Head and Neck Pathology

CC

A 53-year-old woman (pleomorphic adenoma is most common in the fourth to sixth decades of life, with a slight female predilection), who is a schoolteacher, is referred for evaluation of a mass inferior to her right ear.

HPI

Over the past 8 months, the patient had noticed a progressively enlarging mass anterior and inferior to her right ear. (Pleomorphic adenoma is the most commonly occurring benign tumor of the major salivary glands. It typically grows slowly, at a rate of less than 5 mm per year). The patient explained that the mass has slowly enlarged, prompting her to bring it to her dentist's attention. There is no associated pain, paresthesias, or motor deficits (motor and sensory nerve deficits are not commonly seen with benign salivary neoplasms). She denies any constitutional symptoms, including fever, chills, night sweats, appetite changes, and weight loss (systemic symptoms associated with inflammatory or malignant processes).

PMHX/PSHX/Medications/Allergies/SH/FH

The patient sees her dentist yearly for routine maintenance. She drinks alcohol on social occasions and has never smoked. (Tobacco use and alcohol consumption are not known to be risk factors for the development of pleomorphic adenomas. A potential risk factor is exposure to certain chemicals and dyes, but this association is very weak.)

There is no previous history of head and neck cancer or facial cosmetic surgery (it is important to be aware of previous surgeries in the area of the pathology). The patient has completed all her childhood immunizations, including the mumps vaccine as part of the MMR vaccine (therefore mumps are less likely to be the cause of the parotid swelling).

Examination

General. The patient is a well-developed and well-nourished, 53-year-old woman in no apparent distress.

Vital signs. Blood pressure is 135/90 mm Hg, heart rate 80 bpm, respirations 16 per minute, and temperature 36.9°C.

Maxillofacial. Examination of the eyes and ears is unremarkable. The tympanic membranes are clear bilaterally. Cranial nerves II to XII are intact, with no weakness of the muscles of mastication (V). There is no sensory deficit in the V1-V3 distributions. Facial mimetic muscles are intact and symmetrical (involvement of the facial or trigeminal nerve would be suggestive of a malignant process).

There is a visible swelling in the right subauricular area that distorts the facial contour ( Figure 7-1 ). Palpation reveals a well-circumscribed, freely moveable, firm, rubbery, 1- to 1.5-cm, nontender mass above the angle of the mandible. (Benign processes are typically slow growing and push, rather than infiltrate, local structures, such as the overlying skin; adjacent structures, such as blood vessels and nerves, are usually not involved). There is no warmth, erythema, ulceration, or induration of the overlying soft tissue (signs of an inflammatory or a malignant process).

Intraoral. The parotid papillae appear noninflamed bilaterally, with expression of clear saliva from Stensen's duct (purulent drainage from the duct would be indicative of suppurative parotitis). No mucosal ulcerations are present, and there is no intraoral extension of the mass (consistent with a benign process).

Neck. No palpable submandibular or cervical lymphadenopathy (palpable lymph nodes would be indicative of a malignant neoplastic process).

Imaging

Several imaging modalities may be used for the evaluation of a parotid mass, including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and sialography. The most commonly used initial studies of choice are CT and MRI.

Histologic confirmation is ideally performed preoperatively by means of fine-needle aspiration (FNA). This is best performed by an experienced cytopathologist and can provide diagnostic information guiding definitive treatment. FNA can have a high false-negative rate; therefore, ultrasonographic or CT guidance can be used to recheck when results are inconclusive. Should the FNA results continue to be inconclusive, the clinician should proceed with definitive surgical resection of the tumor with facial nerve preservation, if possible. It is not necessary to perform an open biopsy of the parotid gland, because 80% of parotid masses are benign; therefore, a parotidectomy is appropriate as a diagnostic and treatment modality. Patients should be prepared preoperatively for the possibility of facial nerve deficit. If the integrity of the nerve is maintained during the procedure, facial nerve function returns.

Sialography can be used to identify sialoliths and ductal obstruction and to differentiate parenchymal from nodal disease. A CT scan can also help differentiate nodal from parenchymal disease and is particularly useful in assessing larger lesions with atypical ultrasonic features. However, it is not as reliable as sialography for identification of ductal pathology. MRI offers excellent visualization of the glandular pathology and tumors. It is often the imaging modality of choice. Neither CT nor MRI can reliably outline the surgical anatomy of the mass relative to cranial nerve VII.

