Pediatric History and Physical Examination History

Identifying Data: Patient's name; age, sex. List the
patient’s significant medical problems. Name and
relationship to child of informant (eg, patient, parent, legal
guardian).
Chief Complaint: Reason given for seeking medical care
and the duration of the symptom(s).
History of Present Illness (HPI): Describe the course of
the patient's illness, including when it began and the
character of the symptom(s); aggravating or alleviating
factors; pertinent positives and negatives. Past diagnostic
testing.
Past Medical History (PMH): Past diseases, surgeries,
hospitalizations; medical problems; history of asthma.
Birth History: Gestational age at birth, whether preterm,
obstetrical problems.
Developmental History: Motor skills, language
development, self-care skills.
Medications: Include prescription and over-the-counter
drugs, vitamins, herbal products, homeopathic drugs,
natural remedies, nutritional supplements.
Feedings: Diet, volume of formula per day.
Immunizations: Up-to-date?
Drug Allergies: Penicillin, codeine?
Food Allergies:
Family History: Medical problems in family, including the
patient's disorder. Asthma, cancer, tuberculosis, HIV,
diabetes, allergies.
Social History: Family situation, living conditions,
alcohol, smoking, drugs. Level of education.
Review of Systems (ROS): General: Weight loss or weight gain, fever, chills, fatigue, night sweats. Skin: Rashes, skin discolorations. Head: Headaches, dizziness, seizures. Eyes: Visual changes. Ears: Tinnitus, vertigo, hearing loss. Nose: Nose bleeds, nasal discharge. Mouth and Throat: Dental disease, hoarseness, throat pain. Respiratory: Cough, shortness of breath, sputum (color and consistency). Cardiovascular: Dyspnea on exertion, edema, valvular disease. Gastrointestinal: Abdominal pain, vomiting, diarrhea, constipation. Genitourinary: Dysuria, frequency, hematuria. Gynecological: Last menstrual period (frequency, duration), age of menarche; dysmenorrhea, contraception, vaginal bleeding, breast masses. Endocrine: Polyuria, polydipsia. Musculoskeletal: Joint pain or swelling, arthritis, myalgias. Skin and Lymphatics: Easy bruising, lymphadenopathy. Neuropsychiatric: Weakness, seizures. Pain: Quality (sharp/stabbing, aching, pressure), location, duration

Physical Examination
General appearance: Note whether the patient looks “ill,”
well, or malnourished.
Physical Measurements: weight, height; head
circumference if less than 36 months, body mass index
(BMI). Plot on age-appropriate growth charts.
Vital Signs: Temperature, heart rate, respiratory rate,
blood pressure.
Skin: Rashes, scars, moles, skin turgor, capillary refill (in
seconds).
Lymph Nodes: Cervical, axillary, inguinal nodes: size,
tenderness.
Head: Bruising, masses, fontanels.
Eyes: Pupils: equal, round, and reactive to light and
accommodation (PERRLA); extra ocular movements
intact (EOMI). Funduscopy (papilledema, hemorrhages,
exudates).
Ears: Acuity, tympanic membranes (dull, shiny, intact,
infected, bulging).
Mouth and Throat: Mucous membrane color and
moisture; oral lesions, dentition, pharynx, tonsils.
Neck: Thyromegaly, lymphadenopathy, masses.
Chest: Equal expansion, rhonchi, crackles, rubs, breath
sounds.
Heart: Regular rate and rhythm (RRR), first and second
heart sounds (S1, S2); gallops (S3, S4), murmurs (grade
1-6), pulses (graded 0-2+).
Breast: Discharge, masses; axillary masses.
Abdomen: Bowel sounds, bruits, tenderness, masses;
hepatomegaly, splenomegaly; guarding, rebound,
percussion note (tympanic), suprapubic tenderness.
Genitourinary: Inguinal masses, hernias, scrotum,
testicles.
Pelvic Examination: Vaginal mucosa, cervical discharge,
uterine size, masses, adnexal masses, ovaries.
Extremities: Joint swelling, range of motion, edema
(grade 1-4+); cyanosis, clubbing, edema (CCE);
peripheral pulses.
Rectal Examination: Sphincter tone, masses, fissures;
test for occult blood
Neurological: Mental status and affect; gait, strength
(graded 0-5), sensation, deep tendon reflexes (biceps,
triceps, patellar, ankle; graded 0-4+).
Labs: Electrolytes [sodium, potassium, bicarbonate,
chloride, blood urea nitrogen (BUN), creatinine], CBC
(hemoglobin, hematocrit, WBC count, platelets,
differential); X-rays, ECG, urine analysis (UA), liver
function tests (LFTs).
Assessment (Impression): Assign a number to each
problem and discuss separately. Discuss differential
diagnosis and give reasons that support the working
diagnosis; give reasons for excluding other diagnoses.
Plan: Describe therapeutic plan for each numbered
problem, including testing, laboratory studies,
medications.

HYPERBILIRUBINEMIA

DEF: Elevated serum bilirubin.
ETIOL: In the first 3 to 4 postnatal days, healthy term infants can experience a physiologic increase in unconjugated serum bilirubin from cord levels of 1.5 mg/dL or less at birth to a mean value of 6.5 ± 2.5 mg/dL, with means of 7.3 ± 3.9 mg/dL and 5.7 ± 3.3 mg/dL for breast-fed infants and formula-fed infants, respectively. Although most new-borns have hyperbilirubinemia by adult standards, physiologic jaundice is linked to normal development and is usually benign and self-limited. It arises from a developmental delay in the conjugation and excretion of bilirubin; thus, preterm infants can have maximum serum bilirubin levels 30% to 50% higher than term babies, with elevated levels persisting for 6 to 7 days postnatally. Unconjugated or indirect hyperbilirubinemia is also caused by isoimmune hemolytic disease (e.g., ABO, Rh, or minor blood group incompatibilities); structural or metabolic abnormalities of RBCs (e.g., G6PD deficiency, hereditary spherocytosis); hereditary defects in bilirubin conjugation (e.g., Crigler-Najjar syndrome, Gilbert disease); bacterial sepsis; poly-cythemia; hypothyroidism; hemorrhage/hematoma; and breast milk jaundice. Conjugated, or direct, hyperbilirubinemia can be caused by congenital biliary atresia, extrahepatic biliary obstruction, neonatal hepatitis, inspissated bile syndrome, postasphyxia, a1-antitrypsin deficiency, and neonatal hemosiderosis.
CLIN: Jaundice in the first day of life is pathologic and mandates a thorough evaluation. Neonates who are not clinically jaundiced do not require routine bilirubin level determination. Visible cutaneous and scleral jaundice in the newborn is noted when the bilirubin level exceeds 7 to 8 mg/dL. Jaundice progresses from the head downward with increaseing severity of hyperbilirubinemia (i.e., scleral and facial icterus, 6 to 8 mg/dL; shoulder and trunk, 8 to 10 mg/dL; lower body, 10 to 12 mg/dL;generalized, > 12 to 15 mg/dL). When visible jaundice is detected, the rapidity of onset, the presence of blood group incompatibilities between mother and infant, the presence of hematomas or signs of infection, the method of feeding, and the duration and clinical course of jaundice beyond the third day should be noted. Daily inspection of the baby, undressed and in adequate light, is required for monitoring the progression of jaundice. A thorough abdominal examination includes palpation of the liver and spleen to evaluate for hepatosplenomegaly. Clinical manifestations of bilirubin toxicity include opisthotonos, extensor rigidity, tremors, oculomotor paralysis, and hearing loss (i.e., manifestations of basal ganglia and cranial nerve involvement). Fatal cases in the new-born period are characterized by a loss of the suck response and lethargy, followed by hyperirritability, seizures, and death.
STUDIES: A serum bilirubin concentration is obtained when significant visible jaundice is detected on the physical examination. When the indirect bilirubin is ³10 mg/dL and the calculated rate of increase exceeds 0.2 mg/dL/hour, repeat levels should be determined every 12 hours until the levels stabilize or a clear indication for treatment exists. Important studies to review include maternal blood type, infant's blood type, Coombs tests, hematocrit, hemoglobin, reticulocyte count, RBC indices, and RBC smear. Elevation of direct bilirubin (above 1.5 to 2.0 mg/dL) should prompt evaluation for intrinsic liver disease or biliary tract obstruction.
TX: Most cases of neonatal hyperbilirubinemia are developmental, benign, and self-limited, and therefore can be managed with observation, serial bilirubin determinations, and reassurance. For more severe or complicated cases, a specific diagnosis should be sought after initial stabilization of the neonate. Phototherapy can be used to stabilize indirect hyperbilirubinemia resulting from any cause and is generally used to manage hyperbilirubinemia of greater than 15 to 20 mg/dL. When the levels of bilirubin exceed 25 to 30 mg/dL or are rising rapidly in association with hemolysis, exchange transfusion (with phototherapy) is the treatment of choice. Hyperbilirubinemia occurring within the first 3 to 5 days of life in breast-fed infants may be a result of infrequent feedings and/or delayed production of adequate milk (breast-feeding jaundice); continued, frequent feedings usually lead to resolution. Prolonged hyperbilirubinemia in breast-fed infants may be caused by specific factors in breast milk (breast milk jaundice) and resolves with temporary cessation of nursing (24 to 48 hours); serum bilirubin level usually declines promptly (2 to 4 mg/dL), and nursing is subsequently resumed with little or no further increase in bilirubin.

HEPATITIS

DEF: Infectious or idiopathic inflammation of the liver.
ETIOL: Neonatal hepatitis can be caused by a variety of infectious agents, including cytomegalovirus (CMV), rubella, reovirus type 3, herpes simplex, herpes zoster, herpesvirus type 6, adenovirus, enteroviruses, parvovirus B19, hepatitis viruses, human immunodeficiency virus, bacterial sepsis (gram-negative rods, staphylococci, streptococci), syphilis, listeriosis, tuberculosis, and toxoplasmosis. Idiopathic neonatal hepatitis describes neonatal cholestatic liver disease for which all other known causes, including metabolic, infectious, and extrahepatic obstruction, have been ruled out. The incidence of idiopathic neonatal hepatitis is 1 in 5,000 births and accounts for 50% of cases of prolonged neonatal jaundice.
CLIN/STUDIES/TX: The history should focus on maternal infection during pregnancy and delivery and family history of pediatric liver disease. The major types of neonatal hepatitis are as follows:
Idiopathic: More common in premature or small-for-gestational-age (SGA) infants. Fifty percent have jaundice in the first week of life. Hepatosplenomegaly is common. One-third of these infants fail to thrive. Acholic stools may or may not be present. Radionuclide hepatobiliary imaging shows slow liver uptake with positive intestinal excretion. Liver histology is variable, with inflammation, hepatocellular unrest, multinucleated giant cells, and extramedullary hematopoiesis. Diagnosis is made through exclusion of other etiologies, including biliary atresia. Therapy is directed at addressing the malabsorptive consequences of cholestasis, which include malnutrition, growth retardation, fat-soluble vitamin deficiencies, and calcium deficiency.
Toxoplasmosis: Sixty percent have hepatomegaly, and 40% have hyperbilirubinemia. Hepatic pathology is nonspecific and includes mononuclear periportal inflammation and canalicular bile stasis. Diagnosis is made serologically or through identification of the parasite in cerebrospinal fluid (CSF) sediment. Antiparasitic therapy (pyrimethamine and sulfadiazine) may arrest disease progression.
Rubella: Sixty-five percent have hepatomegaly, and 15% have jaundice. Clinical presentation and hepatic pathology are nonspecific. Elevated aspartate aminotransferase (AST) and alanine amino transferase (ALT) levels may occur in addition to acholic stools. Progressive hepatic disease, including fibrosis and failure, is uncommon. No specific therapy is indicated.
Cytomegalovirus (CMV): Hepatosplenomegaly, jaundice, and elevated AST and ALT levels may occur. Liver biopsy shows focal areas of hepatocyte necrosis with portal inflammation composed of lymphocytes and neutrophils. Intranuclear viral inclusions are more commonly noted in bile duct epithelia than in hepatocytes. Giant cell transformation, bile stasis, and extramedullary hematopoiesis may be seen. Diagnosis is made through culture of the organism from urine or tissue. Progression to severe chronic liver disease is rare. Severe disease may be treated with ganciclovir.
Herpes Simplex: Jaundice and massive hepatic necrosis with liver failure may occur. Coxsackievirus and echovirus (types 11, 14, and 19) infection may present similarly. Diagnosis is made through viral isolation and serology. Documented infection is treated with adenine arabinoside or acyclovir.
Syphilis: Eighty percent have hepatomegaly, and 40% are jaundiced. Biopsy may show extramedullary hematopoiesis, parenchymal or portal inflammatory infiltrates, and granulomatous lesions. Although spirochetes may be seen, the diagnosis is typically made by serologic studies. Although penicillin is essential for the therapy of infants infected with syphilis, it may exacerbate syphilitic hepatic disease.

