Syndromes Affecting the Central Nervous System David W. Lui, DMD, MD a,b,*, Roman G. Meyliker, DMD a,b, Samir Singh, DMD a,b KEYWORDS
Lesch-Nyhan syndrome
Marcus Gunn syndrome
Cavernous sinus syndrome
Superior orbital fissure syndrome
Trotter syndrome
Horner syndrome
Frey syndrome
Ramsay-Hunt syndrome KEY POINTS
Many syndromes affecting the central nervous system (CNS) demonstrate both intraoral signs as well as head and neck manifestations.
Their causes include, but are not limited to, genetics, infection, trauma, neoplasm, postsurgery, and idiopathy.
Various treatment methods are available and must be considered when working with patients who present with syndromes affecting the CNS.

Lesch-Nyhan syndrome
Genetics  Extremely rare, present in only 1 in 380,000 live births.1  Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism; however, up to 30% of patients carry de novo mutations.2,3 It is caused by the deficiency of hypoxanthine guanine phosphoribosyl transferase (HPRT), which is a purine salvage enzyme responsible for recycling purine bases into purine nucelotides.4 Specifically, it converts hypoxanthine and guanine into their respective 50 -mononucleotides.5  The gene for HPRT (HPRT1) is encoded on the long arm of the X chromosome at Xq26-Xq27.2 This enzyme is present in all tissues with the highest levels in the basal ganglia, which accounts for the extrapyramidal effects seen in this syndrome.4  Because it is an X-linked disorder, male patients are almost exclusively affected. Female patients may be carriers.5  A phenotypic spectrum exists, which is thought to be based on variability in HPRT levels and activity.4,5 Classic LNS is correlated with severe or complete HPRT deficiency. Patients with partial HPRT deficiency may present with hyperuricemia with or without neurologic and/or behavioral symptoms.4,5 Funding Sources: None. Conflict of Interest: None. a Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University School of Dentistry, 521 North 11th Street, Room 311, Richmond, VA 23298-0566, USA b Division of Oral and Maxillofacial Surgery, Department of Surgery, Medical College of Virginia Medical Center, 521 North 11th Street, Room 311, Richmond, VA 23298-0566, USA * Corresponding author. Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University School of Dentistry, 521 North 11th Street, Room 311, Richmond, VA 23298-0566. E-mail address: [email protected] Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 183–195 1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2014.05.002


Clinical features  Often, children have a normal prenatal and perinatal course with development of symptoms within the first 3 to 6 months.1  LNS has a spectrum of phenotypic presentations. However, classic LNS is characterized by aggressive and self-mutilating behavior (most commonly persistent lip, tongue, and finger biting resulting in severe avulsion injury to perioral tissues and amputation of digits), hyperuricemia, and involuntary movements with severe dystonia (Fig. 1A, B).2,6,7  Other features that may be present include developmental delay, megaloblastic anemia, nephropathy, and gout or tophi.2,4  The first sign is the appearance of an orange or reddish sandy material in the diapers of newborns due to uric acid crystalluria and microhematuria.2,3 Additional early findings, within the first year of life, include episodic opisthotonus and the inability of a child to sit in a chair unless secured with chest or waist restraints (see Fig. 1C).1,2,7
Differential diagnosis  Diagnosis is made based on phenotypic presentation, elevated serum uric acid levels (greater than 4e5 mg/dL in children), and HPRT enzyme assays.2,4  A wide array of disorders of purine metabolism exist that exhibit features of LNS such as gout, Arts syndrome, ribosephosphate diphosphokinase, hyperactivity, and adenylosuccinate lyase deficiency.1  From a cognitive and neurobehavioral standpoint, LNS may mimic dyskinetic or athetoid type cerebral palsy, autism, Rett syndrome, Cornelia de Lange syndrome, or Down syndrome.8
Treatment considerations for the oral and maxillofacial surgeon  Treatment has largely been aimed at controlling the presenting symptoms and prevention of severe injury from self-mutilation.

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Fig. 1 Self-injury in Lesch-Nyhan syndrome. (A) Injury from persistent lip biting. (B) Finger amputation from self-mutilating behavior. (C) ¨r PR, Jinnah HA. Lesch-Nyhan disease and the basal Patient in protective physical restraints and wheelchair device. (From Visser JE, Ba ganglia. Brain Res Brain Res Rev 2000;32(2e3):467; with permission.)

 Allopurinol has been used to decrease the overproduction of uric acid.4 This, in turn, delays the development of renal failure.6 Allopurinol, however, has no effect on behavioral, neurologic, and cerebral manifestations of the syndrome.4,6 Dystonia and spasticity have been managed with GABA agonists (eg, benzodiazepines and baclofen), dopamine replacement therapy (eg, L-dopa), and deep brain stimulation to the globus pallidus.4,6 Control of self-injurious behavior has been sought with benzodiazepines, neuroleptics, antiepileptics, and chloral hydrate.6 Recent studies have demonstrated that the limitation of self-mutilating behavior includes a combined approach using physical restraints, behavioral treatment, and pharmacologic therapy.6  In the event that self-mutilating behavior is refractory to medical management, alternative therapies have been proposed. Some have advocated extraction of front teeth or all remaining teeth.6 To avoid this invasive treatment, other investigators have advocated oral protective devices such as lip bumpers or shields, tongue shields, and occlusal bite plates or splints, which have shown some success.6  A recent study by Chen and colleagues4 demonstrated regression in aggressive and self-injurious behavior and to a lesser extent dystonia with oral supplementation of S-adenosylmethionine based on its therapeutic potential to replenish the nucleotide pool in the brain.