A panoramic radiograph can be used as a surveillance imaging tool to exclude the presence of intraductal or glandular calcifications; however, it is not particularly useful in the evaluation of parotid gland lesions.

For the current patient, a panoramic radiograph confirmed no observable pathology. An MRI scan demonstrated a well-circumscribed mass within the substance of the parotid gland, measuring 1.5 cm in diameter, with no homogeneous enhancement ( Figure 7-2 ). There was no evidence of enlarged intraparotid lymph nodes.

Labs

No routine laboratory tests are indicated in the work-up of a parotid mass. A complete blood cell count (CBC) may be obtained to evaluate for an elevation of the white blood cell (WBC) count secondary to an infectious process. The minimum preoperative laboratory examination should include the hematocrit and hemoglobin levels. Further laboratory tests would be dictated by the medical and surgical histories.

For the current patient, the CBC was within normal limits.

Differential Diagnosis

In the current case, the slow, circumscribed growth, lack of fixation, and absence of cranial nerve involvement or adenopathy associated with the lesion suggest a benign process. In addition, the absence of any erythema, pain, or warmth, together with a normal WBC count, implies a noninfectious/inflammatory process. With a swelling in this region, a differential for proliferative processes includes pleomorphic adenoma, subcutaneous lipoma, Warthin's tumor, monomorphic adenoma, and malignant salivary gland neoplasms ( Box 7-1 ).

Assessment

FNA demonstrates a combination of ductal cells, chondromyxoid matrix, and dispersed plasmacytoid and lymphocyte-like myoepithelial cells (classic histology for pleomorphic adenoma), confirming the diagnosis of pleomorphic adenoma.

A pleomorphic adenoma is characterized by a variety of morphologic and histologic patterns. It is considered a true “mixed” tumor, referring to the biphasic proliferation of both ductal epithelial and myoepithelial (mesenchymal) cells. The ductal epithelial cells give rise to glandlike epithelial structures, whereas the myoepithelial cells are responsible for the characteristic pleomorphic extracellular matrix (myxochondroid connective tissue). Within a single tumor there may be cellular, glandular, myxoid, cartilaginous, and even ossified features. This morphologic diversity may be evident only when the lesion is excised and examined in its entirety. Histologically, pleomorphic adenomas may resemble polymorphous, low-grade adenocarcinoma, adenoid cystic carcinoma, basal cell adenoma, or epithelial-myoepithelial carcinoma. The connective tissue lining, or “pseudocapsule,” is an important feature limiting growth but may be incomplete or infiltrated by tumor cells (tumor pseudopodia).

FNA may show various combinations of three elements: ductal cells, chondromyxoid matrix, and myoepithelial cells. An aspirate with more than one of these components, especially when accompanied by the characteristic clinical presentation, makes this a straightforward diagnosis.

Treatment

Enucleation of a pleomorphic adenoma of the parotid gland is associated with recurrence rates of up to 40%. The treatment of choice is a superficial parotidectomy, which has resulted in low morbidity, with recurrence rates of less than 2% to 3%. An attempt should be made to remove the tumor en bloc while maintaining the integrity of the capsule, with a 5-mm cuff of normal tissue. When the capsule is encountered on the deep aspect, it must be carefully dissected from the facial nerve. Maintaining the capsule is thought to be the key factor in minimizing recurrence. This observation led to the development of extracapsular dissection, in which the tumor and capsule are carefully dissected from the parotid gland. This conservative approach is associated with low rates of morbidity (facial nerve damage and Frey syndrome) and recurrence rates of 2% to 3%. Upon excision, the specimen should be delivered to pathology intact, to allow macroscopic evaluation of the integrity of the capsule. Pleomorphic adenomas of the palate should be excised with a 5-mm margin, including the overlying mucosa and underlying periosteum.

For the current patient, a superficial parotidectomy with cranial nerve VII preservation was performed through a face-lift incision. The tumor was excised with a 5- to 10-mm margin of uninvolved surrounding tissue, with the exception of the deep margin, where the capsule was carefully dissected off of the facial nerve.