BRONCHOPULMONARY DYSPLASIA (BPD)

DEF: Chronic lung disease characterized by persistent tachypnea, dyspnea, hypoxemia, and hypercarbia in neonates surviving hyaline membrane disease.
ETIOL: BPD occurs in neonates with a history of pulmonary immaturity and acute lung injury who have been treated with ventilatory support. The premature lung is believed to be particularly susceptible oxygen (O2) toxicity and iatrogenic barotrauma, resulting in persistent respiratory insufficiency. Whether infection (e.g., Ureaplasma), oxidant injury, or barotrauma is the primary insult, the inflammatory process likely exacerbates the prolonged lung damage characteristic of BPD.
CLIN: Most neonates with acute lung disease recover completely within the first week of life. The diagnosis of BPD is suspected when an affected neonate (typically premature) fails to recover as anticipated and instead may have a gradual increase in O2 and ventilatory requirements during the first month of life.
STUDIES: No specific tests exist to confirm the diagnosis of BPD. However, chest radiographic findings of strandlike densities in both lung fields alternating with areas of normal or increased lucency are consistent with BPD. Other disorders to rule out include cystic fibrosis (sweat chloride test), a1-antitrypsin deficiency (a1-antitrypsin levels), patent ductus arteriosus (PDA) (murmur, echocardiography), and viral pneumonia (viral cultures).
TX: Ideally, management of acute lung disease in premature infants should be aimed at preventing BPD by limiting exposure to mechanical ventilation and O2 therapy (if possible), judicious fluid administration, prompt management of PDA, and attention to optimal nutrition. Once diagnosed with BPD, neonates benefit from chronic administration of O2 with maintenance of PaO2 greater than 60 mm Hg or an O2 saturation greater than 90%; this chronic O2 therapy reduces the risk of developing pulmonary hypertension and cor pulmonale, severe complications of BPD. Additional O2 may be required during sleep and feedings. Congestive heart failure can frequently complicate the treatment of BPD. The development of pulmonary and systemic edema often requires chronic parenteral fluid restriction. Enteral fluid is better tolerated. Diuretics may be used with care; thiazide diuretics are preferred because they decrease urinary calcium excretion and may help prevent osteopenia of prematurity. Increased airway resistance and bronchial hyperreactivity may be treated with theophylline or b-adrenergic agents. Antiinflammatory therapy may also reduce O2 requirements and shorten the period of ventilator support. The tachypnea and heightened respiratory effort associated with BPD require that these infants receive increased caloric intake to achieve adequate growth. Caloric intake should be adjusted to enable a sustained weight gain of at least 10 g/kg/day. Infants with BPD have an increased susceptibility for developing severe pneumonia; therefore, respiratory infections should be prevented by avoiding exposure of the infant to patients, hospital personnel, and family members with respiratory symptoms. When viral respiratory infections occur in infants with BPD, O2, bronchodilator, and diuretic use are often increased for at least 1 week. If respiratory failure develops and ventilator therapy is required, mortality is high and recovery prolonged. In comparison with premature infants lacking BPD, survivors of BPD may have an increased incidence of neurodevelopmental abnormalities, visual and hearing deficits, and rehospitalization for respiratory illness in the first year of life. Because lung growth continues for the first few years of life, pulmonary function improves over that time, with most survivors achieving normal exercise tolerance by school age; evidence of increased airway reactivity can persist into adult life in a high percentage of patients.

BOTULISM

DEF: Neurotoxicity caused by Clostridium botulinum exotoxin, which irreversibly blocks acetylcholine release from presynaptic terminals of cholinergic neurons at the neuromuscular junction.
ETIOL: Infant botulism is distinct from food-borne and wound botulism in that it is caused by ingestion of C. botulinum spores rather than the exotoxin itself. Spores germinate in the intestine and generate exotoxin, which is distributed hematogenously. Infant botulism accounts for two-thirds of reported botulism cases in the United States. Although the toxin does not cross the blood–brain barrier, it accesses the cyto-plasmic membrane of peripheral cholinergic nerve endings, preventing exocytosis of acetylcholine at the neuromuscular junction. The resulting flaccid paralysis is potentially fatal. Infant botulism occurs almost exclusively within the first year of life and typically between 5 and 12 weeks of life. Honey has been implicated as the source of spores in 20% of cases; the contaminants have also been recovered from corn syrup. Yard soil is an environmental source of spores.
CLIN: History should focus on food intake and environmental exposures. Constipation often is the first sign of illness and typically is overlooked. Infants become listless and weak over the course of several days to weeks. Bulbar muscle involvement results in difficulty feeding and a weak cry. Drooling and pooling of food and secretions in the posterior pharynx may occur. Ptosis, ophthalmoplegia, diminished facial expression, and generalized muscle weakness and hypotonia (manifested initially as a loss of head control) are common findings. In severe cases, respiratory arrest can occur abruptly and may account for some cases of unexpected sudden death in infancy.
STUDIES: The diagnosis is confirmed by stool culture for C. botulinum, identification of toxin in the blood or stool, and electromyography.
TX: Treatment is directed toward aggressive supportive care, with particular attention to respiratory support. Infant botulism is a self-limited disease, typically lasting 2 to 6 weeks. Antitoxin and antibiotics do not influence the disease course; in fact, bacterial death caused by antibiotics can result in increased toxin release in the GI tract. In severe cases, infants may require prolonged ventilatory support. Constipation may persist for months and may improve with the use of stool softeners and adequate hydration. Close follow-up is required because relapse of infant botulism can occur after apparent resolution of clinical symptoms. The mortality rate of recognized cases of infant botulism is approximately 3%.

BILIARY ATRESIA

DEF: Progressive atresia or hypoplasia of any portion of the biliary system.
ETIOL: The incidence of biliary atresia ranges from 1 in 8,000 to 1 in 20,000 live births. The disorder appears to be acquired rather than a result of abnormal development, based on the rarity of biliary atresia in autopsied fetuses and premature newborns. One causative factor is believed to be infection with reovirus type 3.
CLIN: Infants with biliary atresia are typically born at term and have a normal birth weight. Jaundice develops at age 3 to 6 weeks in otherwise well-appearing, thriving infants. Fifteen percent of infants may have associated defects, including polysplenia (i.e., splenic tissue divided into several equally sized masses), cardiovascular anomalies, and malrotation of the intestine. Family history is usually negative.
STUDIES: Stool is acholic, collected duodenal fluid lacks bilirubin pigment or bile acids, and abdominal ultrasound may show absence of the gallbladder. Radionuclide hepatobiliary imaging demonstrates rapid uptake by the liver without intestinal excretion. Characteristic pathologic findings from percutaneous liver biopsy include bile duct proliferation, bile plugs, and portal and perilobular fibrosis. If the diagnosis is still uncertain after biopsy, surgical exploration with intraoperative cholangiography is used. This procedure enables recognition of biliary atresia and exclusion of other forms of bile duct disease, including stenosis or common bile duct perforation.
TX: If biliary obstruction occurs as a discrete lesion, surgical intervention is directed at drainage of patent portions of bile duct proximal to the atresia. Commonly, the atretic area extends above the level of the porta hepatis and affects intrahepatic bile ducts, making drainage difficult. In 80% of cases, a noncorrectable atresia is found. In these infants, further exploration is indicated to establish drainage of any small, persisting bile duct remnants. This procedure, known as the Kasai hepatoportoenterostomy, consists of transection of the porta hepatis followed by apposition of a Roux-en-Y loop of intestine. The success rate is 90% in infants younger than 2 months. In addition to infant age, the size of the residual duct lumina found during surgery is a factor in the success of this procedure; diameters less than 150 µm are associated with a poor prognosis. Treatment is not definitive, and patients may have progressive liver disease and bouts of bacterial cholangitis, requiring prompt treatment and nutritional support. Biliary atresia without intervention is universally fatal, with the mean age of death younger than 1 year. The Kasai procedure offers valuable time for the infant to grow before hepatic transplantation is necessary. Liver transplantation is essential in infants in whom the Kasai procedure fails, who are referred late (older than 120 days), and who develop liver failure despite some degree of biliary drainage.

ANEMIA IN CHILDREN

ANEMIA

DEF: Hematocrit and hemoglobin concentration below normal levels.
CONDITION: Physiologic anemia of infancy/anemia of prematurity.
ETIOL/CLIN: Soon after birth, erythropoiesis almost ceases because of the oxygen-rich milieu and relative excess of red blood cells (RBCs); this results in a decrease in hemoglobin values during the first several months of life, the severity of which is related to birth weight, perinatal complications, blood transfusion history, and vitamin E deficiency. Nadir hemoglobin values can reach 9.5 g/dL at 3 months in term infants and 6 g/dL in 6- to 8-week-old premature infants. Recovery is heralded by a slight elevation in the reticulocyte count and a rise in hemoglobin levels to those seen throughout the remainder of infancy.
Tx: Healthy term infants and asymptomatic growing premature infants require no therapy. Iron supplementation may be indicated during the recovery phase to support erythropoiesis.

CONDITION: Blood loss.
ETIOL/CLIN: Anemia owing to blood loss is more common in the new-born period than in any other time in childhood. Acute hemorrhage (>20% to 30% blood volume) results in shock. Jaundice is absent. External blood loss commonly occurs from the gastrointestinal (GI) tract. To determine whether hematemesis or melena derives from the infant's or mother's blood, the Apt test for fetal hemoglobin is used. The Kleihauer-Batke stain for fetal hemoglobin–containing RBCs in the mother's blood can provide an estimate of the degree of transplacental hemorrhage. In sick premature infants, the most common cause of blood loss is the iatrogenic withdrawal of multiple specimens for testing.
TX: Treatment depends on the amount and duration of blood loss. Signs of hypovolemia dictate that the infant receive immediate volume replacement [crystalloid, plasma protein fraction, whole blood, packed RBCs (pRBCs)]. pRBCs alone may be indicated for less acute degrees of anemia.

CONDITION: ABO incompatibility.
ETIOL/CLIN: Maternal alloantibody can cross the placenta and may bind antigens on fetal/neonatal RBCs, causing hemolytic anemia. Affected babies present with jaundice during the first several days of life. In some cases, symptomatic anemia does not manifest until 4 to 6 weeks after birth. Although the reticulocyte count is elevated (5% to 15%), anemia is absent or mild. The peripheral smear shows increased nucleated RBCs and microspherocytes. Maternal and fetal blood type testing show the corresponding ABO incompatibility “set-up” (mother is blood group O; baby is A or B). Direct and indirect Coombs testing is positive.
TX: Phototherapy or exchange transfusion may be required to treat hyperbilirubinemia.