Marcus Gunn syndrome
Genetics  Marcus Gunn syndrome is the most common congenital synkinetic eyelid disorder, with a prevalence of 4% to 6% among patients with congenital ptosis.9  Several studies have reported that patients have a higher likelihood to have the left eye affected.10,11 The

syndrome was also found to exhibit equal sex predilection.9  Patients with Marcus Gunn syndrome may also have other eye disturbances such as amblyopia, vertical strabismus, and double elevator palsy. These eye disturbances should be addressed before any corrective ptosis surgery.9
Clinical features  Marcus Gunn syndrome, or trigemino-oculomotor synkinesis, occurs due to an aberrant connection between the motor branches of the third division of trigeminal nerve innervating the pterygoid muscle and the fibers of the superior division of the oculomotor nerve that innervate the levator palpebrae superioris.12  It is clinically characterized as a ptotic eyelid that is rapidly elevated on lateral excursions, opening of the mandible, whistling, sucking, blowing, smiling, speaking, and tongue movements (Fig. 2).13,14
Differential diagnosis  A differential diagnosis to consider is Marin-Amat syndrome. This synkinetic eyelid disorder is characterized as involuntary eyelid closure on jaw opening. It occurs due to an aberrant connection between the facial nerve and the trigeminal nerve.15
Treatment considerations for the oral and maxillofacial surgeon  Eye shields or eye protection should be used during dental or oral and maxillofacial surgery procedures because the eye will open when the mouth opens.13  In a mild case that is not bothersome to the patient, no intervention can be elected.  In a case in which there is moderate-to-severe ptosis, or if the patient has esthetic concerns, a surgical intervention can be considered.  Several corrective procedures exist, including the Fasanella-Servat procedure, bilateral levator muscle excision followed by bilateral fascia lata brow suspension, or bilateral frontalis suspension with levator

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Fig. 2 (A) Child with Marcus Gunn jaw-winking phenomenon demonstrating unilateral left upper eyelid ptosis. (B) Ptosis is resolved by ska-Pawelec G, et al. Marcus Gunn synkinetic upper eyelid elevation with concomitant jaw opening. (From Bartkowski SB, Zapala J, Wyszyn jaw-winking phenomenon: management and results of treatment in 19 patients. J Craniomaxillofac Surg 1999;27(1):26; with permission.)

excision on the affected side.16e18 Other surgical procedures exist; however, it is beyond the scope of this article to describe all methods.

Cavernous sinus syndrome
Genetics  Cavernous sinus syndrome has no genetic basis; however, multiple causes for the syndrome exist and many of these have underlying genetic causes. Discussion of each is beyond the scope of this article.  A study done by Keane19 investigated the most common causes of cavernous sinus syndrome. He found that, among 151 subjects (45 subjects, 30%), tumors were the most frequent cause of this syndrome. The second-most common cause (36 subjects, 24%) was trauma. Selflimited inflammation was the third-most frequent cause (34 subjects, 23%). Carotid aneurysms and fistulas, infection, and other causes composed the remaining 12%.
Clinical features  The cavernous sinus is a paired structure that lies on either side of the sella turcica and lateral to the pituitary gland.20 The contents include an extradural plexus surrounded by a dural fold and the internal carotid artery with associated sympathetic plexus (Fig. 3).21 The abducens nerve runs lateral to the internal carotid artery but medial to the oculomotor nerve (see Fig. 3).21 Within the lateral dural border of the cavernous sinus lie the oculomotor nerve, trochlear nerve, ophthalmic division of trigeminal nerve and maxillary division of the trigeminal nerve (superior to inferior) (see Fig. 3).21 Venous drainage is from the superior and inferior orbital veins.20  The main symptoms of cavernous sinus syndrome are ophthalmoplegia, sensory loss of the ophthalmic and maxillary divisions of the trigeminal nerve distribution, with or without the presence of lid ptosis, anhidrosis, and miosis on the affected side (Fig. 4).20e22  Other symptoms may include orbital congestion and proptosis and periorbital edema, depending on the cause of the syndrome.20,21


Differential diagnosis  The differential diagnosis for cavernous sinus syndrome includes superior orbital fissure syndrome, orbital apex syndrome, Horner syndrome, carotid canal syndrome, and Tolosa-Hunt syndrome.20,21
Treatment considerations for the oral and maxillofacial surgeon  Treatment of this syndrome is aimed at identifying and managing the underlying condition.  Broad categories of diseases resulting in the clinical presentation of cavernous sinus syndrome include bacterial and fungal infection, noninfectious inflammation, vascular lesions, and neoplasms.21  Several infectious processes may result in the development of cavernous sinus thrombosis. Infections of the midface (ie, nasal furuncles) can enter the facial vein and pterygoid plexus and be carried to the cavernous sinus.23 Staphylococcus aureus is the most common microbe in this setting.23 Acute or chronic sphenoid and ethmoid sinusitis may result in cavernous sinus thrombosis. Common pathogens include Staphylococcus aureus and Streptococcus pneumoniae, as well as other

Fig. 3 Coronal section through the cavernous sinus. Meningeal layer in orange, periosteal layer in green. Car. A., carotid artery; CN, cranial nerve; Pit., pituitary; Sphen., sphenoid; V1, V2, V3, cranial nerves V1, V2, V3. (From Campero A, Campero AA, Martins C, et al. Surgical Anatomy of the dural walls of the cavernous sinus. J Clin Neurosci 2010;17(6):747; with permission.)

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Fig. 4 (A) Patient presented with a left intracavernous internal carotid aneurysm (ICICA) occupying the posterior third of the cavernous sinus, demonstrating left-globe proptosis, abducens nerve palsy, and sympathetic nerve impairment with partial Horner syndrome. (B) Patient presented with a right ICICA occupying the anterior third of the cavernous sinus, demonstrating partial right eyelid ptosis and restricted upward gaze of right globe significant for isolated right oculomotor superior division palsy. (From Silva MN, Saeki N, Hirai S, et al. Unusual cranial nerve palsy caused by cavernous sinus aneurysms: clinical and anatomic considerations reviewed. Surg Neurol 1999;52(2):144e5; with permission.)

anaerobic streptococcus species.23 In the case of chronic sinusitis (ie, rhinocerebral aspergillosis and mucormycosis), the most common fungal pathogens include Aspergillus and Mucorales.23 Treatment includes appropriate antifungal or antimicrobial therapy, endoscopic drainage, and anticoagulation (low molecular weight heparin or warfarin).23,24  Of particular clinical importance to the surgeon are odontogenic infections with extension into deep fascial spaces. For instance, infections of the masticator, canine, buccal, or lateral pharyngeal spaces can result in life-threatening complications such as cavernous sinus thrombosis and erosion into the internal carotid artery.25 Pathogens most commonly involved include Streptococcus species, Fusobacterium, and Bacteroides.23 Management includes surgical incision and drainage of the affected spaces, in addition to appropriate antimicrobial therapy.25  An example of a noninfectious cause is an inflammatory pseudotumor that is responsive to steroid administration.21,26

