a multi-disciplinary team of specialists will determine the best time to medically or surgically intervene. If your baby has micrognathia, you may meet with:

• A pediatric otolaryngologist (ENT)
• A craniofacial plastic surgeon
• A pediatric geneticist
• A pediatric pulmonologist

Most children with micrognathia are able to be treated without undergoing surgery. Most infants with micrognathia can be managed by placing the baby on the stomach or side to sleep and feeding the baby in an upright position. Occasionally the baby may need a special tube inserted through the infant’s nose (nasopharyngeal tube) which opens the air passages or special accommodations for feeding. For infants who cannot be managed conservatively, a number of surgical procedures are available.

Non-surgical therapies

Non-surgical therapies to treat micrognathia include:

• Prone positioning — If your child sleeps on his stomach, the positioning thrusts his tongue base forward and clear his airway.
• Nasopharyngeal airways — This flexible tube with a flared end can be inserted into your child’s nostril and into the nasal passageway to create an open airway.
• Non-invasive positive pressure ventilation, such as CPAP (continuous positive airway pressure) or BiPAP (Bi-level positive airway pressure) that is managed by pulmonology for obstructive sleep apnea.

If these minimally-invasive measures do not work, your child may require surgery.

Micrognathia surgery

Surgical treatments for micrognathia include:

• Tongue-lip adhesion procedure, in which the base of your child’s tongue is tied to the lower jaw closer to the chin, effectively moving the tongue-base forward to clear the airway.
• Mandibular distraction osteogenesis (MDO), which makes the lower jaw larger by slowly lengthening the lower jaw bone and relieving airway obstruction.
• Tracheostomy, which creates an opening though the neck into the trachea to bypass the airway obstruction caused by a small jaw. This procedure is only rarely performed to treat micrognathia.

Mandibular distraction osteogenesis

Mandibular distraction osteogenesis is a surgical procedure that makes the lower jaw larger by slowly lengthening the lower jaw bone. The surgeon makes cuts on both sides of the lower jaw and attaches turning devices which expand the space in the bone cut. By turning the devices, the jaw moves forward (and with it, the tongue). The airway will then get bigger, and within a couple of weeks from the surgery, the breathing/sleeping problem will be improved.

Risks for mandibular distraction osteogenesis surgery include damage to tooth buds, sensory nerve damage, facial nerve damage, relapse of the original condition, and infection. After 6 weeks, the new bone has formed and the devices are removed. Usually, the child can go home during this period of bone formation. Additional benefits of mandibular distraction osteogenesis are improved feeding, decreased reflux, and avoidance of a permanent breathing tube called a tracheostomy.

Follow up

Regardless of whether or not a child undergoes surgery as an infant, he or she will need to be followed for:

• Jaw growth
• Dental (tooth) development
• Lower lip sensation
• Airway health

Sometimes, a second (or even first) mandibular distraction osteogenesis surgery is needed during childhood if breathing and sleep apnea problems persist. Many children born with micrognathia will eventually need orthodontic care, as well. Some eventually require corrective jaw surgery after growth is complete in adolescence.

Micrognathia prognosis

Micrognathia prognosis depends on the final syndromic diagnosis. Outcomes for children with micrognathia are generally good, but can vary depending on the severity of the condition, how quickly it was diagnosed, and how it was treated. Additional surgeries may be necessary dependent upon your child’s jaw growth and development. Your child will require long term monitoring until they have reached skeletal maturity in adolescence. In some cases, the growth of the mandible can accelerate and normalize into adulthood.

Early diagnosis and ongoing monitoring help clinicians determine the best time to medically or surgically intervene to give your child the best long-term quality of life.

Exocrine pancreatic insufficiency

Exocrine pancreatic insufficiency (EPI) is a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly, or maldigestion, resulting in malabsorption ¹⁾. This inadequate digestion with nutrient and, especially, fat malabsorption occurs when intraduodenal levels of lipase fall below 5–10% of normal enzyme output ²⁾, leading to pancreatic steatorrhea, weight loss, and a potential decrease in quality of life ³⁾. Furthermore, in exocrine pancreatic insufficiency, due to cystic fibrosis (CF) or chronic pancreatitis, there is decreased bicarbonate output causing a lower intestinal pH, which precipitates bile salt acids and impairs micelle formation of fats ⁴⁾. Fat maldigestion is compounded by decreased pancreatic secretion of lipase and colipase, further dampening hydrolysis of intraluminal fat.

The cause of exocrine pancreatic insufficiency includes pancreatic and nonpancreatic causes ⁵⁾. Numerous conditions account for the cause of exocrine pancreatic insufficiency, with the most common being diseases of the pancreatic tissue including chronic pancreatitis, cystic fibrosis, and a history of extensive necrotizing acute pancreatitis.

Many diagnostic tests are available to diagnose exocrine pancreatic insufficiency, however, the criteria of choice remain unclear and the causes for a false-positive test are not yet understood.

Treatment for exocrine pancreatic insufficiency includes dietary management, lifestyle changes (i.e., decrease in alcohol consumption and smoking cessation), and pancreatic enzyme replacement therapy ⁶⁾.

Exocrine pancreatic insufficiency causes

The exocrine pancreas produces three main types of enzymes: amylase, protease, and lipase ⁷⁾. Under normal physiologic conditions, the enzymes, specifically lipase, break undigested triglycerides into fatty acids and monoglycerides, which are then solubilized by bile salts. Because the exocrine pancreas retains a large reserve capacity for enzyme secretion, fat digestion is not clearly impaired until lipase output decreases to below 10% of the normal level ⁸⁾.

A leading cause of exocrine pancreatic insufficiency is chronic pancreatitis ⁹⁾. Other pancreatic causes include a history of extensive necrotizing acute pancreatitis, pancreatic cancer, pancreatic surgery, and cystic fibrosis. Non-pancreatic causes are celiac disease, diabetes mellitus, Crohn’s disease, gastric surgery, short bowel syndrome, and Zollinger–Ellison syndrome ¹⁰⁾.

Chronic pancreatitis

Chronic pancreatitis is an ongoing inflammatory process with irreversible morphological changes to the pancreas and a gradual loss in pancreatic parenchyma. There are three major groups of mutations that account for chronic pancreatitis (PRSS1, SPINK1, and CFTR). Theories of pathogenesis include oxidative stress, toxic-metabolic derangements, loss of ductal function or obstruction, and necrosis-fibrosis ¹¹⁾.

In chronic pancreatitis, approximately 20% of patients develop exocrine pancreatic insufficiency over time as a result of progressive loss of acinar cell function ¹²⁾. Layer et al. ¹³⁾ found that the median duration from the onset of symptomatic disease to exocrine pancreatic insufficiency was significantly longer in early-onset chronic pancreatitis (median age of onset being 19.2 years) than in late-onset idiopathic chronic pancreatitis (median age of 56.2 years) or alcoholic pancreatitis (median age of 13.1 years).

Cystic fibrosis

Cystic fibrosis is an autosomal recessive disorder caused by a mutation of the gene that encodes for a chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR). In ductal epithelial cells, CFTR is highly expressed and functions to transport fluid and anions into the lumen ¹⁴⁾. Dysfunction of the CFTR gene leads to a decrease in luminal fluid volume and decreased pH, resulting in protein precipitation within the ductal lumen and loss of normal acinar cell function.