The procedure is usually initiated by making a modified Blair incision with a no. 15 scalpel blade. The dissection is taken down to the subdermal plane, and the flap is elevated in the preauricular region. The neck extension is dissected through the platysma, and the great auricular nerve is identified and preserved if possible. The anterior border of the sternocleidomastoid muscle is identified, and the proximal third is dissected. The muscle belly is retracted laterally, and the posterior belly of the digastric muscle identified deep to the sternocleidomastoid muscle. The preauricular portion of the dissection is deepened in the pretragal plane to the extent of the bony-cartilaginous junction of the external auditory meatus. The upper and lower portions of the dissections are then joined, and the root of the facial nerve is identified, approximately 4 mm above the posterior belly of the digastric muscle. A nerve stimulator is used for verification. The roots of the facial nerve are then identified, from the frontal, zygomatic, buccal, marginal mandibular, and cervical aspects. The parenchyma of the parotid is then elevated in a superficial plane over the preserved nerve roots. The parotid gland is mobilized anteriorly to include the pleomorphic adenoma. The external carotid artery is usually identified at the deep aspect and left intact. The specimen is removed en bloc and submitted for pathologic examination. The branches of the facial nerve are usually tested after the surgery.

The wound is thoroughly irrigated, and Jackson-Pratt (JP) drains are placed in a dependent fashion. The skin is closed in a layered fashion consisting of deep 3-0 and 4-0 Vicryl sutures, with particular attention to closure of the superficial musculoaponeurotic system to prevent Frey syndrome. The skin can be closed with nonresorbable 5-0 Prolene sutures, which are usually removed about 1 week after surgery.

Complications

Early complications can include facial nerve paralysis, hemorrhage, hematoma, infection, skin flap necrosis, trismus, salivary fistula, sialocele, and seroma formation. Long-term complications include Frey syndrome, hypoesthesia of the greater auricular nerve, tumor recurrence, and cosmetic deformity from the soft tissue defect ( Box 7-2 ).

Discussion

Salivary gland tumors are rare, with an annual overall incidence of 2.5 to 3 per 100,000 population. The majority of parotid (80%) and submandibular gland (60%) tumors are benign. Fifty percent of tumors originating from the minor salivary glands, but only 10% of tumors of the sublingual gland, are benign. Pleomorphic adenoma compromises about 40% to 70% of all salivary gland tumors. It is the most frequent salivary gland tumor in both children and adults and the most common tumor of both major and minor salivary glands. Approximately 75% of pleomorphic adenomas occur in the parotid gland. Ten percent are found in the submandibular gland, and another 10% are found in the palate. Pleomorphic adenomas make up 60% to 70% of all parotid neoplasms, 40% to 60% of submandibular gland tumors, and 40% to 70% of minor salivary gland tumors.

A pleomorphic adenoma classically presents as a painless, firm swelling. It may be lobulated, irregularly dome shaped, or smooth. The consistency is typically rubbery or semisolid, and there may be isolated areas that are softer. If untreated, it enlarges slowly over months or years. The connective tissue capsule generally limits growth, but tumors can become very large if neglected.

In the parotid gland, pleomorphic adenoma most commonly presents in the inferior aspect of the superficial lobe. Deep lobe invasion may manifest as a mass of the soft palate or lateral pharyngeal space. CT or MRI scans can help localize tumor or differentiate lymph nodes from tumor.

The most common intraoral sites are the palate and upper lip. When arising from minor glands of the palate, pleomorphic adenomas are most commonly located lateral to the midline at the junction of the hard and soft palate. Minor gland tumors may cause localized pressure resorption of the palate but do not tend to invade the underlying bone.

Histopathologically, permanent hematoxylin- and eosin–stained sections demonstrate typical histology, including glandlike epithelial cells forming nests, chords, and ductlike structures within a heterogeneous stromal background of myxoid, chondroid, and mucoid material, along with a distinct fibrous connective tissue lining ( Figure 7-3 ).

CC

* The authors and publisher wish to acknowledge Dr. Aric Murphy and Dr. David M. Weber for their contribution on these topics in the previous edition.

A 20-year-old patient presents to the office complaining of a painless mass in her lower lip. (Mucoceles are more common in young adults but can be seen in all age groups, including infants. There is no gender predilection.) Irritation fibromas can also be present on the commissure or lower lip but are more commonly found on the cheek with repeated trauma. Both fibromas and mucoceles are a result of repeated trauma to the intraoral mucosal lining.