 Carotid-cavernous fistulas may be divided into direct or indirect fistulas. Direct fistulas demonstrate direct continuity between the cavernous segment of the carotid artery and the cavernous sinus. They form after closed head injuries or ruptured aneurysms and present with a classic triad of chemosis, pulsatile exophthalmos, and a bruit over the affected eye.20 Management includes endovascular treatment using detachable balloons, onyx (ethylene vinyl alcohol copolymer), or coils.20,27,28 Indirect fistulas form a shunt with the meningeal branches of the carotid artery and often spontaneously resolve.20  Giant internal carotid aneurysms (>2.5 cm) cause pain and ophthalmoplegia. Endovascular embolization or coiling may be indicated in select patients (see Fig. 1).20  Neoplasms that may cause cavernous sinus syndrome include pituitary adenomas, malignancy with perineural spread (ie, nasopharyngeal carcinoma [NPC]), meningioma, and hemangiomas. These lesions usually require excision.20

Syndromes Affecting the Central Nervous System

Superior orbital fissure syndrome
Genetics  This syndrome has no genetic predilection.  Although the syndrome is fairly uncommon, causes of superior orbital fissure syndrome include tumors in the retrobulbar space, retrobulbar hematomas, infection in the cavernous sinus or retrobulbar space, as well as facial trauma.29,30  The incidence of traumatic superior orbital fissure in cases involving facial fractures was reported to be 0.3%.30  In the case of blow-in fractures of the orbit, the incidence of superior orbital fissure syndrome was reported to be as high as 10%.31  In a study by Chen and colleagues,30 four cases of carotid-cavernous sinus fistula were confirmed by angiography out of 33 cases of superior orbital fissure syndrome.
Clinical features  It is important to note the anatomy of the superior orbital fissure because its contents reflect the clinical features of the syndrome. The superior orbital fissure contains the trochlear, lacrimal, and frontal nerves, as well as the superior ophthalmic vein, the superior and inferior branches of the oculomotor nerve, the nasociliary nerve, and the abducens nerve (Fig. 5).32,33  Superior orbital fissure syndrome is characterized by ptosis of the upper eyelid, ophthalmoplegia, hypoesthesia of the ipsilateral V1 dermatome, proptosis, and mydriasis (Fig. 6).34,35 Additional clinical signs include lacrimal hyposecretion and loss of the corneal reflex.
Differential diagnosis  If there is visual acuity involvement, orbital apex syndrome should be considered. Cavernous sinus syndrome should also be considered if there is involvement of V2 dermatome instead of V1 division of the trigeminal nerve.

Fig. 5 Diagram displaying the contents of the superior orbital fissure. a, artery; n, nerve; v, vein. (From Anderson BC, McLoon LK. Cranial nerves and autonomic innervation in the orbit. In: Dartt DA, editor. Encyclopedia of the eye. Oxford (United Kingdom): Academic Press; 2010. p. 539; with permission.)

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Treatment considerations for the oral and maxillofacial surgeon  Appropriate imaging should include CT scan with angiography and/or magnetic resonance angiography if a carotid-cavernous sinus fistula is suspected. If a carotid-cavernous sinus fistula is diagnosed, prompt embolization is recommended.36,37  Obtain ophthalmologic consultation for patients with associated globe injuries.  Treatment modalities in the literature have been controversial. There are advocates for high-dose steroid therapy and surgical decompression, as well as for no intervention.36,38  In the event of facial fractures requiring repair, open reduction and internal fixation may generally be performed without fear of causing a worsening of associated cranial nerve palsies.30  Early repair of orbital blow-in fractures had a favorable outcome in subjects with associated superior orbital fissure syndrome.31

Trotter syndrome
Genetics  Although Trotter syndrome itself has no genetic basis, it is based on a constellation of clinical symptoms secondary to the uncontrolled growth of nasopharyngeal carcinoma (NPC). There is, however, an identifiable genetic pattern for NPC.  NPC is a rare epithelial malignancy with only 25 to 30 cases per 100,000 person-years reported.39 It is most commonly seen in Southeast Asia and the Mediterranean Basin.39 NPC is a multifactorial condition.  Infection with Epstein-Barr virus has been associated with NPC, after numerous studies demonstrated the presence of its’ DNA in nasopharyngeal tumors.39,40  Human leukocyte antigen (HLA), which are responsible for presentation of viral antigens to the immune system, are located within the major histocompatibility complex on chromosome 6p21.3.39 Furthermore, genomewide association studies of NPC have consistently identified single nucleotide polymorphisms within the HLA coding region, suggesting strong evidence for association between these mutations and NPC.39,41  An association between diets high in preservatives (salted fish, eggs, and vegetables) and NPC has also been found.42
Clinical features  The syndrome was first described by Trotter in 1911 as a neoplastic lesion deep to the lateral nasopharyngeal wall.43 A classic triad of presenting symptoms (ie, deafness, neuralgia along the mandibular division of the trigeminal nerve, and soft palatal paralysis or immobility) was originally described (see Fig. 1).43 Symptoms corresponded to the lateral and anterior spread of the neoplasm submucosally and, in late stages, included other symptoms.43,44  The first symptom of decreased hearing or frank deafness is due to involvement of the eustachian tube.44,45 As the lesion progresses, involvement of the third division of the trigeminal nerve leads to neuralgias of the side of the head, ear, and lower jaw, as well as paresthesia of the tongue.44,45 As the levator veli palatini muscle becomes

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Fig. 6 Superior orbital fissure syndrome demonstrates ptosis, pupillary dilation, and ophthalmoplegia. (A) Right lid ptosis. (B) Radiograph showing a fracture (red arrows) causing compression of superior orbital fissure. (C) Right pupillary dilation. (DeF) Right ophthalmoplegia. (From Turvey TA, Golden BA. Orbital Anatomy for the Surgeon. Oral Maxillofac Surg Clin North Am 2012;24(4):528; with permission.)