Exocrine pancreatic insufficiency is most commonly observed at birth or soon after due to in utero exocrine pancreatic damage. Waters et al. ¹⁵⁾ showed that, during newborn screening, 63% of infants with cystic fibrosis are exocrine insufficient and almost 30% of the pancreas-sufficient group will become exocrine insufficient over the next 36 months. Individuals with class IV, V, or VI mutations (less severe CFTR mutations and hence some preserved CFTR function), tend to suffer from exocrine pancreatic insufficiency later in life ¹⁶⁾. Corey et al. ¹⁷⁾ compared 1000 patients from CF clinics in Boston and Toronto and demonstrated that prolonged untreated exocrine pancreatic insufficiency is associated with a worse long-term outcome and that patients maintained on a high fat diet (100 g per day) with higher doses of exogenous pancreatic enzymes did better than those on a low fat, lower pancreatic enzyme regimen. Overall, pancreatic insufficiency requiring lifelong pancreatic exocrine replacement therapy (PERT) is found in about 85% of CF patients ¹⁸⁾.

A rare complication of PERT is seen only in patients with cystic fibrosis on very high doses of enzymes. Fitzsimmons et al. ¹⁹⁾ found that, in children with cystic fibrosis, there was a strong correlation between high daily doses of PERT and the development of fibrosing colonopathy. However, this represents a small case series published in New England Journal of Medicine in 1997, which were not biopsy proven with very few cases reported since then. Factors related to cystic fibrosis, including thick intestinal secretions, dosing of PERT, and agents in the enteric coating of the pancrelipase preparations may be the precipitating factors causing this complication ²⁰⁾. Therefore, it has been recommended that, in children and adults with cystic fibrosis, the daily dose should remain below 2500 lipase units/kg of body weight per meal or 10000 lipase units/kg of body weight per day ²¹⁾.

Post pancreatic surgery

Factors that contribute to exocrine pancreatic insufficiency following pancreatic surgery are a decrease in pancreatic tissue volume, extensive denervation following lymph node dissection, and surgically altered anatomy ²²⁾. Conditions such as pancreatic cancer, intraductal papillary mucinous neoplasms, premalignant mucinous cystic lesions, and benign tumors of the pancreas may all lead to exocrine pancreatic insufficiency via obstruction of the pancreatic duct. The degree of exocrine pancreatic insufficiency following pancreatic surgery is dependent on the extent of pancreatic resection combined with the degree of residual pancreatic parenchymal function with full manifestation of exocrine pancreatic insufficiency seen following a total pancreatectomy ²³⁾. The mechanism of exocrine pancreatic insufficiency in patients undergoing a Whipple procedure may be related to a mistiming of secreted endogenous pancreatic enzymes mixing with chyme.

Large systematic reviews report a 19–80% incidence of exocrine pancreatic insufficiency following a distal pancreatectomy ²⁴⁾; however, this wide variation may be in part a result of the different diagnostic methods employed ²⁵⁾. Post-operative incidence of exocrine pancreatic insufficiency after Whipple surgery is 56–98% ²⁶⁾. In addition, Halloran et al. ²⁷⁾ analyzed 40 patients following resection for pancreatic malignancy and found that exocrine pancreatic insufficiency was common and sustained after surgery, but was not associated with significant symptoms. These patients with newly developed exocrine pancreatic insufficiency, however, did have a tendency towards poorer quality of life.

Celiac disease

Celiac disease is a chronic inflammatory intestinal disorder that may occur in genetically predisposed people triggered by the ingestion of gluten. This disease has a United States and British prevalence of approximately 1% ²⁸⁾. In celiac disease, although exocrine pancreatic function is intrinsically normal, reduced levels of cholecystokinin release as a result of the duodenal villous atrophy, accounts for impaired gall bladder contraction and reduced exocrine pancreatic secretion ²⁹⁾.

Diabetes mellitus

Diabetes mellitus can predispose to exocrine pancreatic insufficiency and, conversely, longstanding exocrine pancreatic insufficiency can be associated with diabetes ³⁰⁾. In diabetes, there are several possible causes which can account for exocrine pancreatic insufficiency – the lack of the trophic action of insulin (and potentially of glucagon and somatostatin) on acinar cells, autoimmune damage of islet cells, causing destruction of both endocrine and exocrine tissue, and decreased exocrine pancreatic secretion as a complication of diabetic neuropathy ³¹⁾. Therefore, the lack of insulin production and the autoimmunity in type I diabetes explain the higher observed prevalence of exocrine pancreatic insufficiency compared to those with type II diabetes (about 60% vs. 30%) ³²⁾. In addition, a recent article by Soave et al. ³³⁾ showed that the lower the immunoreactive trypsinogen levels at birth in newborns with cystic fibrosis, reflecting more severe exocrine pancreatic disease in utero, the earlier in life they developed cystic fibrosis-related endocrine disease (diabetes).

All infants

Based on the study by Lebenthal and Lee ³⁴⁾ indicating that the duodenal fluid of newborns and infants contained no amylase and negligible lipase at least for the first month of life, all healthy term infants are exocrine pancreatic insufficient. Normally, this is compensated for by amylase and lipase present in breastmilk. However, in formula-fed infants, exocrine pancreatic insufficiency would be expected. In fact, a recent study by Martin et al. ³⁵⁾ confirmed that formula-fed preterm infants had impaired fatty acid absorption evident through 6 or more weeks postnatal age compared to breastmilk-fed infants, and this is consistent with limited pancreatic lipase production by the pancreas ³⁶⁾. Thus, all infants, both term and preterm, represent the largest population of individuals with exocrine pancreatic insufficiency. The clinical implications of developmental pancreatic insufficiency in non-breast-fed infants is unknown, but may play a role in early nutrient deficits in critically ill newborns such as the preterm infant.

Exocrine pancreatic insufficiency symptoms

Symptoms of exocrine pancreatic insufficiency can include steatorrhea (clay-colored, loose, greasy, foul-smelling large stools), abdominal discomfort, bloating, and weight loss. Although floating stools are often thought of being indicative of steatorrhea, they are not; rather sticking to the toilet bowl is a more specific sign.

Exocrine pancreatic insufficiency diagnosis

A multitude of tests for exocrine pancreatic insufficiency have been developed over the past several decades and classified as direct versus indirect measures of exocrine pancreatic function. However, many of these have poor sensitivity or specificity (e.g. serum trypsin levels, qualitative stool fat) and/or are available at only limited centers such as with the 13C mixed triglyceride (13C-MTG) breath test.

72-hour fecal fat test

The gold standard has been the 72-hour stool collection while the patient consumes a diet containing 100 g of fat per day. Fat malabsorption is diagnosed at > 7 g of fat per 100 g of stool per day, with severe steatorrhea at ≥ 15 g per day ³⁷⁾. Unfortunately, this test is time-consuming and not easily tolerated due to bloating, abdominal discomfort, flatulence, and worsening steatorrhea. Additionally, errors can occur in stool collections and recording of fat intake ³⁸⁾. Diseases that impact mucosal fatty acid uptake, such as Crohn’s disease, bacterial overgrowth, and short bowel syndrome, can cause abnormal values despite normal exocrine pancreatic function. However, the 72-hour stool collection has served to measure the effectiveness of PERT in exocrine pancreatic insufficiency ³⁹⁾ for United States Food and Drug Administration (FDA) approval of PERTs.