CONDITION: Rh incompatibility.
ETIOL/CLIN: Incompatibility between the mother and child in the major antigen of the rhesus complex can cause erythroblastosis fetails. Rh-negative mothers sensitized to D-positive blood produce antibodies that cross the placenta and coat D-positive fetal blood, resulting in hemolytic anemia. Severely anemic fetuses may die in utero, or neonates may be born with hydrops fetails, characterized by anasarca (from hypoalbuminemia and congestive heart failure), severe anemia, and massive hepatosplenomegaly. Less severely affected neonates (benefiting from early detection and vigorous treatment during pregnancy and delivery) may have less severe anemia. Direct and indirect Coombs testing is positive. Hyperbilirubinemia is present. The peripheral smear shows polychromasia, nucleated RBCs, and no microspherocytes.
TX: Early detection during prenatal care and Rhogam therapy prevent maternal sensitization. Intrauterine transfusion of pRBCs can correct fetal anemia. Treatment during the neonatal period consists of exchange transfusion for marked anemia and hyperbilirubinemia and pRBCs for less severe anemia. Careful follow-up is required during the first 2 to 3 months of life to monitor for delayed anemia resulting from persistent anti-D antibody.

CONDITION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
ETIOL/CLIN: G6PD deficiency is the most common inherited intrinsic disorder of RBCs. It typically occurs in black, Mediterranean, and Asian males. Oxidant stresses from drugs or infection cause hemoglobin to precipitate, forming Heinz bodies seen on the peripheral smear. Oxidant stresses at delivery and premature birth may trigger neonatal hemolysis and hyperbilirubinemia. The diagnosis is made with specific screening tests and enzyme assays.
TX: Hemolysis and hyperbilirubinemia may require exchange transfusion.

CONDITION: Hereditary spherocytosis.
ETIOL/CLIN: Hereditary spherocytosis is the most common congenital hemolytic anemia presenting with jaundice and anemia during the neonatal period. It is an autosomal dominant disorder common in whites of northern European descent. The blood smear contains numerous microspherocytes. There is no evidence of ABO incompatibility (i.e., negative Coombs test).
TX: Hemolysis and hyperbilirubinemia may require exchange transfusion.

CONDITION: Anemia related to mechanical or toxic factors.
ETIOL/CLIN: Mechanical or toxic factors. Damage to erythrocytes can occur from toxins produced by infection or from mechanical injury mediated by fibrin strands or altered microvasculature, such as in disseminated intravascular coagulation (DIC).
TX: Treatment depends on the etiology. Blood product transfusion may be required.

CONDITION: Decreased RBC production.
ETIOL/CLIN: Anemia resulting from diminished RBC production is uncommon at birth and is reflected by a diminished or absent reticulocyte count. Causes include malignancy, sepsis (relative myelosuppression), iron deficiency, Diamond-Blackfan syndrome (congenital pure RBC aplasia), and a-thalassemia syndromes.
TX: Treatment depends on the etiology. Vigorous resuscitation measures and blood transfusions may be required.

Ototoxicity

Rita M. Schuman
Gregory J. Matz

Drug-induced inner ear damage is a common finding in present-day medical practice. In many developing countries, where drugs such as the aminoglycosides are frequently prescribed to treat pneumonia, diarrhea, and tuberculosis, the incidence of ototoxicity is high (1). Physicians in practice need to recognize that ototoxic drugs can cause significant auditory and in many instances, poorly recognized, vestibular toxicity. Physicians therefore need to be cognizant of the many categories of drugs that produce ototoxicity.

Early examples of drug ototoxicity are arsenic, the salicylates, and quinine. Salicylates, for example, administered in doses in excess of 2,700 mg a day, once commonly used to treat arthritis, were found to cause a transient flat, bilateral sensorineural hearing loss and tinnitus. There has never been a case of permanent hearing loss following salicylate use in therapeutic drug dosing; however, most patients experience complete reversal within 2 to 3 days. Later, in the 1960s, thalidomide, a well-known drug used at that time and now known to cause amelia and phocomelia, was also discovered to cause aplasia of the inner ear.

The introduction of the first aminoglycoside, streptomycin, in 1944 by Waxman, who was awarded the Nobel prize for this discovery, heralded a new era of antibiotic therapy for the treatment of tuberculosis. Unfortunately, Hinshaw and Feldman at the Mayo Clinic described a significant number of patients with vestibular toxicity from this drug (2). A few years later, an analog of streptomycin, dihydrostreptomycin, was used in clinical practice with the hopes of reducing the streptomycin ototoxicity. Dihydrostreptomycin, however, was also shown to have an unacceptably high incidence of cochlear toxicity and was subsequently withdrawn from the market. Likewise, other early aminoglycosides, such as kanamycin and neomycin had unacceptably high rates of cochlear toxicity when used systemically and therefore are rarely used in that manner today. Later, a newer aminoglycoside, gentamicin, was shown to have about a 3% incidence of vestibular injury (3). Subsequent aminoglycosides such as netilmicin, tobramycin, and amikacin were developed to reduce this incidence of toxicity. In fact, netilmicin has been found to be the least ototoxic of all of the aminoglycosides available (4).

Other considerations must include the cancer chemotherapeutic agents, such as cisplatin, which has been found to result in a moderate level of ototoxicity with resultant permanent bilateral hearing loss. Clinicians are also faced with a sporadic low incidence of ototoxicity with drugs such as vancomycin and the macrolides. Most studies in the literature regarding the ototoxicity of the macrolides have been found to be reversible. The mechanism by which these drugs are toxic is unknown. Finally, numerous case reports have also indicated that hydrocodone in combination with acetaminophen can cause a rapidly progressive sensorineural hearing loss. (5). The mechanism of toxicity at this time is unknown.

Ototoxicty of Ototopical Antibiotics
It is well known that systemic administrations of aminoglycosides can cause both cochlear and vestibular toxicity. This naturally leads to the question of whether these drugs, which are used extensively to treat ear infections through topical administration to the middle ear, can cause ototoxicity. Animal data have been quite uniform in that almost all of the aminoglycoside antibiotics used in the middle ear as topical otic preparations are ototoxic (6). The use of aminoglycoside ototopical drops confined to the external auditory canal, however, presents little, if any, risk of ototoxicity.

Current review of the literature reveals documentation of a total of 54 cases of gentamicin vestibular toxicity from ototopical use in the middle ear or open mastoid cavity (7) (Table 148.1). In addition, 24 of these patients developed an associated auditory toxicity. A review of the literature in the above cited study also included 11 patients who experienced auditory toxicity from the topical use of neomycin-polymyxin-based eardrops. It was therefore recommended that when possible,
topical antibiotic preparations free of potential ototoxic side effects should be used in preference to ototopical preparations that have had the potential for ototoxic injury if the middle ear or mastoid are open (17). Aminoglycoside-containing antibiotic topical drops are not FDA approved for use in the middle ear or open mastoid cavity. Indeed, current labels contain warnings against the use of these drugs if the tympanic membrane is not intact. Although the evidence suggests that otologic damage from topical preparations with ototoxic potential is infrequent, the evidence also indicates that they offer no advantage over nonototoxic agents (17). If these ototoxic agents are considered, potentially ototoxic, antibiotic preparations should be used only in acutely infected ears and use should be discontinued shortly after the infection has resolved. Finally, if the clinician must use potentially ototoxic antibiotics in the middle ear or mastoid space, the patient or parents should be warned of the risk of ototoxicity (17).

Ototoxicity of Systemic Drugs

Table 148.2 lists the major classes of drugs that cause ototoxicity—the aminoglycoside antibiotics, the macrolides, loop diuretics, cisplatin, and the salicylates. These drugs are listed because they are commonly seen in otolaryngology consultation practice. There are currently no meta-analysis studies that evaluate ototoxicity for these drugs. Included in the bibliography are two reviews that include ototoxic evaluations for gentamicin and cisplatin in a large cohort of patients. Omitted for the sake of brevity in Table 148.2 are the low-incidence ototoxic drugs, such as chloroquine, which is rarely used in clinical practice in the United States.

For various reasons, the incidence of aminoglycoside ototoxicity in neonates and children is lower than adults (23). In children, it can be useful to obtain pretreatment audiograms to rule out preexisting hearing loss in patients who are to receive a course of aminoglycoside antibiotics. In the United States, that drug is usually gentamicin.

Genetics of Otoxicity

It is well known that aminoglycosides are some of the most common ototoxic drugs causing acquired hearing loss. It was observed that many patients were developing hearing loss, despite the low dosages of aminoglycosides administered. It was also noted that certain families had an exceptionally high number of members with similar findings of aminoglycoside ototoxicity. Based on these observations and the ongoing research regarding the pathophysiology of hearing loss, it has been proposed that certain individuals may have a genetic predisposition or susceptibility to the ototoxic effects of certain drugs and in particular, the aminoglycosides (24).
Recent advances have identified that certain mutations in mitochondrial DNA are found to be associated with a number of hearing disorders, including ototoxicity. Mitochondrial DNA is a double-stranded molecule forming a closed circle. Replication and transcription occurs within the mitochondria, ultimately forming proteins involved with ATP synthesis and electron transport. This specific type of DNA is transmitted exclusively by the maternal line, equally affecting both male and female offspring.

In the early 1990s it was first discovered that a mutation at position 1555 in the nucleotides of the mitochondrial 12S ribosomal RNA was responsible for aminoglycoside toxicity in several Chinese families (25). It was also cited as a cause for a number of cases of nonsyndromic deafness in patients with no previous aminoglycoside exposure. Since that discovery, similar research has been conducted on numerous other families, as well as on sporadic patients with documented sensorineural hearing loss following the administration of intravenous aminoglycosides. These subsequent studies confirmed that these patients also had identical nucleotide mutations of their mitochondrial DNA. It has been proposed that the specific mutation creates another binding site for the aminoglycosides, thus increasing the patient's sensitivity to ototoxicity (26). Most of this work was conducted on an international basis, where severe infections such as tuberculosis more often require widespread use of intravenous aminoglycosides.

A large quantity of research continues in this area. As more becomes known about the genetics of hearing loss and the specific mutations that predispose patients to the ototoxic effects of some drugs, it may be possible to develop molecular tests to identify these patients prior to treatment. With that information, it may be possible to reduce the number of patients suffering from the toxicities of these antibiotics.

Chemoprevention of Ototoxicity
In some instances, it may be necessary to use ototoxic drugs in order to effectively treat patients. In light of this fact, it is necessary to develop mechanisms by which it is possible to protect the inner ear from the toxicities of both the ototoxic intravenous antibiotics and the chemotherapeutic agents such as cisplatin. Some of the agents that have been proposed and studied include iron chelators (deferoxime) (27,28), antioxidants including L-N-acetyl cysteine (29), vitamin E, alpha-tocopherol (30,31,32), as well as the salicylates (33,34).

Recent research has demonstrated that administration of aminoglycosides causes the formation of an iron complex that is involved in the generation of free radicals, resulting in hair cell death and subsequent hearing loss (28). Based on this discovery, attempts have been made to use deferoxamine, an iron chelator, to help attenuate these toxic effects. Animal studies have been promising, but considerations must be taken so as to not alter the serum concentrations of the drugs, and a better understanding is needed of the side effects of administering iron chelators to patients and the potential of altering serum iron levels (27).
Cisplatin, a common chemotherapeutic agent used in head and neck cancer, is well known to cause bilateral, irreversible sensorineural hearing loss. Evidence suggests that glutathione reduction secondary to free radical production ultimately causes hair cell damage. Various chemoprotectants have been shown to exert antioxidant properties that ultimately reduce the ototoxic effects of cisplatin. Recent studies with vitamin E (31), L-N-Acetyl cysteine (29), and sodium thiosulfate (35) confirm this theory. Most of the research, however, has thus far been with animals. Further human studies must be done to truly know if these advances will be clinically significant and will ultimately reduce the ototoxic effects.