affected, mobility of the ipsilateral soft palate becomes compromised.44 Further progression to the ipsilateral medial pterygoid muscle results in trismus and, in late stages, cervical lymphadenopathy was noted.43,44  The aforementioned symptoms, which mimic temporomandibular disorders, are associated with NPC.45 Because of these nonspecific symptoms, diagnosis is often delayed for 6 to 9 months.45
Differential diagnosis  The differential diagnosis includes temporomandibular joint disorders, myofascial pain disorder, sinusitis, trigeminal neuralgia, otitis media, and scleroderma.46  Generally, CT and MRI are important in identification of NPC. However, CT may fail to show the tumor at an early stage. MRI with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) should be used as a first choice if NPC is suspected in its early stages.45  Clinical features of Trotter syndrome may often produce a spurious diagnosis of temporomandibular joint disorders. Because of this, Reiter and colleagues45 highlighted several distinguishing features to aid in the early diagnosis of malignancy. These include continuous ear symptoms (ie, decreased hearing, fullness, and tinnitus), abnormal electromyogram patterns of the soft palate, absence of degenerative changes of the temporomandibular joint seen on imaging, and, in later stages, severe hard-end limitation in mouth opening.
Treatment considerations for the oral and maxillofacial surgeon  The treatment of NPC requires a multidisciplinary approach involving a head and neck surgeon, radiation and medical oncologist, and a dentist, as well as an oral and maxillofacial surgeon.42  NPC is typically treated with radiation therapy with or without concurrent chemotherapy. Radiation is

administered to the nasopharynx and bilateral necks reaching doses of 60 to 70 Gy in 35 to 40 fractions.42 For this reason, dental clearance before initiation of radiation therapy is paramount in the prevention of osteoradionecrosis of the jaw if postradiation oral surgery is anticipated. Concurrent combination chemotherapy may include cisplatin and 5-fluorouracil (5-FU), or Taxol and 5-FU, to avoid late toxicity effects.42 Local recurrence may be treated with brachytherapy or surgical intervention.42  Surgical therapy is reserved for local recurrence with regional involvement. Contraindications to surgery include internal carotid involvement, erosion into skull base, and intracranial involvement (Fig. 7).42,47  Local recurrence may be treated by resection using a variety of surgical approaches: Lateral rhinotomy with medial hemimaxillectomy, endoscopic nasopharyngectomy, Weber-Ferguson incision with maxillary swing approach, lateral infratemporal approach, and Le Fort I down fracture.42  Regional recurrence will require either a radical neck dissection or a modified radical neck dissection with removal of levels I through V nodes.42

Horner syndrome
Genetics  Because Horner syndrome is a sequela of an underlying disease process, it is not associated with a specific genetic trait or inheritance pattern.  The most common identifiable cause of Horner syndrome is postganglionic lesions followed by preganglionic lesions, whereas the central lesions were the least common.48

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Fig. 7 (A) NPC with extension into mandibular division of trigeminal nerve in the masticator space (white arrow); Meckel cave and sphenoid sinus (black arrows). (B) NPC extension into sphenoid sinus, cavernous sinus, and maxillary division of trigeminal nerve (black arrows). (C) Encasement of internal carotid artery by NPC (black arrows). (From Moonis G, Cunnane MB, Emerick K, et al. Patterns of perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 2012;20:445; with permission.)


Clinical features  Horner syndrome or oculosympathoparesis is caused by an interruption of sympathetic innervation along a three-neuron pathway to the eye and its adnexa. It is classically characterized as unilateral miosis, ptosis, apparent enophthalmos, and anhidrosis of the affected side (Fig. 8).49,50  Ptosis is a result of interruption of the sympathetic ¨ller muscle, which accounts for innervation of the Mu approximately 2 mm of upper eyelid elevation. Miosis is caused by unopposed parasympathetic innervation to the iris constrictor muscle. The facial anhidrosis occurs because of lack of sympathetic innervation to the sweat glands of the face.51 The apparent enophthalmos is due

Fig. 8 A patient with Horner syndrome displaying right miosis, ptosis, and apparent enophthalmos. (From Rempell JS, Harris NS, Brown DF, et al. Left eye ptosis. J Emerg Med 2009;36(4):396; with permission.)

to ptosis of the upper lid and slight elevation of the lower eyelid, resulting in narrowing of the palpebral fissure, which gives the impression of enophthalmos.52  Knowledge of the anatomy of the sympathetic innervation involving Horner syndrome is necessary. First-order neurons originate in the posterior lateral hypothalamus and travel down the spinal cord to synapse with secondorder neurons between C8 and T2 at ciliospinal center of Budge-Waller. These second-order neurons travel superiorly along the sympathetic chain passing through the inferior and middle cervical ganglions and, eventually, synapse with third-order neurons at the superior cervical ganglion. Postganglionic or third-order neurons from the superior cervical ganglion continue to ascend along the carotid artery nerve to innervate the sweat glands of the face. In addition, these third-order neurons travel along the ophthalmic division of the trigeminal to innervate the lacrimal gland, the dilator muscle of the ¨ller muscle, and its analog in the lower eyelid pupil, Mu (Fig. 9).51,53
Differential diagnosis  Lesions can occur along course of the sympathetic innervations to the end organs that are involved in Horner syndrome. - Diseases associated with first-order neurons include Arnold-Chiari malformation, syphilis, basal skull

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Frey syndrome

Fig. 9 Diagram displaying the anatomy of the oculosympathetic pathway. AS, ansa subclavia; CCA, common carotid artery; ECA, external carotid artery; FON, first-order neuron; ICA, internal carotid artery; ICG, inferior cervical ganglion; MCG, middle cervical ganglion; SCG, superior cervical ganglion; SON, second-order neuron; TON, third-order neuron. (From Reede DL, Garcon E, Smoker WR, et al. Horner’s syndrome: clinical and radiographic evaluation. Neuroimaging Clin N Am 2008;18(2):370; with permission.)

tumors, cerebrovascular accident, multiple sclerosis, intrapontine hemorrhage, neck trauma, pituitary tumor, and syringomyelia.54 - Diseases associated with second-order neurons include Pancoast tumor; birth trauma with injury to lower brachial plexus; aneurysm or dissection of aorta; subclavian or common carotid artery; iatrogenic complications from surgical intervention such as radical neck dissection, thyroidectomy, carotid angiography, coronary artery bypass graft, chest tube insertion, or central venous catheterization; Hodgkin disease; leukemia; tuberculosis; mediastinal tumor; odontogenic abscess; acute otitis media; neuroblastoma; and lumbar epidural anesthesia.54,55 - Diseases associated with third-order neurons include internal carotid artery dissection, migraines, cluster headaches, carotid artery thrombosis, carotidcavernous fistula, herpes zoster, orbital apex tumor, or idiopathic conditions.54
Treatment considerations for the oral and maxillofacial surgeon  The presence of Horner syndrome is a sign for a potential underlying disease. Treatment of the underlying condition often resolves the symptoms. However, many