Fecal elastase test

The pancreas produces pancreatic elastase 1, which is a highly stable enzyme during intestinal transit ⁴⁰⁾. This proteolytic enzyme can be measured in a fecal sample by an enzyme-linked immunosorbent assay ⁴¹⁾. Because pancreatic elastase is highly stable during intestinal transit, the fecal concentration correlates well with exocrine pancreatic secretion ⁴²⁾. Diagnostic testing using fecal elastase has some advantages over other tests because it does not require a timed stool collection or special diet, has a high negative predictive value, and has a high sensitivity in moderate to severe exocrine pancreatic insufficiency when formed stools are analyzed ⁴³⁾. The reference range of less than 200 μg/g feces can be applied to both children and adults for the diagnosis of exocrine pancreatic insufficiency ⁴⁴⁾. Some consider values less than 100 μg/g feces as diagnostic of exocrine pancreatic insufficiency, with fecal elastase values between 100 and 200 μg/g to be indeterminate and difficult to interpret ⁴⁵⁾.

In mild to moderate exocrine pancreatic insufficiency, diagnostic testing using fecal elastase has a lower sensitivity (as low as 30%) and specificity, possibly resulting in an underestimation of exocrine pancreatic insufficiency ⁴⁶⁾. In childhood, however, fecal elastase is a useful noninvasive screening test for exocrine pancreatic insufficiency, demonstrating a negative predictive value of 99% for ruling out exocrine pancreatic insufficiency ⁴⁷⁾. Since fecal elastase is measured as a concentration in stool, watery stools will almost invariably result in low elastase values being measured and thus this non-invasive, pancreatic function test should be performed in a clinical setting where exocrine pancreatic insufficiency is suspected and a formed stool can be analyzed. This has replaced the more cumbersome 72-hour fecal fat test. In addition, PERTs do not have to be stopped for fecal elastase testing since the porcine enzymes do not cross react with the human fecal elastase antibody.

Laboratory studies

A complete laboratory evaluation is required not only to diagnose exocrine pancreatic insufficiency but also to determine the extent of the malabsorption and assess manifestations of the underlying disease, if present.

Blood tests

These can include the following:

• Complete blood count (CBC). A complete blood count (CBC) may reveal microcytic anemia due to iron deficiency or macrocytic anemia due to vitamin B-12 or folate malabsorption. Serum iron, vitamin B-12, and folate concentrations may help establish the diagnosis of exocrine pancreatic insufficiency. Prothrombin time (PT) may be prolonged because of malabsorption of vitamin K, a fat-soluble vitamin. A study by Lindkvist et al found that serum nutritional markers (eg, magnesium, albumin, prealbumin) can be used to determine the probability of exocrine pancreatic insufficiency in patients with chronic pancreatitis ⁴⁸⁾.
• Antigliadin and antiendomysial antibodies. Serum levels of antigliadin and antiendomysial antibodies can be used to help diagnose celiac sprue. The serum immunoglobulin A (IgA) level can be assessed to rule out IgA deficiency.
• Malabsorption can involve electrolyte imbalances such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis. Protein malabsorption may cause hypoproteinemia and hypoalbuminemia. Fat malabsorption can lead to low serum levels of triglycerides, cholesterol, and alpha- and beta-carotene. The Westergren erythrocyte sedimentation rate (ESR) may provide a clue to an underlying autoimmune disease.

Stool tests

Determination of fecal elastase and chymotrypsin (2 proteases produced by the pancreas) can be used to try to distinguish between pancreatic causes and intestinal causes of malabsorption.

Malabsorption tests

These can include the following:

• Fat absorption tests. See 72-hour fecal fat test above.
• D-xylose test. If the 72-hour fecal fat collection results demonstrate fat malabsorption, the D-xylose test is used to document the integrity of the intestinal mucosa. D-xylose is readily absorbed in the small intestine. Approximately half of the absorbed D-xylose is excreted in urine without being metabolized. If absorption of D-xylose is impaired by either a luminal factor (eg, bacterial overgrowth) or a reduced or damaged mucosal surface area (eg, from surgical resection or celiac disease), urinary excretion will be lower than normal. Cases of pancreatic insufficiency usually result in normal urinary excretion because absorption of D-xylose is still intact.
• Carbohydrate absorption test. A simple sensitive test for carbohydrate malabsorption is the hydrogen breath test, in which patients are given an oral solution of lactose ⁴⁹⁾. In cases of lactase deficiency, colonic organisms digest the unabsorbed lactose, which results in an elevated hydrogen content in the expired air. Bacterial overgrowth or rapid transit also can cause an early rise in breath hydrogen, in which case it is necessary to use glucose instead of lactose to make a diagnosis. However, 18% of patients are hydrogen nonexcretors, in whom the hydrogen breath test will yield false-negative test results.
• Bile salt absorption test. The bile salt breath test can determine the integrity of bile salt metabolism. The patient is given an oral conjugated bile salt, such as glycine cholic acid with the glycine radiolabeled in the carbon position. The bile salt is deconjugated and subsequently metabolized by bacteria. If interrupted enterohepatic circulation (eg, from bacterial overgrowth, ileal resection, or disease), a radioactively labeled elevated breath carbon dioxide level will be noted.
• Schilling test. Malabsorption of vitamin B-12 may occur as a consequence of an intrinsic factor deficiency (eg, from pernicious anemia or gastric resection), pancreatic insufficiency, bacterial overgrowth, ileal resection, or disease. The 3-stage Schilling test can often help differentiate these conditions.
• C¹³-D-xylose breath test. A study by Hope et al suggested that small intestinal malabsorption in chronic alcoholism may be identified by means of a C¹³-D-xylose breath test ⁵⁰⁾. The investigators evaluated this test in 14 alcoholics, compared the results with those obtained from untreated celiac disease patients and healthy control subjects, and correlated the breath test findings with the morphologic findings from the duodenal mucosa. In this study, absorption of C¹³-D-xylose was significantly less in the alcoholic patients than in healthy control subjects, whereas the time curve of C¹³-D-xylose absorption in the alcoholics was similar to that in the untreated celiac patients ⁵¹⁾. In addition, although few changes were observed on light microscopy in the alcoholics, morphologic pathology (primarily reduced surface area of microvilli) was observed on electron microscopy in the majority of the patients.

Pancreatic function tests

These can include the following:

• Direct testing – Secretin test, cholecystokinin (CCK) test, secretin-CCK test
• Indirect testing – Qualitative fecal fat analysis, fecal elastase and fecal chymotrypsin level analysis

Pancreatic function can be measured directly by using endoscopy or the Dreiling tube method after stimulation with secretin or cholecystokinin (CCK). Direct pancreatic function testing is the most sensitive approach to assessment of exocrine pancreatic function and is usually performed at specialized centers ⁵²⁾. Various methods have been developed ⁵³⁾.