HPI

The patient was recently evaluated by her general dentist and was subsequently referred for evaluation and treatment of a persistent mass in her lower lip. The lesion was noticed 1 month earlier and has gradually increased to its current size (some patients give a history of recurrent swelling that periodically ruptures). The mass developed after trauma to the lower lip during function and has proved to be a site of continued trauma due to its persistence. Although trauma (e.g., lip biting) has been associated with mucoceles, a positive history of trauma is frequently lacking.

PMHX/PDHX/Medications/Allergies/SH/FH

Noncontributory. There is no association between preexisting medical conditions and the incidence of mucoceles or irritation fibromas.

Examination

Maxillofacial. There is asymmetrical prominence of the patient's lower lip (most common site). There are no other areas of swelling or lymphadenopathy.

Intraoral. Examination reveals no pathology of the hard or soft palate, tongue, floor of the mouth, or buccal mucosa. A soft, 1-cm, painless mass is appreciated just inferior and medial to the right labial commissure ( Figure 7-4 ). The mass is fluctuant, soft, and nontender with a bluish mucosal discoloration. There is some evidence of trauma to the mass from the adjacent dentition. The tissue overlying the mass has become fibrotic as a result of repetitive trauma.

Imaging

No imaging studies are indicated unless there is suspicion of other pathologic processes.

Labs

No routines labs are indicated unless dictated by underlying medical conditions.

Differential Diagnosis

Despite the classic characteristic clinical findings, salivary gland tumor needs to be considered on the differential diagnosis. Salivary gland tumors of the minor glands can occur on the lips but are more commonly seen in the upper lip rather than the lower lip.

The differential diagnosis also includes an irritation fibroma. This lesion is commonly pink and nonfluctuant and does not have history of intermittent swelling and rupturing (as opposed to a mucocele). An irritation fibroma usually presents as a pedunculated, round, nonulcerated lesion that is frequently found along the linea alba in patients with chronic cheek biting. The lesion is slightly pale but has the same consistency as the surrounding mucosa, with no erythema.

Biopsy

Although the clinical examination can be highly suspicious of a mucocele, histopathologic analysis is the only confirmatory test. An excisional biopsy (removal of the entire lesion) is both diagnostic and the definitive treatment.

Assessment

An excisional biopsy was performed under local anesthesia confirming the diagnosis of a mucocele.

Histopathologic examination of a mucocele demonstrates spillage of mucin surrounded by dense granulation tissue, which may be seen in association with minor salivary glands. An inflammatory response (neutrophils) may be observed.

Treatment

The current patient was seen in the clinic for excisional biopsy under local anesthesia. Care was taken to evert the lower lip with finger pressure against the skin. This provides increased exposure of the mass on the mucosal surface. A straight-line incision is made perpendicular to the vermillion border over the length of the mass on the mucosal surface. This is followed with careful blunt and sharp dissection around the mucocele and the offending gland. The surgical specimen was labeled and sent to pathology, and a diagnosis of a mucocele was confirmed.

An alternative surgical approach to treatment of a mucocele includes excision or marsupialization with a carbon dioxide laser. Cryotherapy has also been used for the treatment of mucoceles. Direct application of liquid nitrogen is made with a cotton-tip applicator. A major advantage of this technique is compliance in pediatric patients.

Complications

The most common complication associated with treatment of a mucocele is recurrence. This can be minimized by the removal of any adjacent minor salivary glands. For patients who experience problematic recurrence, a carbon dioxide laser can be used to ablate the surgical field, which is left to heal by secondary epithelialization. Excision or dissection of larger mucoceles of the lower lip can pose a risk to the labial branch of the mental nerve, resulting in postoperative neurosensory dysfunction.

Discussion

Mucoceles, also called mucus retention cysts or mucus extravasation phenomenon, by definition are cavities filled with mucus produced by trauma to minor salivary glands. With functional trauma to the soft tissue and underlying glands, mucus leaks into the adjacent tissues, creating a mucocele. It is the most common lesion affecting the oral mucosa. It can grow to a few millimeters in size and rarely is larger than 1.5 cm. The lower lip is the most common site of a mucocele due to its susceptibility to trauma. Seldom are these lesions seen in the upper lip, even though it has an equivalent number of minor salivary glands. In a recent study of the distribution of mucoceles in 263 patients, 78% occurred in the lower lip and 3% occurred in the upper lip. These findings are consistent with previous studies. Mucoceles do not have an epithelial lining (in contrast to salivary duct cysts). The extravasation of mucus produces a wall of inflamed fibrous tissue.