Genetics  There are no known inheritance patterns because Frey syndrome is an acquired disease.  Gustatory sweating is most commonly seen secondary to parotid surgery; however, it also can occur after radical neck dissection or blunt and penetrating trauma to the region overlying the parotid gland.56,57 There is no age or sex predilection.58  The incidence of Frey syndrome after parotid surgery varies with reports ranging from 2% to 80%.59 Interestingly, if tested using a Minors starch-iodine test, more than 90% of patients after parotid surgery will exhibit some evidence of Frey syndrome.60 Symptoms are perceived in only about 25% to 50% of patients, and they are severe enough to warrant treatment in only 6% to 15% of cases.60,61  Frey syndrome usually has a latency of 6 to 18 months. It can, however, occur in less than 6 months or more than 36 months.58  In the pediatric population, case reports of auriculotemporal syndrome following trauma after forceps delivery have been published in the literature.62
Clinical features  The classic appearance of Frey syndrome is sweating, flushing, and sensation of warmth in the preauricular and temporal areas during mastication.59  The Minor iodine-starch test can be used to delineate the extent of the lesion. The test is administered by applying an alcohol-iodine-oil solution to the affected side of the face. The solution is allowed to dry and lightly covered with starch powder. The patients are then given a lemon candy for a gustatory stimulus for 10 minutes. Blue discoloration of the starch iodine mixture is interpreted as a positive finding (Fig. 10).63e65  The condition occurs from the severing of postganglionic parasympathetic cholinergic secretomotor fibers from the otic ganglion. These fibers, which are carried by the auriculotemporal nerve, become misdirected during axonal regeneration and feed the sympathetic fibers to the sweat glands of the skin, causing gustatory sweating. This phenomenon explains the delay in appearance of clinical symptoms.56,66
Differential diagnosis  Food allergy can be misdiagnosed in cases with facial flushing without hyperhidrosis, especially among the pediatric population.67  CNS tumors, although extremely rare, should be suspected in cases without evidence of localized trauma.68
Treatment considerations for the oral and maxillofacial surgeon  Patients with Frey syndrome who have mild signs with no symptoms can be observed. Those patients who show symptoms and whose quality of life is affected should be counseled. All risks and benefits should be discussed before starting therapy.  Medical therapy includes topical anticholinergics such as atropine, glycopyrrolate, scopolamine hydrobromide,

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191 shown to be an effective, safe, and minimally invasive treatment with long-lasting effect.70  Surgical treatment has been proposed, such as transection of the glossopharyngeal nerve, resection of the auriculotemporal nerve, or tympanic neurectomy. These modalities have variable success rates and are not recommended.58

Ramsay-Hunt syndrome

Fig. 10 Positive result of the Minor iodine-starch test in a patient with Frey syndrome, showing the area in dark blue due to gustatory sweating in the affected parotid area. (From Malatskey S, Rabinovich I, Fradis M, et al. Frey syndrome-delayed clinical onset: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94(3):339; with permission.)

or antiperspirants containing aluminum chloride in alcohol solution. These agents usually provide temporary relief, have poor compliance, and may possess adverse side effects.56,69  More recently, intracutaneous injections of botulinum toxin A (BTX-A) into the affected area has been widely accepted. BTX-A injections work by preventing the release of the neurotransmitter acetylcholine at cholinergic synapses. This treatment modality has been


Genetics  Ramsay Hunt syndrome (RHS) has an incidence of 5 per 100,000 per year. It is the second-most frequent cause in nontraumatic peripheral facial palsy.71 The prevalence of RHS is more frequent in adults than in children who have facial palsy.72  In the pediatric population, the incidence is also higher in older children than in children younger than 6-yearsold. Children are also found to have milder symptoms and a better prognosis for complete recovery of facial animation and hearing when compared with adults.
Clinical features  RHS occurs because of the reactivation of the varicellazoster virus in the geniculate ganglion, involving the seventh cranial nerve.  Clinically, it is characterized by acute peripheral facial palsy with a painful herpetic eruption on the ipsilateral auricle, external ear canal, anterior two-thirds of the tongue, or palate (Fig. 11).73,74 In addition to these classic symptoms, patients also frequently have vestibulocochlear dysfunction due to the close proximity of the eighth cranial nerve to the geniculate ganglion.75 These patients frequently reported tinnitus, hearing loss, nausea, vomiting, vertigo, and nystagmus.76  In addition to the classic presentation, other cranial nerves, such the glossopharyngeal, trigeminal, vagus, abducens, and hypoglossal, have also been known to be involved.77,78

Fig. 11 (A) A patient with vesicular lesions of the auricle and external auditory meatus. (B) Facial nerve palsy resulting in both weakness of the lips (white arrows) and loss of nasolabial folds (black arrows) on the right face with facial animation. (From Taguchi T, Ueda S, Kudo T, et al. Ramsay-Hunt syndrome. J Infect 2011;62(2):181; with permission.)

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Differential diagnosis  Many conditions can produce isolated facial nerve palsy similar to RHS; however, they can frequently be ruled out by a thorough history and physical. Those conditions ´ syninclude Bell’s Palsy, sarcoidosis, Guillain-Barre drome, Lyme disease, otitis media, multiple sclerosis, cerebrovascular accident, as well as peripheral lesions causing compression of the facial nerve.79
Treatment considerations for the oral and maxillofacial surgeon  Treatment with prednisone and acyclovir has proven to be effective, especially if started early after onset of facial paralysis.80 Early administration of therapy 3 days after onset of facial paralysis showed a significantly higher recovery when compared with patients whose therapy was started 7 days or more after onset of facial paralysis.81

Lui et al.  Partial nerve degeneration was shown to be reduced when early therapy was started with acyclovir-prednisone.82 Recovery from hearing loss was also shown to be more successful when therapy was started earlier.