Direct testing

Whereas the cholecystokinin (CCK) test measures the ability of the acinar cells to secrete digestive enzymes, the secretin test measures the ability of the ductal cells to secrete bicarbonate. Although both tests yield abnormal results in advanced exocrine pancreatic insufficiency, it is not known which of the 2 secretagogues offers better sensitivity for early exocrine pancreatic insufficiency. In uncertain cases, both cholecystokinin (CCK) and secretin tests may be ordered.

Secretin test

In the secretin test, porcine or human synthetic secretin is given in doses ranging from 0.5 to 5 clinical units (CU)/kg. Duodenal fluid is continuously collected in 15-minute aliquots for 1 hour. The fluid is analyzed for bicarbonate concentration, volume, and total bicarbonate output.

A bicarbonate concentration lower than 80 mEq/L in all 4 aliquots represents exocrine insufficiency. A peak bicarbonate cutoff of 90 mEq/L has been advocated by some investigators. A peak bicarbonate concentration lower than 50 mEq/L is indicative of severe exocrine insufficiency. When the bicarbonate concentration is equivocal, volume and total bicarbonate output are used as secondary diagnostic parameters.

Cholecystokinin test

Use of a cholecystokinin (CCK) receptor agonist (eg, cerulein) as a hormonal stimulant provides information on pancreatic enzyme-secreting capacity. Two endoscopic tubes are placed: (1) a single-lumen gastric tube and (2) a double-lumen duodenal tube. The gastric tube continuously collects and discards gastric fluid to prevent acidification of the duodenum. One duodenal lumen continuously collects duodenal drainage fluid, whereas the other is used for administration of a mannitol-saline solution containing a nonabsorbable marker (polyethylene glycol [PEG]).

An accurate determination is made of enzyme concentration, enzyme output, and fluid volume on the basis of recovery of the PEG marker. Measurement of perfusion markers requires a specialized laboratory.

Secretin-cholecystokinin test

Many pancreatic research centers use the combined secretin-cholecystokinin (CCK) test, which allows simultaneous assessment of ductal and acinar secretory capacity. Many dosing regimens have been used for this test. The 2 hormones are administered, and the concentration and output of both bicarbonate and pancreatic enzymes are evaluated.

Indirect testing

Pancreatic function can also be measured indirectly. Qualitative fecal fat analysis via microscopic examination of random stool samples is used as a screening test only ⁵⁴⁾. In addition, measurement of fecal elastase and fecal chymotrypsin levels may serve as an indirect indicator of pancreatic function; however, sensitivity is limited to moderate or severe disease, and the result can be falsely positive as a result of dilution by watery stools ⁵⁵⁾. The typical findings in exocrine pancreatic insufficiency are increased fecal fat and decreased enzymes.

A prospective study by González-Sánchez et al suggested that with regard to sensitivity, specificity, and positive and negative predictive values, results from the fecal elastase-1 (FE-1) test are similar to those from the C¹³-mixed triglyceride breath test in the diagnosis of exocrine pancreatic insufficiency in chronic pancreatitis. However, the triglyceride breath test appeared to be more accurate than the FE-1 test in operated patients with chronic pancreatitis ⁵⁶⁾.

Abdominal imaging

Abdominal imaging can help in identifying features of chronic pancreatitis, which is the most common cause of exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency treatment

Management approaches to exocrine pancreatic insufficiency include the following ⁵⁷⁾:

• Lifestyle modifications (eg, avoidance of fatty foods, limitation of alcohol intake, cessation of smoking, and consumption of a well-balanced diet)
• Vitamin supplementation (primarily the fat-soluble vitamins A, D, E, and K)
• Pancreatic enzyme replacement therapy (PERT), which is the therapeutic mainstay

Long-term monitoring of patients with exocrine pancreatic insufficiency should focus on the following 2 issues:

• Correction of nutritional deficiencies
• Treatment of causative diseases (when possible); such treatment will vary according to the specific disease present

Dietary management and lifestyle changes

Fat malabsorption is the predominant cause of the symptoms of pancreatic steatorrhea resulting in weight loss as well as deficiencies of fat-soluble vitamins A, D, E, and K. In patients with chronic pancreatitis, a low fat diet has been the recommendation in order to minimize the pain of this disease and, in conjunction with pancreatic enzyme replacement therapy (PERT), to effectively treat steatorrhea. However, in patients with cystic fibrosis, a high fat diet in conjunction with increased amounts of pancreatic enzyme replacement therapies (PERTs) has been shown to improve the associated cystic fibrosis lung disease and thus low fat diets are no longer advocated in this disease. Fat soluble vitamins A, D, E, and K should be supplemented if indicated, and taken with pancreatic enzyme replacement therapy (PERT) ⁵⁸⁾. Consulting a dietitian is helpful to assess nutritional adequacy ⁵⁹⁾. In addition, smoking has been proven to be a risk factor in acute pancreatitis, chronic pancreatitis, pancreatic cancer ⁶⁰⁾, and to be associated with reduced exocrine pancreatic function ⁶¹⁾. Therefore, smoking and alcohol cessation is recommended in exocrine pancreatic insufficiency due to chronic pancreatitis.

Pancreatic enzyme replacement therapy

The elimination of malabsorption, reduction of maldigestion-related symptoms, and the prevention of malnutrition-related morbidity and mortality is the goal for pancreatic enzyme replacement therapy (PERT) ⁶²⁾. This is most evident in cystic fibrosis, where prior to the availability of pancreatic enzyme replacement therapy (PERT), infants died within the first year of life. Prior to 2010, pancreatic enzymes were not FDA regulated and had variable consistency of activity. As a result, in 2010, the FDA mandated approval of all prescribed formulations of pancreatic enzyme replacement therapy (PERT). It should be noted that the clinical trials were relatively small (less than 40 subjects) and tested in subjects who were known to respond to PERTs. All pancreatic enzyme preparations are extracts from porcine pancreas (pancrelipase) and are available in preparations encapsulated in mini-microspheres or microtablets, which vary in particle size and pH-related release kinetics ⁶³⁾. Enteric-coated pancreatic microspheres are designed to be acid resistant and pH-sensitive to protect lipase from denaturation by gastric acid. Unfortunately, confusion has arisen due to the many different dosage strengths of PERTs (Table 1) ⁶⁴⁾.

Table 1. Current Food and Drug Administration (FDA) approved pancreatic enzyme replacement therapies (PERTs)

Brand	Units of lipase
Creon	3000; 6000; 12,000; 24,000; 36,000
Zenpep	3000; 5000; 10,000; 15,000; 20,000; 25,000
Pancreaze	4200; 10,500; 16,800; 21,000
Ultresa	13,800; 20,700; 23,000
Viokase	10,440; 20,880 (requires acid suppression)
Pertzye	8000; 16,000

[Source ⁶⁵⁾ ]

Enteric-coated pancreatic enzymes are most effective at a pH > 6. However, in patients with cystic fibrosis, the duodenal pH is < 6 ⁶⁶⁾. The use of acid-suppression medications can increase gastric pH levels and theoretically improve the efficacy of pancreatic enzyme replacement therapy (PERT) and decrease exocrine pancreatic insufficiency symptoms ⁶⁷⁾. Current data may suggest a trial of acid blockers in patients with cystic fibrosis who have refractory steatorrhea ⁶⁸⁾. However, a recent retrospective study demonstrated no improvement of the coefficient of fat absorption (72-hour fecal fat test) when using a proton pump inhibitor in pediatric patients with cystic fibrosis ⁶⁹⁾.