Summary

One of the authors of this chapter (GJM) has written previously about the use of high-frequency audiometry (8 to 12 Hz) as a predictor of drug-induced ototoxicity (36). Although conventional audiometry may still have a role in monitoring patients exposed to ototoxic medications, high frequency testing is often problematic. It is an extremely difficult test to do for all practical purposes and is often not done clinically for that reason. Few centers perform pretreatment conventional audiograms from 0.25 Hz to 8 Hz when the two most common ototoxic drugs, gentamicin and cisplatin, are given. The authors are not aware of any outcome studies that demonstrate that pretreatment and post-treatment audiograms reduce the incidence of predicted ototoxicity. Some centers have found, however, that it may be beneficial to perform one pretreatment audiogram followed by serial audiograms, in addition to closely monitoring the serum drug levels of the ototoxic medications being administered. The use of vestibular testing both pretreatment and post-treatment for patients receiving long-term gentamicin is also difficult to do in the clinical setting. This is an important factor because gentamicin is mostly a vestibular toxic drug. Some centers do perform electronystagmography, rotational testing, and platform posturography in working up possible vestibular symptoms and have found these tests to be helpful.
It is now well known that the aminoglycoside antibiotics act synergistically with some drugs, thus increasing the incidence of ototoxicity. For example, the use of aminoglycoside antibiotics with loop diuretics can produce an unexpectedly high incidence of ototoxicity. This has been extensively documented in human case reports as well as in animal studies. Ethacrynic acid, an ototoxic loop diuretic, has been shown to increase the permeability of the stria vascularis, facilitating the diffusion of the aminoglycoside into the endolymph. Finally, it has been found that diuretics given prior to the administration of aminoglycosides are less damaging than if done in the reverse (37). Most recently noted is a similar response to aminoglycoside antibiotics and the use of metronidazole (38).
It is unclear at this time if antiviral and protease inhibitors are responsible for the anecdotal reporting of neurosensory hearing loss in patients with human immunodeficiency virus (39). Prospective studies are needed to confirm whether nucleoside analog reverse transciptase inhibitor or antiviral agents cause hearing loss in this patient population. The use of chemoprevention measures as described in animal studies show promise, but so far no prospective clinical trials have been performed and the authors are not aware of any medical centers with protocols to address this issue at this time.
The two most common ototoxic drugs given today in clinical practice are gentamicin and cisplatin. The patients selected in these groups are different. Gentamicin is normally monitored not by audiograms but by serum peak and trough levels. When gentamicin has to be given for long-term therapy (i.e., osteomyelitis), consideration has to be given to genetic testing to see if a patient is going to be more susceptible to ototoxic injury, thus giving the clinician the opportunity to obtain informed consent from the patient. Likewise, accurate dosing during chemotherapy has reduced the incidence of ototoxicity. Further research is necessary to determine if any of the chemopreventative agents will be successful in further animal and ultimately human trials to reduce the unfortunate toxicities of these necessary drugs.

Balance Function Tests

Colin L. W. Driscoll
J. Douglas Green Jr

Balance is maintained through complex interaction of the vestibular, visual, and somatosensory information that is combined within the brainstem to generate a motor response correcting the perturbation. Abnormalities within any portion of the system can cause a sensation of imbalance or dizziness. Dizziness is one of the most common reasons for seeking medical evaluation, and the otorhinolaryngologist is often the primary contact. Evaluating patients for dizziness can be frustrating for both patient and physician. The symptoms are difficult for patients to describe, the differential diagnosis is broad, and many tests have to be considered. An understanding of the balance tests currently available and the pathophysiologic principles on which they are based improves treatment of these challenging patients. The particular approach to dizziness is affected by type of practice, available resources, and patient population.
The main goals of the diagnostic evaluation are to determine the location and severity of lesions within the balance system and to help formulate and guide a treatment plan. The etiologic evaluation of the balance system dysfunction necessitates compilation of other data, including those from a comprehensive history and physical examination and other directed laboratory and radiologic examinations. In most cases, clues revealed during the history and physical examination lead to a diagnosis, and treatment can begin without additional testing. Balance function testing should be interpreted in light of the history and physical exam findings and often provides confirmatory information as to pathophysiologic processes involved. Formal balance function testing provides information as to the site and side of the lesion, to ascertain who is likely to benefit from vestibular rehabilitation, to assess recovery of vestibular function, and to document contralateral function when a destructive procedure is contemplated. Clinical decision support systems have been described to help office personnel determine which patients may need balance function testing (1).
This chapter reviews tests for assessing the balance system (Table 131.1). These balance system tests, usually administered by an audiologist or trained technician, require specialized equipment and dedicated space. The basic physiologic principles of the tests are reviewed.

Electronystagmography
The electronystagmography (ENG) test battery is the workhorse of balance function testing. It is a combination of tests that together provide complementary information about the vestibular and oculomotor systems. Rather than a diagnosis, the tests provide data that must be used in conjunction with the findings of the history, physical examination, and other studies to determine a diagnosis. The ENG battery typically consists of the vestibular and oculomotor tests listed in Table 131.2.
The ENG tests are based on the well-studied neurophysiologic characteristics of the vestibulo-ocular reflex. Motion of the head, or simulated motion through labyrinthine stimulation, produces compensatory eye movement. These eye movements are observable and recordable responses that provide the basis for interpretation of the various tests. Changes in eye position are recorded by means of taking advantage of the natural difference in electrical charge between the cornea (+) and the retina (-), the corneal-retinal potential. Electrodes record the changes in potential when the eye moves [electrooculography (EOG)]. The advantages of this recording technique are low cost, ease of administration, noninvasiveness, avoidance of head restraint, and extensive experience in interpreting the data. The technique does have technologic limitations. The signal is susceptible to changes in skin resistance due to perspiration, interference from eye-blink artifacts, and a poor signal-to-noise ratio. Although abnormal eye movements can be revealed by means of direct visualization during testing, it is preferable in most cases to have quantifiable data to characterize the abnormalities. Furthermore, some parts of the test require that the eyes be closed to prevent fixation suppression. Nystagmus is the primary ocular movement measured and is defined by its direction (horizontal, vertical, or torsional) and velocity (degrees per second). Direction is determined by the fast component, and velocity is calculated from the slow-phase component.
New technologies for observing and recording eye movement continue to be developed (2,3). Video ENG systems, vidoenystagmography, are now available that use small video cameras to observe and monitor horizontal, vertical, and torsional eye movement during vestibular evaluations (Fig. 131.1). With this system, tests that require the patient to move are performed with a lightweight goggle assembly. Pursuit, gaze, and saccade testing can be performed with an oculomotor module with tracking targets for each eye. The eyes are illuminated with near-infrared light that is not visible to the patient but allows the cameras to pick up and project images of the eyes on video monitors. This system has several advantages over traditional ENG testing techniques. Nonelectrode eye movement recording eliminates artifacts, the need for frequent recalibration, and impedance testing. Vertical eye movements can be accurately recorded. Torsional eye movements can be visualized and recorded without fixation suppression. Disconjugate eye movements are more easily identified. A portable unit allows testing at home, in an intensive care unit, or at any other remote location. The disadvantages are high cost, need to wear goggles, and unfamiliarity with the equipment. Most companies that manufacture ENG equipment now offer a videonystagmography system to make use of these advantages.
Virtual reality testing systems are being developed and promise to provide a means to produce visual stimuli that were previously impossible (4). Images can be produced on a visual display, and because the system is software driven, the images can be manipulated quickly and with tremendous flexibility. For example, cross-axis stimulation (head motion in one plane and eye motion in another) becomes easy to perform.
The sequence of ENG tests is important to prevent obtaining misleading results. For example, testing for benign paroxysmal positional vertigo is performed at the beginning of the test series to avoid fatiguing of the response. The tests must be performed with proper attention to detail and accurate calibration. Patient anxiety, fatigue, lack of cooperation, and medications can adversely affect test results.
Interpretation of ENG results is critical to proper diagnosis and treatment and should be performed by qualified audiologists and physicians who are trained and familiar with the equipment being used for testing. Increasingly, specialists in other fields, chiropractors, and poorly trained medical doctors are investing in ENG equipment in hopes of financial gain, often without knowledge of how to interpret the ENG test results and how to apply them in clinical practice. It is essential that otorhinolaryngologists offering ENG testing be familiar with interpretation of the results. Several excellent courses are available to otorhinolaryngologists offering ENG testing within their offices.

Spontaneous and Gaze Nystagmus
Spontaneous nystagmus refers to nystagmus that is present without visual or vestibular stimulation. Spontaneous nystagmus can sometimes be seen only with loss of visual fixation (e.g., milder forms of spontaneous vestibular nystagmus) or may be seen with both eyes open and with loss of visual fixation (e.g., congenital nystagmus and severe vestibular nystagmus). Spontaneous nystagmus can be observed both at the bedside and in the vestibular laboratory. However, although reduction of visual fixation can be achieved easily in the laboratory using infrared video goggles or EOG with eye closure, at the bedside, achieving a reduction in visual fixation while still maintaining an ability to observe eye movements can be challenging. Observing a patient's eye with an ophthalmoscope while the other eye is occluded allows the examiner to assess spontaneous nystagmus with reduced visual fixation. The most common type of spontaneous nystagmus, that is, spontaneous vestibular nystagmus, occurs with unilateral peripheral vestibular lesions. Spontaneous vestibular nystagmus is always unidirectional and increases when the patient gazes in the direction of the quick component of the nystagmus. This gaze dependent change in nystagmus intensity is called “Alexander's Law.” As noted previously, loss of visual fixation also increases the magnitude of spontaneous vestibular nystagmus. Thus, judicious use of gaze direction and presence or absence of visual fixation can aid the examiner both at the bedside and in the laboratory in judging whether or not a spontaneous nystagmus is a result of a vestibular abnormality. Failure of fixation suppression is highly suggestive of a central pathologic condition.
Gaze nystagmus, also known as gaze-evoked nystagmus, is a bidirectional nystagmus with right beating nystagmus on right gaze and left beating nystagmus on left gaze. Many patients with gaze-evoked nystagmus also will manifest an up-beating nystagmus on upward gaze. Note that down-beating nystagmus in any gaze position, even in downward gaze, is not considered a component of gaze-evoked nystagmus and should be regarded as a manifestation of a central nervous system abnormality at the level of the craniocervical junction unless proven otherwise. Gaze-evoked nystagmus can be seen in normal individuals when horizontal gaze exceeds 30 degrees from the straight-ahead position. Thus, it is best to limit the amount of gaze deviation when assessing a patient for gaze-evoked nystagmus to less than 30 degrees. Gaze-evoked nystagmus occurs as a result of inadequate gaze-holding, thereby leading to a slow drift of the eyes back toward the straight ahead gaze position with the drift interrupted intermittently by rapid, nystagmus fast phases in the direction of gaze. Bidirectional gaze-evoked nystagmus is always a result of a central nervous system abnormality and never is the result of a peripheral vestibular abnormality. There are many etiologies for gaze-evoked nystagmus. The most common cause of gaze-evoked nystagmus is a medication effect (e.g., from anticonvulsants).