The oral fibroma (irritational or traumatic) is one of the most common exophytic, soft tissue lesions seen in the oral cavity, with an incidence of 12 lesions per 1,000 population. It is considered a reactive hyperplasia of fibrous connective tissue in response to local irritation or trauma. These lesions have limited growth potential, and the lesion may even decrease in size after prolonged removal of irritation or trauma.

Clinically, the fibroma can occur anywhere in the oral cavity, but it is most common in the buccal mucosa along the occlusal plane. Other common sites are the labial mucosa, tongue, and gingiva. Fibromas often appear pink due the absence of vascularity. Most commonly, they appear as a well-circumscribed nodule that is often pedunculated or sessile. Rarely do the lesions exceed 2 cm in the greatest dimension. In some cases, the lesion can appear white due to hyperkeratosis from continual irritation. Occasionally, the fibroma can appear mildly erythematous and even ulcerated, if recently traumatized. Fibromas most commonly occur between ages 30 and 50 years, favoring females to males in a 2 : 1 ratio in cases submitted for biopsy. Treatment is conservative surgical excision, and the prognosis is excellent, with rare recurrence. It is important to submit the lesion for histopathologic diagnosis, because some benign, and even malignant, tumors can mimic the clinical appearance of the fibroma.

Histologically, the lesion appears as a nodular mass of fibrous connective tissue covered by stratified squamous epithelium; this is consistent with the diagnosis of a traumatic (irritation) fibroma of the buccal mucosa

Occasionally, chronic inflammatory infiltrates can be seen in the connective tissue portion of the lesion.

CC

* The authors and publisher wish to acknowledge Dr. Matthew J. Karban for his contribution on this topic in the previous edition.

A 4-year-old boy presents to the pedodontist because he has had a sore mouth and decreased oral intake for the past 2 days.

Acute herpetic gingivostomatitis is an infection that typically affects children. The most common age of onset is 6 months to 5 years. A second peak occurs in the early 20s. The majority (90%) of primary infections are asymptomatic. By adulthood about 60% to 95% of the population is affected by a herpes virus.

HPI

The patient's mother reports that he has been in distress with mouth pain and has not been eating well for the past few days (pain is the most common presenting symptom). The parents noticed multiple vesicles and ulcers in his mouth 2 days earlier. He has had a low-grade temperature over the past 2 days, which they have treated with acetaminophen (in the pediatric population, decreased oral intake is often the first sign of a developing infectious/pathologic process).

It is important to distinguish primary and recurrent infection. Primary infection tends to be more severe and can occur anywhere in the oral cavity. Symptoms typically last 1 week and can be associated with malaise, lymphadenopathy, and fever. Recurrent disease occurs sporadically and tends to be limited to the keratinized mucosa.

PMHX/PSHX/Medications/Allergies/SH/FH

The patient has never been to the dentist. He does not have any known drug allergies and is not on any medications. The mother admits to having recurrent herpes labialis several weeks ago.

Herpes simplex virus (HSV) is transmitted via direct contact with infected secretions from the saliva and other bodily fluids. The main risk factor is a known exposure to the virus. When HSV-1 comes into contact with the host, the virus migrates to the sensory nerve endings and frequently to the trigeminal ganglia. The virus then enters a latent phase for 7 to 10 days before replication. Recurrent disease with HSV-1 characteristically involves the distribution of the trigeminal nerve.

Examination

General. The patient is an uncooperative, anxious boy in otherwise good health.

Vital signs. His blood pressure is 105/70 mm Hg, heart rate 100 bpm, respirations 18 per minute, and temperature 38.9°C (febrile).

Maxillofacial. He has palpable cervical lymph nodes (this is commonly seen with acute herpetic gingivostomatitis). The face is symmetrical, with no other obvious signs of infection or edema.

Intraoral. Multiple vesicles and ulcerations extend over the buccal and labial alveolar mucosa and dorsal tongue ( Figures 7-5 ) (primary acute herpetic gingivostomatitis can affect both the keratinized and nonkeratinized mucosa, but recurrent infection preferentially involves the keratinized tissue). Ulcerations measure from 1 to 3 mm in diameter and are covered by a pseudomembrane and an erythematous border. The gingiva is erythematous and painful, and there is copious saliva production with drooling. The ulcers present as foul-smelling ulcers when they rupture due to the friable pseudomembrane.