Uncoated exogenous pancreatic enzymes, such as Viokase (Aptalis Pharma), are thought to mix well with intragastric nutrients and rapidly release high duodenal lipase amounts for fat digestion ⁷⁰⁾. The addition of acid-suppression medications is required to prevent degradation of non-enteric coated pancreatic enzymes ⁷¹⁾. Only non-enteric pancreatic enzymes have been shown to improve the pain in a subset of patients with chronic pancreatitis. The use of unprotected exogenous enzymes in combination with enteric-coated enzymes has previously been recommended for the treatment of refractory exocrine pancreatic insufficiency ⁷²⁾; however, Kalnins et al. ⁷³⁾ showed no improvement in nutrient digestion (fecal fat, energy, and nitrogen output) when unprotected pancreatic enzymes were added to the conventional enteric-coated enzymes in 14 pediatric patients with cystic fibrosis.

Dosing and frequency of pancreatic enzyme replacement therapy administration

Dosing and frequency of administration are difficult aspects of pancreatic enzyme replacement therapy (PERT) treatment since different enteric-coated microspheres are not bioequivalent in vitro ⁷⁴⁾ and there are not enough clinical studies between preparations to define in vivo bioavailability. In these in vitro studies, the preparations varied in dissolution time (49–71 min half-life time) and in optimum pH (pH 5.0–5.8).

Several countries have recommended different doses of pancreatic enzyme replacement therapy (PERT). The Australasian Pancreatic Club ⁷⁵⁾, The Italian Association for the Study of the Pancreas ⁷⁶⁾ and The Spanish Pancreatic Club ⁷⁷⁾ recommend 25,000–50,000 lipase units per main meal in adults. Unfortunately, the evidence for these recommendations is relatively weak as emphasized by The Australasian Pancreatic Club in their recent study on the management of pancreatic exocrine insufficiency ⁷⁸⁾. In addition, a study from the Netherlands by Sikkens et al. ⁷⁹⁾ found that 70% (n = 161) of the patients with exocrine pancreatic insufficiency caused by chronic pancreatitis were under-treated and reported steatorrhea-related symptoms, despite pancreatic enzyme replacement therapy (PERT) (median enzyme intake of 6 capsules, 25,000 lipase units per day). These differences in recommendations demonstrate the significant confusion over dosing and administration amongst medical practitioners.

Likewise, there is no consensus over frequency of pancreatic enzyme replacement therapy (PERT) administration. In 1977, DiMagno et al. ⁸⁰⁾ demonstrated that administration of pancreatic enzyme replacement therapy (PERT) during a meal was as effective as hourly administration over the day to decrease steatorrhea. Other recommendations based on several reviews are to take 50% of the exogenous pancreatic enzymes at the beginning of the meal and 50% half-way through ⁸¹⁾, pancreatic enzymes during or immediately following the meal ⁸²⁾, or lastly, 25% of the enzymes with the first bite, 50% during the meal, and 25% with the last bite ⁸³⁾. In addition, a recent randomized three-way crossover study of 24 patients using 40,000 lipase units per meal compared three different administration schedules with pancreatic enzyme replacement therapy (PERT) before meals, during meals, or after meals using the 13C-MTG breath test to measure fat absorption ⁸⁴⁾. The percentage of patients who normalized fat digestion was 50%, 54%, and 63%, respectively. Thus, no statistically significant differences were found between different administration schedules, however, they did recommend giving pancreatic enzyme replacement therapy (PERT) during or after meals.

In a patient with suspected exocrine pancreatic insufficiency with a known history of pancreatic disease, empiric therapy with pancreatic enzyme replacement therapy (PERT)s may be indicated without formal testing. A clear response would be both diagnostic for exocrine pancreatic insufficiency as well as therapeutic. In addition, if there is a poor response to pancreatic enzyme replacement therapy (PERT), one should consider concurrent gastrointestinal comorbidities such as lactose intolerance, enteric bacterial infection, parasites (especially giardia), small intestinal bacterial overgrowth, biliary disease (cholestasis), colitis, celiac disease, short bowel syndrome, and Crohn’s disease ⁸⁵⁾. Other reasons could be insufficient dosing, lack of compliance, inadequate timing of pancreatic enzyme replacement therapy (PERT) administration, and poor diet (Table 2).

Table 2. Treatment strategies for lack of response to pancreatic enzyme replacement therapy (PERT)

Treatment strategies
• Increase dosage
• Check compliance with the patient
• Add acid inhibitor
• Consider adding enzymes during and towards end of meal
• Consider microspheres, possibly adding a rapid release enzyme preparation
• Look for evidence of concurrent gastrointestinal disorder

[Source ⁸⁶⁾ ]

Pancreatic enzyme replacement therapy (PERT) should be taken with the first bite of a meal and consider adding extra enzymes during or towards the end of the meal. Thus, if consumption of a meal is less than 15 min, all enzymes can be taken at the beginning of the meal; for a 15- to 30-minute meal, we suggest taking half the enzyme capsules with the first bite and the other half in the middle of the meal; for more than 30 minutes, we recommend taking one third at the beginning, one third in the middle and one third at the end. The rationale for taking pancreatic enzymes throughout the meal is to mimic the action of our own endogenous pancreatic enzymes, where secretion from the gland occurs throughout a meal. Specifically, the more food that is ingested and/or the grater the amount of fat in the diet, the higher the amount of endogenous pancreatic enzyme secretion; thus, the number of pancreatic enzyme replacement therapy (PERT) capsules consumed should reflect this. Table 3 gives a suggested clinical overview of pancreatic enzyme replacement therapy (PERT) dosing for different age groups ⁸⁷⁾.

Table 3. Pancreatic enzyme replacement therapy (PERT) suggested dosing in different age groups

Age group	Units of lipase
Infant	2000–4000 units/120 mL formula or breastmilk
Child age < 4 years	1000 units/kg/meal 500 units/kg/snack
Child age ≥ 4 years	500 units/kg/meal 250 units/kg/snack
Adult starting dose	50,000 units/meal 25,000 units/snack
Adult maximum dose	150,000 units/meal 70,000 units/snack

[Source ⁸⁸⁾ ]

What is prolactinoma

Prolactinoma is a benign (noncancerous) pituitary tumor which produces the hormone called prolactin. Prolactinomas are adenomas arising from lactotroph cells in the pituitary gland that secrete prolactin and prolactinomas are the most common type of pituitary tumor and most frequently diagnosed functioning pituitary tumor type, accounting for about 40% of all pituitary adenomas ¹⁾. Almost all pituitary tumors are noncancerous (benign). Prolactinoma may occur as part of an inherited condition called multiple endocrine neoplasia type 1 (MEN 1). Symptoms of prolactinoma are caused by hyperprolactinemia too much prolactin in the blood or by pressure of the tumor on surrounding tissues. Prolactinoma tumors come in various sizes, but the vast majority are less than 10mm (<1 cm or 3/8 of an inch) in diameter. These small tumors occur more often in women. Larger tumors are more common in men. They tend to occur at an older age. The tumor can grow to a large size before symptoms appear.