Positional and Positioning Tests
Positional tests are designed to detect the response to changes in direction of gravitational force. The patient is moved slowly into a series of stationary positions with the eyes closed, and presence or absence of nystagmus is assessed. The nystagmus can be either fixed or direction changing. If nystagmus is elicited in the positional tests, the entire body is turned to determine whether neck torsion is responsible. Interpretation of results is controversial and necessitates consideration of the number of positions that elicit nystagmus and the velocity of the nystagmus. Positional nystagmus of peripheral origin can fatigue with repeated testing, is usually direction fixed, and often is associated with caloric weakness. The direction of nystagmus caused by a peripheral lesion typically does not change independently of head movement (5). Direction-changing nystagmus without an accompanying change in head position indicates the presence of a central disorder.
The positioning test used most often is the Dix-Hallpike maneuver. The patient is rapidly moved from sitting to supine with the head turned and hanging below the level of the table. If nystagmus is elicited, the maneuver is repeated to determine the existence of fatigability. A response that fatigues suggests a peripheral problem. The patient's eyes are kept open to allow the examiner to evaluate for torsional nystagmus, which can indicate benign positional vertigo due to loose otoconia within the labyrinth. Torsional nystagmus cannot be recorded with conventional ENG. Head hanging to the right produces counterclockwise torsional nystagmus, and head hanging to the left produces clockwise torsional nystagmus. A variant of benign positional vertigo affecting the horizontal semicircular canal produces pure horizontal nystagmus.

Bithermal Caloric Tests
Bithermal caloric tests are used to evaluate the function of the horizontal semicircular canals. Changes in temperature stimulate fluid flow (equivalent to a very slow frequency of only 0.002 to 0.004 Hz) within the horizontal semicircular canal; if the system is functioning, nystagmus is elicited. The very slow frequency of stimulation is not a condition normally experienced during daily life. Each ear is tested independently, and the responses are compared.
Caloric testing is performed with the patient supine and head elevated 30 degrees. The external auditory canal is irrigated directly with 250 mL of water at 7 degrees above and below body temperature for 30 seconds. An alternative is to place a small, distensible balloon in the ear canal and fill it with water (closed-loop system). Ocular movements are recorded for approximately 2 minutes, beginning with stimulation. Fixation suppression is evaluated during this time. The slow-phase velocity of elicited nystagmus is calculated and recorded as an objective measure of the response. Warm and cool air irrigation or a closed-loop system can be substituted for direct irrigation if the tympanic membrane is perforated. The responses of the right and the left ears are compared. A difference greater than 20% usually is considered abnormal and is reported as left- or right-sided weakness. The total right-beating responses is compared with the total left-beating responses, and the result is reported as a right or left directional preponderance. A difference greater than 30% is considered significant. Abnormal directional preponderance without unilateral weakness suggests a central pathologic condition. The results indicating central or peripheral disorders are summarized
A monothermal caloric screening test has been suggested to minimize procedure time and patient discomfort. This test has been criticized for a high false-negative rate. However, the results of a study by Jacobson et al. (6) suggest that if appropriate failure criteria are used, the sensitivity reaches 93% and the specificity 98%. Patients who fail the screening test need conventional bithermal testing.
Patients with a complete unilateral or bilateral caloric loss should be tested with ice caloric irrigation of the affected ear(s). Frequently, nystagmus can be elicited with this stronger stimulus. Ice caloric stimulation is uncomfortable for the patient and should be limited in use. It should be noted that the absence of caloric response to warm, cool, or ice water irrigations cannot be taken as an indication of complete lack of function. This should be confirmed by rotational chair testing.

Electronystagmography Fistula Test
If a fistula exists between the middle ear space and the inner ear fluid, application of positive or negative pressure in the external ear canal may produce a fluid shift resulting in nystagmus. Objective nystagmus or a clear subjective response suggests a perilymph fistula or dehiscence of the horizontal or superior semicircular canal.

Saccadic System
The saccadic system is used to move a target from theperiphery of the retina to the fovea. Targets more than20 degrees from the line of sight are normally located by means of a combination of eye and head movement, called gaze saccade (7). This test is performed while the patient sits facing a light bar and keeps his or her head stationary. Lights on the bar are activated to the left and right of center by 10 to 20 degrees, and the patient is asked to shift gaze to each new target. Electrooculographic recording techniques are used. Latency, maximum velocity, duration, gain (overshoot or undershoot), refixation saccade, glissade (postsaccadic drift, or slip of the eye), and other variables are measured and observed.
Abnormal saccades can be caused by lesions in a wide variety of locations. However, they are most commonly caused by a central pathologic disorder rather than a peripheral vestibular one. An abnormal saccadic response can be caused by lesions in the cerebellum (dorsal cerebellar vermis), brainstem (particularly the paramedian pontine reticular formation and medial longitudinal fasciculus), or ocular muscles and nerves. Cerebellar lesions typically manifest as saccadic overshoot or undershoot dysmetria. Dysmetria is an error in range, rate, or direction in performance of precision voluntary movement. It usually is found through past pointing in a finger-to-nose test (8). Different patterns of abnormalities and testing paradigms can help to localize a lesion (9). Age, fatigue, lack of attention, sedatives, drug intoxication (phenytoin), and other factors can cause slow saccades or increase latency.

Pursuit System
The smooth pursuit system stabilizes images of moving objects on the fovea (7). Healthy persons can pursue an object moving at a velocity of about 30 degrees per second. At faster rates, the image can slip, and a corrective saccade is used to catch up. Smooth pursuit usually is tested with sinusoidal stimuli, such as a pendulum, light-emitting diodes, or a laser, with a frequency range of 0.2 to 0.7 Hzand a horizontal range less than 20 degrees to the left and right. Electrooculographic techniques are used to record gain, phase lead or lag, symmetry, and other variables. Because the smooth pursuit system is distributed throughout the brainstem and cerebellum, anatomic localization is not possible (9). If age, alertness, medications, and congenital nystagmus are eliminated as causes of abnormal test results, a central cause is suggested. Saccadic pursuit suggests cerebellar disease. Reduced bilateral gain can be caused by a brainstem lesion. Patients with Alzheimer disease and schizophrenia can perform worse with sinusoidal stimuli than with fixed velocity stimuli (9).

Optokinetic System
The optokinetic system differs slightly from the pursuit system in that it allows persons to keep the visual field in focus while they or most of the environment are moving. The vestibulo-ocular reflex alone is not adequate to generate compensatory eye movements at low frequency. In clinical testing, this effect is achieved by keeping the patient stationary and moving the environment. About 90% of the visual field must be filled with the target to avoid simply testing the pursuit system. A rotating drum with thin vertical stripes or stripes projected on the wall are common stimuli. The patient is instructed to look straight ahead. As the targets pass by, there should be small amplitude excursions of the eye (stare nystagmus). If the patient fixes on the target, longer excursions occur, and the pursuit system is being tested (look nystagmus) (9). Separating the smooth pursuit system and the optokinetic system can be even more difficult. Experiments indicate that both systems are responsible for eye movement during stimulation. If, however, the lights are extinguished, the smooth pursuit system response drops to zero almost instantly. With the lights out, patients continue to have nystagmus for approximately 25 seconds. It is believed that this nystagmus [optokinetic afternystagmus (OKAN)] is caused by the optokinetic system alone (7). Because of the contribution of the pursuit system, it is not possible to conclude that the optokinetic system is normal without having nystagmus for approximately 25 seconds following optokinetic stimulation.
The optokinetic system is widely distributed throughout the brainstem and cerebellum; therefore, abnormalities are not site specific. Absence or asymmetry of the OKAN occurs with peripheral vestibular lesions. Bilateral labyrinthectomy profoundly reduces or eliminates OKAN (10). These findings suggest an interaction between the vestibuloocular reflex and the optokinetic system (7). The OKAN becomes asymmetric after unilateral vestibular ablation; the result is stronger and more prolonged nystagmus directed at the side of the lesion (10). A problem is that the sensitivity in identifying unilateral vestibular disease is not high (10). In a study involving 12 patients who had undergone removal of acoustic neuroma, OKAN helped identify the side of the lesion for only 7 of the patients (10). Baloh et al. (11) found abnormal test results among patients with cerebellar atrophy.
Optokinetic testing is not routinely used but can be indicated as a confirmatory examination when abnormal pursuit is identified. Combining the results of OKAN with those of rotary testing can be helpful in determining the side of the lesion. Another potential use might be to exclude vestibular disease, especially for patients who cannot undergo caloric testing (10). As more is learned about the production of optokinetic nystagmus, clinical usefulness can expand.

Rotary Chair, Sinusoidal Harmonic Acceleration
Rotational testing paradigms offer the theoretic ability to test the semicircular canals under more physiologic, that is, higher frequency, conditions than can be achieved with caloric testing. The stimulus can be precisely controlled and is repeatable. Because both ears are tested simultaneously, the results reflect the integrated function of both ears (12). In this test, the rotary chair is oscillated from side to side at a series of preprogrammed rates (Fig. 131.2). The acceleration frequencies tested range from 0.01 to1.28 Hz with a maximum velocity of 50 degrees per second.
More rapid rotational velocities may result in head slippage adversely affecting test results. An infrared camera is mounted to the chair to monitor the patient and eye movement. Mental alerting tests are used, as in ENG. As the chair begins to rotate to the right, standard EOG techniques are used to record slow compensatory eye movement to the left. Saccadic eye movement returns the eye to a central position. This movement is eliminated mathematically, and slow-phase movement is compared with chair movement. Three basic characteristics are measured—phase, gain, and symmetry of eye movement. Testing is comfortable for the patient and takes approximately 15 minutes.
Interpretation of the results requires integration with complementary data and the clinical history. Symmetry represents a comparison between the peak slow-wave velocity when the patient is rotated to the left and the peak slow-wave velocity with rotation to the right. For a patient with acute, uncomplicated unilateral peripheral weakness, the symmetry measure shows weakness on the affected side. A problem is that symmetry can be misleading in many cases. Spontaneous nystagmus, irritation of the labyrinth, vestibular compensation, and cerebellar lesions can produce erroneous data. The value of symmetry alone as an indicator of the side of a lesion is controversial. Caution is needed in interpretation of the results. Symmetry often improves with compensation after a vestibular insult and can be useful for monitoring recovery (11). Asymmetry or directional predominance can also be seen withmigraine-associated dizziness, a common form of dizziness.
The phase variable is the relation between maximum chair velocity and maximum slow-phase velocity. Eye velocity typically leads chair velocity, the so-called phase lead. The phase lead often is exaggerated among patients with central or peripheral vestibular disease. If abnormal, this value is nonlocalizing. Some laboratories also include a step test in addition to sinusoidal acceleration testing described previously. In the step test, the system time constant is measured by varying the speed at which the chair rotates. This test can be performed simultaneously with the sinusoidal acceleration testing, providing additional vestibulo-ocular reflex information.
Gain is the ratio of maximum eye velocity to maximum chair velocity. A gain of one indicates that slow-phase eye velocity equals chair velocity and is opposite in direction. If there is no eye movement, the gain is zero. A problem is that gain can fluctuate markedly with changes in alertness. Consistent testing is critical to obtain valid results. The gain values used in calculating phase and symmetry must be accurate. Low gain values alert the physician that the results may be inaccurate. Depressed gain values under good testing conditions suggest bilateral peripheral lesions. Abnormally high gain can indicate the presence of a cerebellar lesion that is decreasing vestibular inhibition. Another caution is that there can be considerable differences in results between laboratories, depending on the specific data analysis algorithms used and operator intervention (13).
Rotary testing is useful to (a) monitor changes in vestibular function over time, especially bilateral lesions or lesions due to vestibular toxicity, (b) monitor compensation after acute injury, and (c) identify residual labyrinthine function for patients with no response during caloric testing or low-frequency rotary chair testing (12,14).
Off-vertical-axis rotation is a variation of rotary chair evaluation (15). The testing procedure is similar, except that the chair can be tilted 30 degrees. Earth horizontal axis (barbecue spit) rotation is another variation. The proposed advantage is that otolith function is incorporated into the response. The role of this type of testing is being investigated. Data suggest that a single labyrinth is sufficient to produce normal semicircular canal–otolith interaction; therefore, the value of the test may be limited (15). Another modification is to test unilateral otolith-ocular response. During constant angular rate rotation, the patient is displaced laterally on the rotating turntable, so that one labyrinth becomes aligned with the rotary axis and the second (eccentric) labyrinth is solely exposed to inertial acceleration (16).