Extremities. Right thumb displays similar erythematous vesicles and ulcerations (consistent with herpetic whitlow).

Imaging

No imaging modalities are necessary for the diagnosis and management of acute herpetic gingivostomatitis.

Labs

The diagnosis of acute herpetic gingivostomatitis is mainly a clinical diagnosis, but several laboratory tests are available for detecting an active herpes viral infection. Some of these tests include viral cultures, direct immunofluorescence, and a Tzanck smear. The Tzanck smear involves unroofing the vesicles and scraping of the tissue bed for cytologic examination. Identification of multinucleated epithelial giant cells with eosinophilic viral inclusions is the hallmark feature.

Assessment

Acute (primary) herpetic gingivostomatitis.

Treatment

Acute herpetic gingivostomatitis is a self-limiting condition usually resolving within 3 weeks from the onset of symptoms. Treatment predominantly involves observation and palliative care. This may involve topical anesthetics and over-the-counter pain relief, such as acetaminophen or ibuprofen. Fluids and electrolyte status should be monitored as needed to avoid dehydration.

Pharmacologic treatment is often minimal due to the self-limiting course of the herpes virus. In more severe cases, pharmacotherapy can be of use if administered appropriately. Conventional antiviral therapy (e.g., acyclovir, valacyclovir, and penciclovir) has proved effective and can shorten the healing times by several days.

Primary acute herpetic gingivostomatitis can be managed on an outpatient basis with aggressive oral hydration, analgesia, and topical and systemic antiviral therapy. The main criteria for hospital admission include severe dehydration and pain.

Adult patients are typically managed on an outpatient basis. Severe disease refractory to treatment may indicate an underlying cause of immunosuppression that may require further evaluation for recurrent, persistent, or refractory disease.

Complications

The main complications include potential nutritional deficiencies and inadequate fluid intake leading to dehydration, ocular involvement, herpetic whitlow, and central nervous system involvement.

Ocular herpes is relatively rare, affecting 50,000 patients in the United States per year. Stromal keratitis occurs in 25% of patients affected with ocular symptoms, involves inflammation of the deep layers of the cornea, and can lead to globe rupture and blindness. Herpetic whitlow is an intense, painful infection of the hand, involving one or more fingers, that typically affects the terminal phalanx. HSV-1 is the cause in approximately 60% of cases of herpetic whitlow, and HSV-2 is the cause in the remaining 40%. In children, HSV-1 is the most likely causative agent. Infection involving the fingers usually is due to autoinoculation from primary oropharyngeal lesions as a result of finger-sucking or thumb-sucking behavior in patients with herpes labialis or herpetic gingivostomatitis. In the general adult population, herpetic whitlow is most often due to autoinoculation from genital herpes; therefore, it is most frequently secondary to infection with HSV-2. Before the use of gloves, herpetic whitlow was common among dentists, transmitted by the infected oropharyngeal secretions of patients. Transmission easily can be prevented by the use of gloves and by scrupulous observation of universal fluid precautions.

Although a prodrome of fever and malaise may be observed, most often the initial symptoms are pain and burning or tingling of the infected digit. This usually is followed by erythema, edema, and the development of 1- to 3-mm grouped vesicles on an erythematous base over the next 7 to 10 days. These vesicles may ulcerate or rupture and usually contain clear fluid, although the fluid may appear cloudy or bloody. Lymphangitis and epitrochlear and axillary lymphadenopathy are not uncommon. After 10 to 14 days, symptoms usually improve significantly, and lesions crust over and heal.

After the initial infection, the virus enters cutaneous nerve endings and migrates to the peripheral ganglia and Schwann cells, where it lies dormant. They are protected from antibody detection due to the blood-brain barrier and therefore lie dormant in the cell bodies of the gasserian ganglion. The primary infection usually is the most symptomatic. Recurrences observed in 20% to 50% of cases are usually milder and shorter in duration.

More than 2,100 cases of herpetic encephalitis are seen in the United States per year, making it a rare but extremely serious brain disease. HSV-1 is almost always the culprit, except in newborns. In about 70% of infant herpes encephalitis, the disease occurs when a latent HSV-2 virus is activated. Untreated, herpes encephalitis is fatal in more than 70% of cases. Fortunately, rapid diagnostic tests and treatment with acyclovir have significantly improved both survival rates (up to about 80%) and complication rates.