Prolactinoma tumor is often detected at an earlier stage in women than in men because of irregular menstrual periods.

Prolactinomas occur most commonly in people under age 40. Prolactinomas can occur in both men and women, but more often in women than men and rarely occur in children. Most prolactinomas occur in women between 20 and 34 years old. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people.

Prolactin stimulates the breast to produce milk during pregnancy. After giving birth, a mother’s prolactin levels fall unless she breastfeeds her infant, but prolactin receptors have been found in several tissues, including the liver, ovary, testis, and prostate ²⁾. The primary action of prolactin is the initiation and maintenance of lactation, each time the baby nurses, prolactin levels rise to maintain milk production. Moreover, prolactin can act as a growth factor, neurotransmitter, or immunoregulator via autocrine or paracrine mechanisms ³⁾.

Although small benign pituitary tumors are fairly common in the general population, symptomatic prolactinomas are uncommon.

The outlook for prolactinomas depends heavily on the success of medical and surgical therapies. Tests to scan for recurrence following treatment are important.

Very few patients with prolactinomas require surgery, as most prolactinomas (particularly microprolactinomas) shrink in size following treatment with medication. Treat prolactinoma with bromocriptine or cabergoline.

Hormone replace therapy may be required after treatment.

Is osteoporosis a risk in women with high prolactin levels?

Women whose ovaries produce inadequate estrogen are at increased risk for osteoporosis. Hyperprolactinemia can reduce estrogen production. Although estrogen production may be restored after treatment for hyperprolactinemia, even a year or 2 without estrogen can compromise bone strength. Women should protect themselves from osteoporosis by increasing exercise and calcium intake through diet or supplements and by not smoking. Women treated for hyperprolactinemia may want to have periodic bone density measurements and discuss estrogen replacement therapy or other bone-strengthening medications with their doctor.

How do oral contraceptives and hormone replacement therapy affect prolactinoma?

Oral contraceptives are not thought to contribute to the development of prolactinomas, although some studies have found increased prolactin levels in women taking these medications. Because oral contraceptives may produce regular menstrual bleeding in women who would otherwise have irregular menses due to hyperprolactinemia, prolactinoma may not be diagnosed until women stop oral contraceptives and find their menses are absent or irregular. Women with prolactinoma treated with bromocriptine or cabergoline may safely take oral contraceptives. Similarly, postmenopausal women treated with medical therapy or surgery for prolactinoma may be candidates for estrogen replacement therapy.

The pituitary gland

The pituitary gland (hypophysis) is located at the base of the brain where it sits in the middle of the head in a bony box called the sella turcica, where a pituitary stalk (infundibulum) attaches it to the hypothalamus. The gland is about 1 centimeter in diameter and consists of an anterior pituitary or anterior lobe, and a posterior pituitary, or posterior lobe. The pituitary stalk (infundibulum) contains both blood vessels and nerves. The pituitary gland controls a system of hormones in the body that regulate growth, metabolism, the stress response, and functions of the sex organs via the thyroid gland, adrenal gland, ovaries, and testes. The optic nerves sit directly above the pituitary gland. Enlargement of the gland can cause symptoms such as headaches or visual disturbances. Pituitary tumors may also impair production of one or more pituitary hormones, causing reduced pituitary function, also called hypopituitarism.

The pituitary gland, sometimes also called the master gland, because it plays a critical role in regulating growth and development, metabolism, and reproduction. The pituitary gland (hypophysis) produces prolactin and other key hormones including:

• Growth hormone (GH), which regulates growth
• Adrenocorticotropin (ACTH), which stimulates the adrenal glands to produce cortisol, a hormone important in metabolism and the body’s response to stress
• Thyrotropin (TSH or thyroid stimulating hormone), which signals the thyroid gland to produce thyroid hormone, also involved in metabolism and growth
• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which regulate ovulation and estrogen and progesterone production in women and sperm formation and testosterone production in men.

Prolactin production and release is mediated via tonic inhibition by dopamine secreted by the hypothalamus.

Figure 1. The pituitary gland location

Figure 2. Pituitary gland

Figure 3. The hypothalamus and pituitary gland (anterior and posterior) endocrine pathways and target organs

Prolactinoma and pregnancy

If a woman has a small prolactinoma, she can usually conceive and have a normal pregnancy after effective medical therapy. If she had a successful pregnancy before, the chance of her having more successful pregnancies is high.

A woman with prolactinoma should discuss her plans to conceive with her physician so she can be carefully evaluated prior to becoming pregnant. This evaluation will include an MRI scan to assess the size of the tumor and an eye examination with measurement of visual fields. As soon as a woman is pregnant, her doctor will usually advise her to stop taking bromocriptine or cabergoline. Although these drugs are safe for the fetus in early pregnancy, their safety throughout an entire pregnancy has not been established. Many doctors prefer to use bromocriptine in patients who plan to become pregnant because it has a longer record of safety in early pregnancy than cabergoline.

Bromocriptine (Parlodel) is an ergoline derivative, a dopamine D2 receptor agonist with agonist and antagonistic properties on D1 receptors. It is generally required to multiple dosing throughout the day because of its short half life ⁴⁾. In women taking bromocriptine during early pregnancy, the incidence of abortions, ectopic pregnancies, or congenital malformations is no higher than that in the general population ⁵⁾. In a study of 2,587 pregnant women, out of which 2,437 were to increase the risk of spontaneous abortion, congenital abnormalities, or multiple pregnancies, and did not affect post-natal development ⁶⁾. In other studies, among 6,329 patients treated with bromocriptine during early pregnancy, the risk of spontaneous abortions was 9.9%, which was not higher than that in the general population (10.9%) ⁷⁾. Moreover, long-term follow-up to 9 years of children born from mothers taking bromocriptine did not cause detrimental effects on fetal outcomes in term of physical development as well as no psychomotor developmental abnormality reported to 5.5 years (1–20 years) follow-up ⁸⁾.

Furthermore, optimal outcome was found with continuous use of bromocriptine throughout pregnancy in around 100 cases ⁹⁾.

Cabergoline (Dostinex) is an ergoline derivative dopamine agonist with higher affinity and selectivity for D2 dopamine receptors. It has long duration of action allowing administration once or twice weekly with better tolerability and patient compliance ¹⁰⁾. Moreover, pregnancy rate is higher with cabergoline in infertile women with prolactinoma than with bromocriptine ¹¹⁾.

The same results have been reported in women who were on cabergoline before and during pregnancy ¹²⁾. In one report, over 800 such pregnancies have been described ¹³⁾ (of which approximately 350 were exposed during the first weeks of pregnancy), with no significant difference in the frequency of spontaneous abortion, premature delivery, multiple pregnancy, or neonatal malformations ¹⁴⁾.