Vestibular Autorotation Test
The vestibular autorotation test is a method of evaluating the vestibuloocular reflex (head-shaking nystagmus) that has distinct clinical and practical advantages over rotary chair testing and ENG (2,17,18,19,20,21). Patients are wired with conventional EOG electrodes to record horizontal and vertical eye movement and are fitted with a lightweight headband containing an EOG amplifier and rotational velocity sensor. The patient is instructed to fix on a target and to rotate the head in synchrony with an auditory cue. The auditory cue accelerates to a maximum of 6 Hz and maintains this velocity for 13 seconds for a total test time of 18 seconds. The test is repeated three times in the horizontal and vertical dimensions. Phase, gain, and symmetry data are collected over the frequency range of 2 to 6 Hz (17).
The vestibular autorotation test has several attractive characteristics. The vestibular system is evaluated at frequencies more physiologic than the ultralow frequencies used in conventional ENG or rotary chair testing (20,22,23,24). The vestibular autorotation test can be performed efficiently, does not require dedicated space, is portable, allows testing in the vertical plane, and is well tolerated by patients. A potential disadvantage is that it includes the cervical-ocular reflex, but this is thought to be an unimportant contribution at the frequencies used. Vestibular autorotation testing also requires patients to rotate their heads appropriately, which may be problematic for elderly patients or patients with cervical pathology. Interpretation of the results is the same as with ENG and rotary chair testing. The clinical value of headshake nystagmus in evaluating dizziness has been challenged. Jacobson et al. (21) reported a sensitivity of only 27% and a specificity of 85%.

Dynamic Posturography
Computerized dynamic posturography came into the clinical realm in 1985 with the introduction of the Equitest system developed by NeuroCom. Posturography consists of two tests—the sensory organization test and the movement coordination test. The sensory organization test protocol calls for evaluation under six conditions in which sensory and proprioceptive inputs are varied (Fig. 131.3). During the sensory organization test portion, the patient's anterior and posterior body sway is recorded, and a performance index is calculated on a scale of 0% to 100% (fall, 0; no sway, 100). During the movement coordination test, the patient stands quietly on a platform, with the visual surround fixed (Fig. 131.4). The platform then undergoes a series of translational and rotational movements. The principal measurement recorded is the latency to onset of active recovery from destabilizing perturbation. Amplitude and symmetry of the neuromuscular responses also are recorded.
Several classification systems to assist with interpretation of results have been proposed (25). Table 131.4 summarizes one system (9). Although these patterns seem to suggest the site of the lesion, the test is not designed or suited for this purpose. A patient with abnormal scores on tests 5 and 6 can have a central or peripheral vestibular disorder. Patients with a compensated unilateral peripheral vestibular dysfunction have normal performance on tests 5 and 6. A patient with abnormal scores on conditions 1, 2, 3, and 4 is more likely to have a nonvestibular lesion or functional disorder (aphysiologic sway). A diagnosis of functional disorder is suggested when test results on the more difficult conditions (tests 4, 5, and 6) are equal to or better than those recorded during testing of the easier conditions (tests 1, 2, and 3).
The postural evoked responses in the movement coordination test portion of the evaluation are useful in validating the sensory responses and in identifying a central pathologic disorder. The tests are based on the automatic muscle responses thought to be triggered by proprioceptive changes. The response requires normal muscle, nerve, spinal cord, cerebellar, brainstem, and cortical function and is thus a diffusely distributed response. It is likely that the response is modulated by vestibular and other sensory input.
The most common test for perilymphatic fistula is ENG of the vestibuloocular reflex. Dynamic posturography offers an alternative testing strategy that eliminates potentially confounding effects from the visual and proprioceptive systems. Dynamic posturography can eliminate visual and somatosensory input and therefore better isolate the vestibular apparatus. Positive and negative pressures can be applied to the external auditory canal by means of standard tympanometry techniques, and postural adjustments can be analyzed (23). This test can be more sensitive than the traditional ENG fistula test (26,27). However, lack of a definitive test for the existence of a perilymph fistula impedes development of a clear relation.
Posturography can be combined with standard electro-myographic techniques. Electromyography is beneficial in identifying particular muscle response patterns triggered by changes in visual or somatosensory input controlled by the computerized dynamic posturography apparatus. These testing strategies are most useful in research aimed at understanding the complex interactions that allow maintenance of postural control.
Posturography is especially beneficial in documenting overall postural stability and in identifying particular balancing strategies. It is useful for vestibular rehabilitation and for monitoring improvement or decompensation. The computerized dynamic posturography evaluation is comfortable for patients, and they feel that their balance is being thoroughly tested. The test results correlate more closely than those of other balance function test results with the Dizziness Handicap Inventory, which is a subjective measure of overall balance limitations (28).

Pediatric Testing
Vestibular testing of children presents several challenges. Mental alerting, lack of tolerance of uncomfortable stimuli, inability to follow verbal commands, and inability to remain still all make testing difficult. Modifications of the standard adult ENG battery allow oculomotor, positional, and caloric testing (29). Simultaneous minimal caloric irrigations improve tolerability by reducing the degree of induced nystagmus and time of the procedure. Of course, the data obtained are not as informative as those provided by alternate binaural testing. Closed-loop irrigation systems can improve tolerance. Vestibular autorotation testing can prove useful in children, but more experience is needed. Rotational chair testing can be performed on most children, and very young children can sit on a parent's lap. Computerized dynamic posturography can be performed on older children, but normative data are not available. Most testing protocols can be shortened to minimize testing time and improve compliance.

Vestibular Evoked Myogenic Potentials
Standard caloric testing performed as part of an ENG battery evaluates the superior vestibular nerve because the lateral semicircular canal is being stimulated. A relatively new test can be performed using equipment traditionally used for auditory brainstem response testing to evaluate the function of the inferior vestibular nerve. Colebatch and Halmagyi (30) described the electromyographic response of the neck musculature to a loud, ipsilateral, broad band click. The afferent limb of the response is thought to be due to stimulation of the saccule with transmission via the inferior vestibular nerve to the brainstem and vestibular nuclei. The efferent limb of the response is via the spinocerebellar tract with the response typically recorded on the ipsilateral sternocleidomastoid muscle. The desire for inferior vestibular nerve evaluation has greatly increased the use of this test, which is termed the vestibular evoked myogenic potential (VEMP).
As experience with VEMP accumulates, the limitations and benefits of testing are becoming more apparent. Patients older than 60 years may have a reduced response in VEMP amplitude, which is thought to potentially be due to deterioration of saccular function (31). Pathologic changes in the brainstem, such as multiple sclerosis, may result in delayed potentials with variability noted in the response of the test to common conditions such as acoustic neuromas, Ménière disease, and vestibular neuritis (32). Surprisingly, early Ménière disease frequently demonstrates normal VEMP responses with progressive loss of the potentials with disease progression.

Dynamic Visual Acuity
Movement of the head causes significant retinal slip and loss of visual acuity unless the vestibulo-ocular reflex produces an appropriate compensatory response. Patients with dizziness frequently complain of visual blurring and unsteady visual sensations, particularly with head movement. The lack of visual stability on the retina can be quite disconcerting to patients and may prove dangerous forpatients during driving. Several commercial devices are available that can assess dynamic visual acuity. These tests use a rotational velocity sensor in combination with a computer screen to evaluate vision during head movement, giving a functional assessment of the vestibulo-ocular reflex in both horizontal and vertical planes (33).
Age does seem to affect dynamic visual acuity results with older patients demonstrating reduction in visual stability. Although some variability has been noted, the test does show good sensitivity and specificity in distinguishing normal patients from those with abnormalities.Patients with bilateral vestibular deficits were shown to have a greater degree of reduction in comparison with unilateral vestibular deficits and patients with nonvestibular dizziness. Surprisingly, oscillopsia did not correlate with abnormalities on vertical dynamic visual acuity in patients with bilateral vestibular loss. This seems to be due to the central preprogramming and the predictability of the head movements. Recent studies demonstrate recovery of the dynamic visual acuity following deterioration after traumatic brain injury associated with dizziness (34).

Vestibular Function and Anatomy

The vestibular system, defined as the peripheral vestibular motion detectors and related central nervous system structures, senses motion in space and converts that motion into information that the remainder of the central nervous system can use to generate appropriate motor reflexes or facilitate complex processes such as the coordination of head, eye, and trunk movements or updating one's perception of his or her orientation in the world. The vestibular system, like the auditory system, converts physical stimuli into neural signals, but the vestibular system detects angular and linear acceleration, rather than sound. The vestibular system is present in all vertebrates and many invertebrates. Yet, despite the importance of spatial orientation in all mobile animals, the vestibular system is largely underappreciated until a malfunction occurs, at which point patients present to a physician, often an otolaryngologist, for treatment and education. This chapter discusses the anatomy of the peripheral vestibular system, the biophysics of sensory transduction, vestibular hair cell types and physiology, vestibular afferent types and physiology, and the organization of sensory inputs to the central nervous system, but it is only an introduction to this important, complex system.
The complexity of challenges presented to the vestibular system on a daily basis is elucidated with a simple example. Figure 130.1 follows an office worker through the simple processes of looking for a book on a shelf. She pushes her chair back, stands, and turns left to face the shelf. She then tilts her head (right ear down) to scan the book titles. One way to describe the motion the worker's head makes between the two positions is to decompose the movement into linear (straight-line) motion and angular (rotational) motion, by considering a path made by the center of her head. In this example, the linear motion can be described as backing away from the desk 2 m, with a leftward motion of 3 m and an upward motion of 1 m (Fig. 130.1B). In terms of rotary motion, the woman pitches her head upward 40 degrees from looking down at the paper to looking horizontal. She turns 90 degrees to the left around a vertical axis to face the bookshelf. She then tilts her head 75 degrees toward the right-ear-down position to read the book titles (Fig. 130.1A). Thus, the motion the worker uses to complete the movement between the starting and ending positions can be characterized by three linear movements and three angular movements.
The vestibular system must be able to detect both linear and angular motion in order for the brain to estimate the orientation of the body in space. An important additional piece of information needed for orientation is the direction of gravitational pull or the gravity vector. Among other things, the knowledge of the orientation of gravity allows humans to maintain a vertical stance. Even in the previous simple example, there is not only a complex interaction between the motions of the head, eyes, and body relative to one another, all of which use information generated by the vestibular system, but there is a visual, somatosensory, and vestibular system interaction that allows the worker to know her orientation relative to her surroundings

Gross Anatomy of Thevestibular System
Vertebrates have what amounts to an inertial guidance system made up of multiple sensors of linear acceleration and multiple sensors of angular acceleration in each inner ear.This guidance system, the vestibular labyrinth, is housed in a portion of the otic capsule in the petrous portion of the temporal bone. The bony labyrinth is the thick bone of the otic capsule that houses the membranous labyrinth suspended in perilymph. The membranous labyrinth holds endolymphatic fluid and the neuroepithelial structures of sensory transduction. The perilymphatic and endolymphatic spaces of the labyrinth are continuous with those of the cochlea; therefore, the composition and homeostatic mechanisms of the perilymph and endolymph discussed in the cochlea chapter (Chapter 129) apply to the vestibular system as well. As in the cochlea, proper function of the vestibular system depends on the unique composition of these fluids.
The vestibular labyrinth is a paired structure, with the right and left labyrinth mirroring one another. Subdivisions of the vestibular labyrinth include the three semicircular canals: the lateral or horizontal canal, the posterior canal, and the anterior or superior canal, all of which detect angular accelerations. The geometric layout of the canals is shown in Figure 130.2. The horizontal canals lie parallel to the line between the external auditory canal and the outer canthus of the eye, which is inclined 30 degrees above the horizontal axial plane. The vertical canals are roughly at right angles to the horizontal canals and to each other. When looking down at the top of the head, the anterior canal is oriented at approximately 45 degrees off midsagittal and 45 degrees anterior to the intraaural line. The posterior canal is aligned roughly 45 degrees behind the intraaural line; thus, the anterior canal on the left is roughly parallel to the posterior canal on the right, and the left posterior canal and the right anterior canal are similarly aligned.
Housed in the vestibule are the otolith organs—the utricle and the saccule—which detect linear acceleration. Neither organ is perfectly planar, but the utricle is primarily aligned parallel to the earth and is roughly aligned with the ipsilateral horizontal canal (Fig. 130.3). At rest, the saccule is perpendicular and at right angles to the utricle. The sensitivity of detection of translational acceleration is greatest in the plane of the macula. Thus, the utricular macula is sensitive in the horizontal plane, and the saccular macula is sensitive in the sagittal plane

Basic Physics of Mechanotransduction
Both the linear (utricle and saccule) and the angular (semicircular canal) acceleration sensors for the inner ear use a three-step process to convert accelerations of the head into useful information for the nervous system (Fig. 130.4). The elements used in these three steps are inertial mass, one or more sensory hair cells, and the nerve fibers connected to the hair cells through synaptic junctions. Figure 130.4A shows the system at rest (no acceleration). Figure 130.4B shows the response when the system is accelerated to the left. The resulting rightward movement of the mass (M) relative to the sensory hair cell deflects the sensory hairs, depolarizes the cell body, and increases the discharge rate of the attached nerve fiber.