Melkersson-Rosenthal syndrome
Genetics  Melkersson-Rosenthal syndrome (MRS) is idiopathic. However, evidence for an autosomal dominant inheritance pattern with a gene defect at chromosome 9p11, which applied to patients with fissured tongue, has been investigated.83
Clinical and histologic features:  MRS is an idiopathic granulomatous neuromucocutaneous disorder.84

Fig. 12 Patient with MRS displaying (A) left midfacial edema, (B) left facial nerve palsy, and (C) lingua plicata (fissured tongue). (From Gerressen M, Ghassemi A, Stockbrink G, et al. Melkersson-Rosenthal syndrome: case report of a 30-year misdiagnosis. J Oral Maxillofac Surg 2005;63:1037; with permission.) (D) Photomicrograph ( 40) of an incisional biopsy taken from the labial mucosa of a patient with MRS, exhibiting multiple focal, non-caseating granulomas. (Slide Courtesy of Dr Dean DeLuke.)

Syndromes Affecting the Central Nervous System  The classic triad of symptoms include asymptomatic orofacial edema (ie, lips, cheeks, chin, as well as the buccal, lingual, gingival, or labial mucosal surfaces), facial nerve palsy, and fissured tongue (Fig. 12).84,85  It typically develops during the second decade of life; however, early manifestations are possible at any age.84 More than 30 cases of MRS have been reported during childhood.84 It affects female patients three times as often as male patients.84  Patients may present with a monosymptomatic form or an oligosymptomatic form. Cheilitis granulomatosa is a monosymptomatic variant of MRS that affects young adults and is characterized clinically by diffuse, nontender, soft-to-firm swelling of one or both lips. The complete triad is present in only about 25% of patients.86  Other associated symptoms include migraine-like headaches, swelling of the oral mucosa and eyelids, and dysgeusia or ageusia.84,85  Histologically, this disorder displays noncaseating epithelioid granulomatous inflammation, dermal edema and mixed perivascular inflammation.85e87
Differential diagnosis  Diagnosis is largely based on presenting clinical findings and corresponding histology.  MRS is grouped into a spectrum of conditions with similar clinical and pathologic features referred to as orofacial granulomatosis.85  Acutely, it may clinically appear to be angioedema. Persistent orofacial swelling between attacks supports the diagnosis.85  The differential diagnoses include Crohn’s disease, sarcoidosis, tuberculosis, Bell’s palsy, focal dental infection, foreign body reaction, and Ascher syndrome.85,88
Treatment considerations for the oral and maxillofacial surgeon  There is no gold standard; treatment is primarily symptomatic therapy.  Nonsurgical management includes systemic and intralesional corticosteroid injection, which may provide short-term relief.85 Anti-inflammatory agents such as clofazimine, dapsone, sulfapyridine, danazol, and hydroxychloroquine have also been investigated.85 A novel treatment using infliximab, a recombinant humanized monoclonal TNF-alpha antibody, to treat patients with MRS has shown some promise.89  Surgical management has been indicated for persistent orofacial edema and facial nerve palsy refractory to nonsurgical management. Wedge resection has been used for diffuse upper and lower lip edema with zplasty for focal lip defects.90 Full-thickness resection of skin and subcutaneous tissues of upper or lower eyelids has been reported.90 Cheiloplasty and facial liposuction have also been effective in improving facial esthetics.91 For persistent facial palsy, procedures such as static and dynamic reanimation, cross-face nerve grafts, and free muscle transfer have been advocated.90

References 1. Kelley RE, Andersson HC. Disorders of purines and pyrimidines. In: Biller J, Ferro JM, editors. Handbook of clinical neurology (neurological aspects of systemic disease part II), vol. 120. Philadelphia: Elsevier; 2014. p. 827e38.

193 2. Nyhan WL. Lesch-Nyhan disease and related disorders of purine metabolism. Tzu Chi Medical Journal 2007;19(3):105e8. 3. Gucev Z, Koceva S, Marinaki A, et al. Lesch-Nyhan syndrome: a novel complex mutation with severe phenotype. Clin Genet 2010; 78:296e7. 4. Chen BC, Balasubramaniam S, McGown IN, et al. Treatment of Lesch-Nyhan with S-adenosylmethionine: experience with five young Malaysians, including a girl. Brain Dev 2013 [Epub ahead of print]. 5. Nguyen KV, Naviaux RK, Paik KK, et al. Lesch-Nyhan Syndrome: mRNA expression of HPRT in patients with enzyme proven deficiency of HPRT and normal HPRT coding region of the DNA. Mol Genet Metab 2012;106:498e501. 6. Arhakis A, Topouzelis N, Kotsiomiti E, et al. Effective treatment of self-injurious oral trauma in Lesch-Nyhan Syndrome: a case report. Dent Traumatol 2010;26:496e500. ¨r PR, Jinnah HA. Lesch-Nyhan disease and the basal 7. Visser JE, Ba ganglia. Brain Res Brain Res Rev 2000;32(2e3):449e75. 8. Ruggieri VL, Arberas CL. Behavioural phenotypes. Biologically determined neuropsychological patterns. Rev Neurol 2003;37(3): 239e53. 9. Pratt SG, Beyer CK, Johnson CC. The Marcus Gunn phenomenon. A review of 71 cases. Ophthalmology 1984;91:27e30. 10. Callahan MA, Beard C. Beard’s ptosis. 4th edition. Birmingham (AL): Aesculapius Pub. Co; 1990. p. 75e7. 11. Bowyer JD, Sullivan TJ. Management of Marcus Gunn jaw winking synkinesis. Ophthal Plast Reconstr Surg 2004;20:92e8. 12. Kumar V, Goel N, Raina UK, et al. “See-saw” Marcus Gunn syndrome. Ophthal Plast Reconstr Surg 2011;27(6):e144e5. 13. Chattopadhyay A, Srinivas K, Sharatchandra B, et al. The Marcus Gunn phenomenon: discussion and report of three cases. Quintessence Int 1995;26(8):563e6. ska-Pawelec G, et al. Marcus 14. Bartkowski SB, Zapala J, Wyszyn Gunn Jaw-Winking Phenomenon: management and results of treatment in 19 patients. J Craniomaxillofac Surg 1999;27(1): 25e9. 15. Rana PV, Wadia RS. The Marin-Amat syndrome: an unusual facial synkinesis. J Neurol Neurosurg Psychiatry 1985;48:939e41. 16. Putterman AM. Jaw-winking blepharoptosis treated by the Fasanella-Servat procedure. Am J Ophthalmol 1973;75:1016e22. 17. Beard C. A new treatment for severe unilateral congenital ptosis and for ptosis with jaw-winking. Am J Ophthalmol 1965;59:252e8. 18. Callahan A. Correction of unilateral blepharoptosis with bilateral eyelid suspension. Am J Ophthalmol 1972;74:321e6. 19. Keane JR. Cavernous sinus syndrome. Analysis of 151 cases. Arch Neurol 1996;53(10):967e71. 20. Bone I, Hadley DM. Syndromes of the superior orbital fissure, cavernous sinus, cerebellopontine angle, and skull base. J Neurol Neurosurg Psychiatry 2005;76:29e38. 21. Lee JH, Lee HK, Park JK, et al. Cavernous sinus syndrome: clinical features and differential diagnosis with MR Imaging. AJR Am J Roentgenol 2003;181:583e90. 22. Silva MN, Saeki N, Hirai S, et al. Unusual cranial nerve palsy caused by cavernous sinus aneurysms: clinical and anatomical considerations reviewed. Surg Neurol 1999;52(2):143e9. 23. Katz B. Lesions produced by infections and inflammations of the central nervous system. In: Miller NR, Newman NJ, Biousse V, et al, editors. Walsh and Hoyt’s clinical neuro-ophthalmology 6th edition (Vol 3: degenerative and metabolic diseases, infectious, inflammatory, and demyelinating diseases). Philadelphia: LWW; 2005. p. 2618e29. 24. Komatsu H, Matsumoto F, Kasai M, et al. Cavernous sinus thrombosis caused by contralateral sphenoid sinusitis: a case report. Head Face Med 2013;9(9):1e5. 25. Brook I. Microbiology and management of deep facial infections and Lemierre syndrome. ORL J Otorhinolaryngol Relat Spec 2003; 65(2):117e20. 26. McCall T, Fassett DR, Lyons G, et al. Inflammatory pseudotumor of the cavernous sinus and skull base. Neurosurg Rev 2006;29(3): 194e200.