In retrospective study on 103 pregnancies in 90 women with hyperprolactinemia and the follow-up of the 61 children, no significant abnormalities related neither to cabergoline doses nor to the time of exposure ¹⁵⁾. Data of 12 years follow-up in the children born from mother treated with cabergoline showed no influence on their post-natal development such as physical problems or of psychomotor retardation ¹⁶⁾. In consistent with previous studies, finding from meta-analysis showed no significant increase in the risk of miscarriages or fetal malformation with dopamine agonist used ¹⁷⁾.

The pituitary enlarges and prolactin production increases during pregnancy in women without pituitary disorders. Women with prolactin-secreting tumors may experience further pituitary enlargement and must be closely monitored during pregnancy. Less than 3 percent of pregnant women with small prolactinomas have symptoms of tumor growth such as headaches or vision problems. In women with large prolactinomas, the risk of symptomatic tumor growth is greater, and may be as high as 32 percent ¹⁸⁾.

The determination of the appropriate treatment option is an individual choice depending mainly on tumor size. The proposed therapeutic approach is shown in Figure ​1 ¹⁹⁾. The outcomes of prolactinomas after pregnancy have been extensively discussed, with variable results. A recent study showed a prolactin normalization rate of more than 40% without medical treatment, for a median follow-up of 22 months after delivery and cessation of lactation ²⁰⁾.

Most endocrinologists see patients every 2 months throughout the pregnancy. A woman should consult her endocrinologist promptly if she develops symptoms of tumor growth-particularly headaches, vision changes, nausea, vomiting, excessive thirst or urination, or extreme lethargy. Bromocriptine or, less often, cabergoline treatment may be reinitiated and additional treatment may be required if the woman develops symptoms during pregnancy.

Figure 4. Approach to managing prolactinomas during pregnancy

Note: DA = dopamine agonist

[Source ²¹⁾]

Impact of Pregnancy and Breastfeeding on Prolactin Levels, Tumor Volume, and Remission Rate

The current literature demonstrates that pregnancy induces remission of hyperprolactinemia in two-thirds of women after discontinuation of dopamine agonist. In one study, pregnancy has been found to induce remission in 76% of non-tumoral hyperprolactinemia, 70% in microprolactinomas, and 64% in macroprolactinomas with higher recurrence rate among patients with macroprolactinomas and those with microprolactinomas with visible tumor on MRI at the time of treatment withdrawal ²²⁾.

In recent study, complete remission was found in 100% with non-tumoral hyperprolactinemia, 66% of patients with microprolactinomas, and 70% with macroprolactinomas ²³⁾. Underlying mechanisms are uncertain but have generally been attributed to the autoinfarction of the tumor ²⁴⁾.

On the other hand, there is no data to suggest breastfeeding is associated with an increased prolactin production or risk of tumor enlargement ²⁵⁾. Thus, women could breastfeed normally and restart dopamine agonist after cessation of lactation.

Prolactinoma complications

Complications of prolactinoma may include:

• Vision loss. Left untreated, a prolactinoma may grow large enough to compress your optic nerve.
• Hypopituitarism. With larger prolactinomas, pressure on the normal pituitary gland can cause dysfunction of other hormones controlled by the pituitary, resulting in hypothyroidism, adrenal insufficiency and growth hormone deficiency.
• Bone loss (osteoporosis). Too much prolactin can reduce production of the hormones estrogen and testosterone, resulting in decreased bone density and an increased risk of osteoporosis.
• Pregnancy complications. During a normal pregnancy, a woman’s production of estrogen increases. In a woman with a large prolactinoma, these high levels of estrogen may cause tumor growth and associated signs and symptoms, such as headaches and changes in vision.

If you have prolactinoma and you want to become or are already pregnant, talk to your doctor. Adjustments in your treatment and monitoring may be necessary.

Prolactinoma causes

The cause of pituitary tumors remains largely unknown. Most pituitary tumors are sporadic, meaning they are not genetically passed from parents to their children.

In some people, high blood levels of prolactin can be traced to causes other than pituitary prolactinoma.

Prescription drugs. Prolactin secretion in the pituitary is normally suppressed by the brain chemical dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin. These drugs include older antipsychotic medications such as trifluoperazine (Stelazine) and haloperidol (Haldol); the newer antipsychotic drugs risperidone (Risperdal) and molindone (Moban); metoclopramide (Reglan), used to treat gastroesophageal reflux and the nausea caused by certain cancer drugs; and less often, verapamil, alpha-methyldopa (Aldochlor, Aldoril), and reserpine (Serpalan, Serpasil), used to control high blood pressure. Some antidepressants may cause hyperprolactinemia, but further research is needed.

Other pituitary tumors. Other tumors arising in or near the pituitary may block the flow of dopamine from the brain to the prolactin-secreting cells. Such tumors include those that cause acromegaly, a condition caused by too much growth hormone, and Cushing’s syndrome, caused by too much cortisol. Other pituitary tumors that do not result in excess hormone production may also block the flow of dopamine.

Hypothyroidism. Increased prolactin levels are often seen in people with hypothyroidism, a condition in which the thyroid does not produce enough thyroid hormone. Doctors routinely test people with hyperprolactinemia for hypothyroidism.

Chest involvement. Nipple stimulation also can cause a modest increase in the amount of prolactin in the blood. Similarly, chest wall injury or shingles involving the chest wall may also cause hyperprolactinemia.

Prolactinoma symptoms

In women, high levels of prolactin in the blood often cause infertility and changes in menstruation. In some women, periods may stop. In others, periods may become irregular or menstrual flow may change. Women who are not pregnant or nursing may begin producing breast milk. Some women may experience a loss of libido-interest in sex. Intercourse may become painful because of vaginal dryness.

In men, the most common symptom of prolactinoma is erectile dysfunction. Because men have no reliable indicator such as changes in menstruation to signal a problem, many men delay going to the doctor until they have headaches or eye problems caused by the enlarged pituitary pressing against nearby optic nerves. They may not recognize a gradual loss of sexual function or libido. Only after treatment do some men realize they had a problem with sexual function.

Prolactinoma symptoms in women:

• Milky discharge from the breasts (galactorrhea) when not pregnant or breast-feeding
• Breast tenderness
• Decreased sexual interest
• Painful intercourse due to vaginal dryness
• Acne and excessive body and facial hair growth (hirsutism)
• Decreased peripheral vision
• Headache
• Infertility
• Irregular menstrual periods (oligomenorrhea) or no menstrual periods (amenorrhea)
• Vision changes

Prolactinoma symptoms in men:

• Decreased sexual interest
• Decreased peripheral vision
• Enlargement of breast tissue (gynecomastia)
• Headache
• Erectile dysfunction (impotence)
• Infertility
• Vision changes
• Decreased body and facial hair

Symptoms caused by pressure from a larger tumor may include:

• Headaches
• Lethargy
• Nasal drainage
• Nausea and vomiting
• Problems with the sense of smell
• Vision changes, such as double vision, drooping eyelids or visual field loss
• Reduction of other hormone production by the pituitary gland (hypopituitarism) as a result of tumor pressure
• Low bone density
• Loss of interest in sexual activity
• Infertility

There may be no symptoms, especially in men. Women tend to notice signs and symptoms earlier than men do, when tumors are smaller in size, probably because they’re alerted by missed or irregular menstrual periods. Men tend to notice signs and symptoms later, when tumors are larger and more likely to cause headache or vision problems.