Neuroepithelium
The sensory hair cells in the membranous labyrinth are similar to those in the cochlea in that both detect small deflections and transmit the information provided by the displacement to the central nervous system (Fig. 130.5). However, significant differences are found between the cochlea and the vestibular neuroepithelia. The vestibular hair cell body is surrounded by supporting and other haircells. Sensory bundles extend from the apical surface of the vestibular hair cell body and are usually in contact with a gelatinous membrane, the motion of which is affected by displacement of the mass element: either the cupula of the semicircular canal or the otolithic membrane for the utricle and saccule. These sensory hair bundles have two distinct ciliary types. The kinocilium is the tallest cilia and is near the edge of the top of the hair cell. Kinocilia are not found on cochlear hair cells. The position of the kinocilium determines the orientation of the hair cell. There are many stereocilia, arranged in columns and rows, and the closer they are to the kinocilium, the taller they are. This arrangement produces an orderly array of stereocilia and a means by which alignment of an individual hair cell can be determined by its so-called morphologic polarization vector, which is shown as an arrow in Figure 130.6. Experimental data show that a functional axis of alignment corresponds with the morphologic one. It is in this axis that a cell responds most vigorously to the displacement of the stereocilia. Displacement of the stereocilia perpendicular to the polarization axis causes no change in the resting potential of the hair cells. On any one sensory organ, neighboring hair cells tend to have polarization vectors that are aligned.
The electrical potential inside the body of hair cells differs from that of the fluids surrounding them because of active transport at the cell membrane. Bending the stereocilia on top of the cell toward the kinocilium opens potassium channels and temporarily increases the resting potential, depolarizing the cell. Deflection away from the kinocilium hyperpolarizes the cell. The channels responsible for transduction are located at the top of stereocilia in the utricle and are opened by relative motion of the stereocilia (1). The hair cells release a neurotransmitter (believed to be glutamate) that is excitatory to the hair cell afferents with which they connect. At rest, there is a baseline release of the neurotransmitter. This release is important because not only does deflection of the hair cell bundle toward the kinocilium (depolarizing the hair cell) increase transmitter release, but deflection of the hair cell bundle away from the kinocilium (hyperpolarizing the hair cell) reduces transmitter release. Thus, one hair cell detects both acceleration and deceleration along the axis of the morphologic polarization vector.
There are two morphologically and physiologically distinct types of hair cell bodies: type I or chalice hair cells and type II or cylindrical hair cells. The body of a type I hair cell is entirely engulfed by one afferent terminal. Efferent innervation is indirect, as the efferent nerve has its synapse on the afferent nerve ending. Type II hair cells can have one or more afferent nerve endings on the body of the cell. Type II hair cells can also be directly or indirectly innervated by vestibular efferent terminals. Type I and type II hair cells are not evenly distributed throughout the neuroepithelium of either the semicircular canal ampullae or the utricular maculae. As discussed later, they are innervated by different classes of vestibular afferents.
The neuroepithelium contains other cell types as well. Supporting cells have the nuclei located at the basal end of the sensory epithelial, above the basement membrane. These cells are believed to make and secrete the extracellular macromolecules of the cupula and otolith membrane. Dark cells can be found at the margins of the transitional epithelium surrounding the neuroepithelium. These dark cells are located directly above pigmented cells and are thought to produce the ionic composition of the endolymph.

Microanatomy and Biophysics of the Semicircular Canals
The semicircular canal is a membranous structure shaped like a torus or hollow doughnut (Fig. 130.7). Maximum sensitivity is to rotation in the plane of the torus. At one end of the torus, there is an enlargement, the ampulla. A gelatinous flap, the cupula, completely seals one side of the ampulla from the other. Because the cupula is elastic, any pressure difference causes it to deflect. The interior of the torus is filled with endolymph, a liquid with the density and viscosity of water. The membranous portion of the canal is attached to the temporal bone. When the head is turned, the membranous labyrinth moves with it, but the endolymph inside has an inertial mass that tends to oppose the turning motion. This oppositional force causes pressure buildup across the cupula, deflecting the cupula from its equilibrium position. Within the physiologic range of motion, this deflection most nearly resembles the motion of the head of a drum or clamped diaphragm when pressure is uniformly applied to one side.
Cilia are embedded in the gelatinous cupula. As the cupula is deflected, the stereocilia bend either toward or away from the kinocilium, producing an increase or decrease, respectively, in the firing rate of the vestibular nerve. The kinocilia are parallel to the long axis of the canal. In the lateral semicircular canal, hair cells are arranged such that the kinocilia are closest to the vestibule; maximal excitation occurs with ampullopetal flow of endolymph. In the posterior and superior semicircular canals, this arrangement is reversed—the kinocilium are farthest from the vestibule. Thus, ampullofugal flow is excitatory.
The crista ampullaris has been divided into central, intermediate, and peripheral zones. In humans and other mammals, type I hair cells are relatively more common in the central zone than in the intermediate and peripheral zones (2). In contrast, type II cells are relatively less common in the central zone than in other zones.
More than half a century ago, Steinhausen constructed a biophysical model of the semicircular canal known as the torsion pendulum model The behavior of this model is determined by the mass of the endolymph, the viscous damping properties of the endolymph, and the springlike restoring force of the cupula. Estimates of these physical properties and knowledge of the geometric properties of the semicircular canal allow observers to relate deflection of the cupula to angular acceleration of the head. With this model, it can be predicted that cupular deflection is proportional to head velocity over a frequency bandwidth of approximately 0.1 to 10 Hz. Above and below this frequency bandwidth, the cupular deflection is not as great, and the sensitivity of the semicircular canal to velocity decreases. At 0 Hz, which corresponds to constant-velocity rotation, the torsion-pendulum model predicts there will be no response at all. The prediction made with this model agrees with the perception of a person who is turned at a constant velocity around a vertical axis. Subjects sense initial acceleration, but in the absence of other cues such as vision, subjects feel they are no longer rotating after 30 to 60 seconds. Rotating subjects who are suddenly brought to a full stop feel a sensation of turning in the opposite direction. This sensation is due to the inertia of the endolymph, which continues to rotate, deflecting the cupula in the direction opposite to that experienced with the initial rotation. Reflexive eye movements measured during these steps of velocity mirror the sensation felt by the subjects and are the basis of cupulometry used in the Bárány test and other tests of the vestibuloocular reflex.

Microanatomy and Biophysics of the Otolith Organs
All the sensors in the vestibular system combine a mass element connected to sensory hair cells (Fig. 130.4). In the case of the otolith organs (utricle and saccule), the mass is composed of calcium carbonate crystals known as otoconia that are embedded in a gelatinous supporting substrate. Displacement of this structure due to linear acceleration or change in orientation with respect to gravity affects a number of sensory hair cells. Each cell has a polarization vector oriented in a slightly different direction, making each one maximally sensitive to acceleration in that particular direction.
The calcium carbonate crystals are suspended in the otolith membrane. Under this membrane are a number of sensory hair cells, each of which can have one or more afferent connections to the vestibular nerve. The drawing in Figure 130.8 is an exploded view. In reality, the stereocilia from the hair cells are in direct contact with the otolith membrane. In Figure 130.8, each of the sensory hair cells has a polarization vector with a small arrow indicating its direction of maximal excitation in the plane. The large arrow at the top of the otolithic mass represents linear acceleration that deflects the otolith mass in the direction of the arrow. Hair cells that have polarization vectors aligned with the arrow and in the same direction are excited maximally, whereas hair cells that have polarization vectors perpendicular to the acceleration are not stimulated.
In the maculae of the utricle and saccule, type I hair cells are relatively more prevalent close to the striola than in the peripheral zone areas. The striola is a zone that runs the length of the macula, is about 100 microns wide, and divides the macula into the medial and lateral extra striola zones. The orientation of the hair cells on either side of the striola is roughly 180 degrees out of phase. Because the striola is C-shaped in the utricle, orientation vectors of hair cells in the utricle are aligned in all directions of the plane of the utricular macula.
It is from an array of these hair cells that the brain can estimate the magnitude and direction of linear acceleration. If all polarization vectors were identically aligned, it would be impossible to determine the magnitude and direction of an acceleration vector in the plane of the otolithic macula. At least two different orientations are needed to resolve the vector in two dimensions. At least three separate orientations are needed to resolve the magnitude and direction of an acceleration vector in three dimensions.
As in the simple example described earlier, each otolith organ has sensory hair cells arranged in a wide variety of orientations of its polarization vectors (Fig. 130.9). Because of this architecture, the asymmetries inherent in the sensitivity of a single hair cell can be canceled out within one otolith organ itself. The orientation of the polarization vectors is toward the striola in the utricular macula and away from the striola in the saccular macula. The right and left otolith organs, like semicircular canals, have mirror symmetry around the sagittal plane. The exact neural connections of the otolith organs have not been as extensively studied as those of the pairs of semicircular canals. Thus, the exact circuitry for resolving linear acceleration in three-dimensional space has not been determined.
A simplified model of the response of the otolith organ to linear acceleration and changes in orientation with respect to gravity can be made with a mass, a spring, and a damper (Fig. 130.4). In this case, the mass is the otoconia macula minus the buoyant force placed on it by the surrounding endolymph. The spring and the damping factors come from the viscoelastic properties of the gelatinous structure in which the otoconia are embedded.
The response characteristics of the otolith organs can be predicted with the above model. Although the specific gravity of the otoconia has been found to be 2.7 times that of the endolymph, the damping forces of the otolithic membrane are more difficult to measure. These damping forces prevent oscillation of the otolith membrane in response to a given linear acceleration. However, when direct recordings are taken from otolith afferents, physiologic performance deviates from that predicted in the model. There are two types of neuronal otolith afferent populations that can be defined that are similar to those in the semicircular canals. The first population appears to respond to head position, and its responses closely follow those predicted with the model for sinusoidal stimulation at frequencies up to 0.1 Hz. A second population of neurons encodes information on linear acceleration. These neurons display increasing gain in proportion to higher-frequency stimuli.
theoretically, how two otolith organs operating in the same plane react to head tilt or to acceleration of the head in the plane of the otolithic macula. If there is no acceleration in that plane, the nerve firing rate of each otolith organ is constant and equal. When the head is tilted to the left, the firing rate of the nerve innervating the left otolith organ increases, while the firing rate of the nerve innervating the right otolith organ decreases. Maximum sensitivity is obtained by means of subtracting the firing rate of the right nerve from that of the left. Acceleration of the head to the right causes deflection of both otoconia to the left in a manner similar to a head tilt to the left. This acceleration produces an increase of the firing rate of the left nerve and decrease in the firing rate of the right nerve. This model (Fig. 130.10) shows that the asymmetry present in one hair cell innervating an otolith organ can be canceled by combining it with a signal from a hair cell that has the same polarization factor in the other side. It also shows that the otolith organs are influenced by both tilt orientation with respect to gravity and linear acceleration.
Einstein recognized that an ambiguity presented between linear acceleration and gravity, and in aviation, is a problem during the acceleration of takeoff, when pilots have trouble differentiating the acceleration of the airplane from the gravity vector. Because translational motion in one direction creates the same inertial force as gravity to tilt in the opposite direction (Fig. 130.10), this problem is known as a tilt-translational ambiguity. Recent research has demonstrated that the central nervous system uses semicircular canal information (activated during tilt but not during translation) in combination with the otolith input to distinguish, for example, tilting the head upward versus accelerating forward as in a car, sled, or airplane (3). This mechanism works poorly at low frequency rotations. In the circumstance where the rotational component of the motion is at low frequency (<0.1 Hz), the brain uses visual or tactile information to help interpret the otolith's signal. In the absence of non-otolith input, such as vision or rotation at frequencies above 0.1 Hz, the system defaults to interpreting linear acceleration as tilt (or gravity). Returning to the aviation example, fighter pilots taking off from an aircraft carrier deck at night will feel as if they are tilted backwards during forward acceleration. The natural correction for this feeling is to steer the plane downward, which could result in disaster.