194 27. Vishnu VY, Petluri G, Gupta V, et al. Parkinson syndrome: a precise localization for abducens palsy. J Neurol Sci 2014;336(1e2): 288e9. 28. Yu Y, Li Q, Huang Q, et al. Embolization of direct carotid cavernous fistula with onyx under transarterial balloon protection. Cardiovasc Intervent Radiol 2014;37(3):679e85. 29. Manstein G, Zachariades N. The superior orbital fissure syndrome. Plast Reconstr Surg 1982;70(6):777. 30. Chen C, Wang T, Tsay P, et al. Traumatic superior orbital fissure syndrome: assessment of cranial nerve recovery in 33 cases. Plast Reconstr Surg 2010;126:205e12. 31. Antonyshyn O, Gruss JS, Kassel EE. Blow-in fractures of the orbit. Plast Reconstr Surg 1989;84:10e20. 32. Reymond J, Kwiatkowski J, Wysocki J. Clinical anatomy of the superior orbital fissure and the orbital apex. J Craniomaxillofac Surg 2008;36(6):346e53. 33. Anderson BC, McLoon LK. Cranial nerves and autonomic innervation in the orbit. In: Dartt DA, editor. Encyclopedia of the eye. Oxford (United Kingdom): Academic Press; 2010. p. 539. 34. Mcavoy CE, Lacey B, Page AB. Traumatic superior orbital fissure syndrome. Eye 2004;18(8):844e5. 35. Turvey TA, Golden BA. Orbital anatomy for the surgeon. Oral Maxillofac Surg Clin North Am 2012;24(4):528. 36. Tytle TL, Punukollu PK. Carotid cavernous fistula. Semin Cerebrovasc Dis Stroke 2001;1(1):83e111. 37. Chen CT, Chen YR. Traumatic superior orbital fissure syndrome: current management. Craniomaxillofac Trauma Reconstr 2010; 3(1):9e16. 38. Acarturk S, Sekucoglu T, Kesiktas E. Mega dose corticosteroid treatment for traumatic superior orbital fissure and orbital apex syndromes. Ann Plast Surg 2004;53(1):60e6. 39. Su WH, Hildesheim A, Chang YS. Human leukocyte antigens and Epstein-Barr Virus-associated nasopharyngeal carcinoma: old associations offer new clues into the role of immunity in infection-associated cancers. Front Oncol 2013;3(299): 1e9. 40. Zur Hausen H, Schulte-Holthausen H, Klein G, et al. EBV DNA in biopsies of Burkitt tumors and anaplastic carcinomas of the nasopharynx. Nature 1970;228(5276):1056e8. 41. Tse K, Su WH, Chang KP, et al. Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3. Am J Hum Genet 2009; 85(2):194e203. 42. Tan L, Loh T. Benign and malignant tumors of the nasopharynx. In: Flint PW, Haughey BH, Lund VJ, et al, editors. Cummings otolaryngology: head and neck surgery. 5th edition. Philadelphia: Mosby Elsevier; 2010. p. 1348e57. 43. Trotter W. On certain clinically obscure malignant tumours of the nasopharyngeal wall. Br Med J 1911;2(2652):1057e9. 44. Asherson N. Trotter’s syndrome and associated lesions. J Laryngol Otol 1951;65(5):349e66. 45. Reiter S, Gavish A, Winocur E, et al. Nasopharyngeal carcinoma mimicking a temporomandibular disorder: a case report. J Orofac Pain 2006;20(1):74e81. 46. Rotter BE. Temporomandibular joint disorders. In: Flint PW, Haughey BH, Lund VJ, et al, editors. Cummings otolaryngology: head and neck surgery. 5th edition. Philadelphia: Mosby Elsevier; 2010. p. 1279e86. 47. Moonis G, Cunnane MB, Emerick K, et al. Patterns of perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 2012;20:435e46. 48. Maloney WF, Younge BR, Moyer N. Evaluation of the causes and accuracy of pharmacologic localization in Horner syndrome. Am J Ophthalmol 1980;90:394e402. 49. Fields CR, Barker FM. Review of Horner’s syndrome and a case report. Optom Vis Sci 1992;69(6):481e5. 50. Rempell JS, Harris NS, Brown DF, et al. Left eye ptosis. J Emerg Med 2009;36(4):395e9. 51. Walton KA, Buono LM. Horner syndrome. Curr Opin Ophthalmol 2003;14(6):357e63.