Prolactinoma diagnosis

A doctor will test for prolactin blood levels in women with unexplained milk secretion, called galactorrhea, or with irregular menses or infertility and in men with impaired sexual function and, in rare cases, milk secretion.

Tests that may be ordered include:

• Pituitary MRI or brain CT scan
• Testosterone level in men
• Prolactin level
• Thyroid function tests

If prolactin levels are high, a doctor will test thyroid function and ask first about other conditions and medications known to raise prolactin secretion. The doctor may also request magnetic resonance imaging (MRI), which is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy. Computerized tomography (CT) scan also gives an image of the pituitary but is less precise than the MRI.

The doctor will also look for damage to surrounding tissues and perform tests to assess whether production of other pituitary hormones is normal. Depending on the size of the tumor, the doctor may request an eye exam with measurement of visual fields.

Prolactinoma treatment

The goals of treatment are to return prolactin secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function. In the case of large tumors, only partial achievement of these goals may be possible.

Prolactinoma medication

Because dopamine is the chemical that normally inhibits prolactin secretion, doctors may treat prolactinoma with the dopamine agonists bromocriptine (Parlodel) or cabergoline (Dostinex). Agonists are drugs that act like a naturally occurring substance. These drugs shrink the tumor and return prolactin levels to normal in approximately 80 percent of patients. Both drugs have been approved by the U.S. Food and Drug Administration for the treatment of hyperprolactinemia. Bromocriptine is the only dopamine agonist approved for the treatment of infertility. This drug has been in use longer than cabergoline and has a well-established safety record.

Nausea and dizziness are possible side effects of bromocriptine. To avoid these side effects, bromocriptine treatment must be started slowly. A typical starting dose is one-quarter to one-half of a 2.5 milligram (mg) tablet taken at bedtime with a snack. The dose is gradually increased every 3 to 7 days as needed and taken in divided doses with meals or at bedtime with a snack. Most people are successfully treated with 7.5 mg a day or less, although some people need 15 mg or more each day. Because bromocriptine is short acting, it should be taken either twice or three times daily.

Bromocriptine treatment should not be stopped without consulting a qualified endocrinologist-a doctor specializing in disorders of the hormone-producing glands. Prolactin levels rise again in most people when the drug is discontinued. In some, however, prolactin levels remain normal, so the doctor may suggest reducing or discontinuing treatment every 2 years on a trial basis.

Cabergoline is a newer drug that may be more effective than bromocriptine in normalizing prolactin levels and shrinking tumor size. Cabergoline also has less frequent and less severe side effects. Cabergoline is more expensive than bromocriptine and, being newer on the market, its long-term safety record is less well defined. As with bromocriptine therapy, nausea and dizziness are possible side effects but may be avoided if treatment is started slowly. The usual starting dose is .25 mg twice a week. The dose may be increased every 4 weeks as needed, up to 1 mg two times a week. Cabergoline should not be stopped without consulting a qualified endocrinologist.

Recent studies suggest prolactin levels are more likely to remain normal after discontinuing long-term cabergoline therapy than after discontinuing bromocriptine. More research is needed to confirm these findings.

In people taking cabergoline or bromocriptine to treat Parkinson’s disease at doses more than 10 times higher than those used for prolactinomas, heart valve damage has been reported. Rare cases of valve damage have been reported in people taking low doses of cabergoline to treat hyperprolactinemia. Before starting these medications, the doctor will order an echocardiogram. An echocardiogram is a sonogram of the heart that checks the heart valves and heart function.

Because limited information exists about the risks of long-term, low-dose cabergoline use, doctors generally prescribe the lowest effective dose and periodically reassess the need for continuing therapy. People taking cabergoline who develop symptoms of shortness of breath or swelling of the feet should promptly notify their physician because these may be signs of heart valve damage.

Common side effects

Nausea and vomiting, nasal stuffiness, headache, and drowsiness are common side effects of these medications. However, these side effects often can be minimized if your doctor starts you with a very low dose of medication and gradually increases the dose.

Cabergoline is the preferred treatment because it appears to be more effective than bromocriptine. It also has less frequent and less severe side effects. However, it’s more expensive than bromocriptine and it’s newer, so its long-term safety record isn’t as well-established.

There have been rare cases of heart valve damage with cabergoline, but usually in people taking much higher doses for Parkinson’s disease. Some people may also develop compulsive behaviors, such as gambling, while taking these medications.

If medication shrinks the tumor significantly and your prolactin level remains normal for two years, you may be able to taper off the medication with your doctor’s guidance. However, recurrence is common. Don’t stop taking your medication without your doctor’s approval.

Prolactinoma surgery

Surgery to remove all or part of the tumor should only be considered if medical therapy cannot be tolerated or if it fails to reduce prolactin levels, restore normal reproduction and pituitary function, and reduce tumor size. If medical therapy is only partially successful, it should be continued, possibly combined with surgery or radiation.

The type of surgery you have will depend largely on the size and extent of your tumor:

• Transsphenoidal surgery. Most people who need surgery have this procedure, in which the tumor is removed through the nasal cavity. Complication rates are low because no other areas of the brain are touched during surgery, and this surgery leaves no visible scars.
• Transcranial surgery. If your tumor is large or has spread to nearby brain tissue, you may need this procedure, also known as a craniotomy. The surgeon reaches the tumor through the upper part of the skull.

Most often, the tumor is removed through the nasal cavity. Rarely, if the tumor is large or has spread to nearby brain tissue, the surgeon will access the tumor through an opening in the skull.

The results of surgery depend a great deal on tumor size and prolactin levels as well as the skill and experience of the neurosurgeon. The higher the prolactin level before surgery, the lower the chance of normalizing serum prolactin. Serum is the portion of the blood used in measuring prolactin levels. In the best medical centers, surgery corrects prolactin levels in about 80 percent of patients with small tumors and a serum prolactin less than 200 nanograms per milliliter (ng/ml). A surgical cure for large tumors is lower, at 30 to 40 percent. Even in patients with large tumors that cannot be completely removed, drug therapy may be able to return serum prolactin to the normal range-20 ng/ml or less-after surgery. Depending on the size of the tumor and how much of it is removed, studies show that 20 to 50 percent will recur, usually within 5 years.

Because the results of surgery are so dependent on the skill and knowledge of the neurosurgeon, a patient should ask the surgeon about the number of operations he or she has performed to remove pituitary tumors and for success and complication rates in comparison to major medical centers. The best results come from surgeons who have performed hundreds or even thousands of such operations. To find a surgeon, contact The Pituitary Society (see For More Information).

Radiation

Rarely, radiation therapy is used if medical therapy and surgery fail to reduce prolactin levels. Depending on the size and location of the tumor, radiation is delivered in low doses over the course of 5 to 6 weeks or in a single high dose. Radiation therapy is effective about 30 percent of the time.