Vestibular Afferents
Based on the anatomy of peripheral termination, there are three distinct vestibular afferent types: calyx, dimorphic, and bouton. Calyx afferents terminate exclusively on type I hair cells at the calyx endings. Calyx endings may terminate on one or several hair cells. Dimorphic afferents have both calyx endings on type I hair cells and bouton endings on type II hair cells. Dimorphic afferents are likely the most prevalent. Bouton afferents have only bouton endings and thus only terminate on type II hair cells. These three afferent types differ immunohistochemically. Calrentinin, a calcium binding protein, is seen only in calyx afferents; peripherin, which is an intermediate filament protein, is seen in bouton afferents; and neither of these markers is seen in dimorphic afferents.
There are other anatomic distinctions between these afferent types. Calyx afferents have characteristically thick axons, whereas bouton afferents are thinner. Dimorphic afferents, however, can be thick or thin. The processes to the calyx endings are thicker than the processes to the bouton endings. The distribution of the three fiber types is also characteristic. Calyx afferent endings are found in the central zone of the crista ampullaris, whereas dimorphic afferents terminate in the central, intermediate, and peripheral zones, and bouton fibers terminate in the peripheral zone. Similarly, utricular calyx afferents terminate in the striola region, whereas dimorphic afferent terminals are seen throughout the macula and bouton afferents and generally terminate peripherally.
Afferents also differ in their discharge regularity, conduction velocity, and sensitivity to vestibular and galvanic stimulation. Although response gains, conduction velocity, and discharge regularity over a population of neurons all fall along a continuum, based on these characteristics, vestibular afferents fall into three general groups that correspond well with the three groups (calyx, dimorphic, and bouton) determined by peripheral morphology. Calyx afferents innervating the central ampulla or striola are large fibers that are irregularly firing, sensitive to galvanic stimulation, and have a low sensitivity to angular motion. Dimorphic afferents may have thick or thin axons. Those terminating more centrally tend to have thicker axons and are irregularly firing, galvanically sensitive, and sensitive to (rotational or linear) stimulation. Dimorphic afferents terminating peripherally (either in the macula or crista) and bouton afferents tend to be thinner fibers with lower galvanic and natural stimulation thresholds and are regularly firing with slower conduction velocities (4). These different afferent types may be of more interest than just physiologic curiosity. The high sensitivity irregular afferents are sensitive to small perturbations but have nonlinear dynamics because they readily silence when the head moves in the inhibitory direction. These afferents may be best suited for quick, nonlinear reflexes such as vestibulospinal responses to inhibit a fall. In contrast, the linear characteristics of the thinner, more regular afferents are appropriate for linear vestibular reflexes, like the vestibuloocular reflex, that must work over a wide range of frequencies and peak velocities (5).
Both semicircular canal afferents and otolith afferents are cosine tuned, which means they have one best characteristic response vector. For utricular afferents, these vectors can lie anywhere in the horizontal plane and are dependent on the orientation vector of the hair cells that they innervate. The response of the afferent is proportional to the cosine angle between the direction of stimulation and the orientation vector of the afferent. Similarly, the rotational vector of maximum stimulation for semicircular canal afferents is in the plane of rotation of the canal. The response of the fiber decreases as cosine of the angle between the plane of rotation and the canal plane. The cosine tuning of the afferent is consistent with the fact that transmitter release by hair cells is proportional to the cosine of the angle between the displacement of the hair cell bundle and the direction of stimulation (Fig. 130.6). Thus, both the hair cells and the afferents are cosine tuned. The coding of the vestibular system is such that the direction of stimulation is encoded by the afferent population stimulated, and the intensity of the movement is encoded by the intensity of the response of the stimulated afferent.
All of the vestibular epithelium are also innervated by vestibular efferent neurons. These neurons have cell bodies in the brainstem in areas around the genu of the facial nerve. Their fibers in humans run mixed with the vestibular afferent fibers and can terminate either presynaptically (on type II hair cells) or postsynaptically on calyx or bouton endings. The function of the vestibular efferent system in mammals is unknown.

Vestibular Brainstem
Vestibular afferents are bipolar neurons that have cell bodies in the inferior and superior Scarpa (vestibular) ganglion. The peripheral (dendritic) processes of these neurons exit the neuroepithelium and collect in the inferior and superior vestibular nerves. The inferior division includes neurons from the posterior canal and saccule, and the anterior division includes utricular, horizontal canal, and anterior canal afferents (Fig. 130.11). Axonal branches of primary afferent ramify in the vestibular nuclei. Afferent terminals from the different end organs primarily innervate the various divisions of the vestibular nuclei, although terminations are seen in the cerebellum and other brainstem nuclei as well. The precise terminations by end organ (semicircular canal or otolith) in the central nervous system are similar in many species (6). Not only does the brainstem region receive convergent output from different branches of the vestibular nerve, but individual neurons receive afferent input from one, two, or more end organs (canal ampullae or otolith maculae). Thus, the vestibular nuclei integrate information from multiple ipsilateral receptors.
There are four major vestibular nuclei in the brainstem: the lateral (Deiters), superior, medial, and inferior (spinal, descending) nuclei. In addition, there are several minor vestibular nuclei, including nucleus y, that are identified in various species by various investigators. The vestibular nuclei not only receive vestibular information but other information pertaining to spatial orientation as well. These inputs include optokinetic signals through the accessory optic system, neck proprioceptive signals, and Purkinje cell projections from the cerebellar cortex. From the vestibular nuclei, vestibular signals are passed throughout the central nervous system. The dominant output of the vestibular nuclei are to the ocular motor nuclei, via the medial longitudinal fasciculus and the ascending tract of Deiters; to the spinal cord, via the medial and lateral vestibulospinal tracts; to the cerebellum, via the cerebellar peduncles; and to the contralateral vestibular nuclei, via the vestibular commissural system. Other pathways connect the vestibular nuclei with the autonomic system, which has implications in motion sickness and blood pressure control, and with the thalamus.
One important function of the vestibular commissural system is inhibition. Experimental data show that the discharge frequencies of neurons excited during ipsilateral angular acceleration are also excited due to a decrease of crossed inhibition, which is caused by a decrease in discharge rate from the contralateral paired semicircular canal. This reciprocal mechanism is the basis of the so-called push-pull connection that increases the sensitivity of the system through use of the difference in signals between the functionally paired semicircular canals (left horizontal–right horizontal, left anterior–right posterior, left posterior–right anterior) in either ear. In this way, the paired canals complement one another and tend to cancel out the asymmetries inherent in the hair cell transduction mechanisms and afferent firing patterns mentioned earlier. The neural signals from these pairs of canals converge in a synergistic way in the nervous system, allowing the system to function even in the presence of a complete unilateral lesion. However, responses in patients with unilateral lesions are more asymmetric than those among healthy persons given high enough angular acceleration to reveal these inherent asymmetries, which are apparent when the push-pull redundancy is not available.
The best studied vestibular reflex is the vestibuloocular reflex. Vestibuloocular reflexes are of two types: compensatory reflexes that stabilize gaze during motion and orienting reflexes that align the eye with the gravitational vector. One of the challenges for the nervous system is to translate signals from the semicircular canal planes into coordinates appropriate for effector action. Those who study the vestibular system use an external frame of reference, as shown in Figure 130.3. Linear acceleration or rotational acceleration occurs around three axes that are perpendicular to each other: the interaural or pitch axis, the nasal-occipital or roll axis, and the rostral-caudal or yaw axis. The vestibule-oculo-motor system, however, is thought to use a coordinate system based on the orientation of the three pairs of semicircular canals. Experiments have shown that stimulation of afferent branches of the eighth cranial nerve that come exclusively from one semicircular canal produces reflexive eye movements that tend to rotate around the axis of greatest sensitivity for that canal. The three agonist-antagonist pairs of eye muscles themselves do not produce eye movements that completely correspond to these axes of orientation of the semicircular canals. Thus, there is a distribution of signals from the semicircular canals to produce compensatory eye movement of the desired magnitude and direction.
According to a simplified analysis, the connection between the three pairs of semicircular canals and the three pairs of eye muscles can be described with a set of nine constant coefficients. First-order analysis indicates that the translation of incoming vestibular systems needed to produce compensatory eye movement is a relatively simple operation for the brain to perform. This operation is contrasted to the more complicated series of commands that must be given when signals from the vestibular system are used to stabilize the head on the neck or the body with leg muscles.
The nervous system can adapt its response by comparing vestibular input to other sensory input. When the head moves, the vestibuloocular reflex tends to stabilize the image of an object in space on the retina by producing an eye movement compensatory to the head movement. At any time, the functional anatomic connections needed to stabilize an object can be thought of as a set of nine constant coefficients that distribute the incoming vestibular systems to the ocular motor neurons to form the reflexive eye movement response. For example, the motion of the head 10 degrees to the right produces eye movement 10 degrees to the left.
Provisions have been made in the nervous system for this response to adapt when necessary, owing to factors such as disease or aging. One such example is people with myopia who wear eyeglasses. If the magnification of the lens is 1.2 times, rotation of the head 10 degrees to the right produces rotation of the world as viewed by the eye 12 degrees to the left and therefore demands a corresponding reflexive eye movement 12 degrees to the left. The nervous system makes this form of adaptive change to resolve a conflict between afferent inputs, in this case vestibular and visual inputs. In this example, the nervous system can correspondingly increase the amount of eye movement produced for a given head movement so that the error between the head motion input and eye motion response is reduced to nearly zero. This gain plasticity requires participation of the floccular lobe of the cerebellum.

Current Vestibular Issues
Like most fields in basic sciences, the vestibular system is actively studied in a number of excellent laboratories. Among the many actively investigated areas are the pharmacology of the vestibular periphery, interactions between active head movements and the passive vestibular reflexes, the role of vestibular signals in spatial orientation, the function of vestibular efferent system, physiologic and cellular mechanisms of adaptation and compensation after vestibular injury, and the adaptation of the vestibular system to microgravity. In addition, efforts are ongoing to develop prosthetic devices to aid patients with vestibular deficits. This research holds the promise of improving our understanding of this vital, well conserved, and underappreciated “sixth” sensory system.