Lui et al. 52. Daroff R. Enophthalmos is not present in Horner syndrome. PLoS Med 2005;2:e120. 53. Reede DL, Garcon E, Smoker WR, et al. Horner’s syndrome: clinical and radiographic evaluation. Neuroimaging Clin N Am 2008;18(2):369e85. 54. Kong YX, Wright G, Pesudovs K, et al. Horner syndrome. Clin Exp Optom 2007;90:336e44. 55. Shanti RM, Aziz SR. Should we wait for development of an abscess before we perform incision and drainage? Oral Maxillofac Surg Clin North Am 2011;23(4):513e8. 56. Clayman MA, Clayman SM, Seagle MB. A review of the surgical and medical treatment of Frey syndrome. Ann Plast Surg 2006;57(5): 581e4. 57. Spiro RH, Martin H. Gustatory sweating following parotid surgery and radical neck dissection. Ann Surg 1967;165:118e27. 58. Rustemeyer J, Eufinger H, Bremerich A. Incidence of Frey’s syndrome. J Craniomaxillofac Surg 2008;36(1):34e7. 59. Linder TE, Huber A, Schmid S. Frey’s syndrome after parotidectomy: a retrospective and prospective analysis. Laryngoscope 1997;107(11):1496e501. 60. Casler JD, Conley J. Sternocleidomastoid muscle transfer and superficial aponeurotic system plication in the prevention of Frey’s syndrome. Laryngoscope 1991;101:95e100. 61. Guntinas-Lichius O, Kick C, Klussmann JP, et al. Pleomorphic adenoma of the parotid gland: a 13-year experience of consequent management by lateral or total parotidectomy. Eur Arch Otorhinolaryngol 2004;261:143e6. 62. Johnson IJ, Birchall JP. Bilateral auriculotemporal syndrome in childhood. Int J Pediatr Otorhinolaryngol 1995;32(1):83e6. 63. Laage-Hellman JE. Gustatory sweating and flushing after conservative parotidectomy. Acta Otolaryngol 1957;48(3):234e52. 64. Choi HG, Kwon SY, Won JY, et al. Comparisons of three indicators for Frey’s syndrome: subjective symptoms, Minor’s starch iodine test, and infrared thermography. Clin Exp Otorhinolaryngol 2013; 6(4):249. 65. Malatskey S, Rabinovich I, Fradis M, et al. Frey syndrome-delayed clinical onset: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94(3):338e40. 66. Celoria G, Falco E, Nardini A, et al. Frey’s syndrome: physiopathology and medical therapy. Minerva Chir 1995;50:1025e7. 67. Moreno-Arias G, Grimalt R, Llusa M, et al. Frey’s syndrome. J Pediatr 2001;138(2):294. 68. Schnarch A, Markitziu A. Dysgeusia, gustatory sweating and crocodile tears induced by cerebellopontine angle meningioma. Oral Surg Oral Med Oral Pathol 1990;70(6):711e4. 69. Hays LL, Novack AJ, Worsham JC. The Frey syndrome: a simple, effective treatment. Otolaryngol Head Neck Surg 1982;90(4): 419e25. ¨nebeck C. Up-to-date report of botuli70. Laskawi R, Drobik C, Scho num toxin type A treatment in patients with gustatory sweating (Frey’s syndrome). Laryngoscope 1998;108(3):381e4. 71. Adour KK. Otological complications of herpes zoster. Ann Neurol 1994;35(Suppl):S62e4. 72. Hato N, Kisaki H, Honda N, et al. Ramsay Hunt syndrome in children. Ann Neurol 2000;48(2):254e6. 73. Hunt JR. On herpetic inflammations of the geniculate ganglion: a new syndrome and its complications. J Nerv Ment Dis 1907;34: 73e96. 74. Taguchi T, Ueda S, Kudo T, et al. Ramsay-Hunt syndrome. J Infect 2011;62(2):180e1. 75. Kansu L, Yilmaz I. Herpes zoster oticus (Ramsay Hunt syndrome) in children: case report and literature review. Int J Pediatr Otorhinolaryngol 2012;76(6):772e6. 76. Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001;71(2):149e54. 77. Shah RK, Blevins NH. Otalgia. Otolaryngol Clin North Am 2003; 36(6):1137. 78. Turner JE, Paul M, Geunes PM, et al. Cranial polyneuropathyd Ramsay Hunt’s syndrome: case report and discussion. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(3):354e7.

Syndromes Affecting the Central Nervous System 79. Tiemstra JD, Khatkhate N. Bell’s palsy: diagnosis and management. Am Fam Physician 2007;76(7):997e1004. 80. Furuta Y, Ohtani F, Mesuda Y, et al. Early diagnosis of zoster sine herpete and antiviral therapy for the treatment of facial palsy. Neurology 2000;55:708e10. 81. Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol 1997;41:353e7. 82. Adour KK, Ruboyianes JM, Von Doersten PG, et al. Bell’s palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial. Ann Otol Rhinol Laryngol 1996;105(5):371e8. 83. Smeets E, Fryns JP, Van den Berghe H. Melkersson-Rosenthal syndrome and de novo autosomal t(9:21)(p11;11) translocation. Clin Genet 1994;45:323. 84. Gerressen M, Ghassemi A, Stockbrink G, et al. MelkerssonRosenthal Syndrome: case report of a 30-year misdiagnosis. J Oral Maxillofac Surg 2005;63:1035e9.

195 85. Kakimoto C, Sparks C, White AA. Melkersson-Rosenthal Syndrome: a form of pseudoangioedema. Ann Allergy Asthma Immunol 2007; 99(2):185e9. 86. Rogers RS III. Melkersson-Rosenthal syndrome and orofacial granulomatosis. Dermatol Clin 1996;14(2):371e9. 87. Weedon D. The granulomatous reaction pattern. In: Weedon D, Strutton G, Rubin AI, editors. Weedon’s skin pathology. 3rd edition. Philadephia: Elsevier; 2010. p. 169e97. 88. Scully C. Orofacial granulomatosis. In: Oral and maxillofacial medicine. 3rd edition. London: Elsevier; 2013. p. 298e301. 89. Barry O, Barry J, Langan S, et al. Treatment of granulomatous cheilitis with infliximab. Arch Dermatol 2005;141(9):1080e2. 90. Glickman LT, Gruss JS, Birt BD, et al. The surgical management of Melkersson-Rosenthal syndrome. Plast Reconstr Surg 1992;89(5): 815e21. 91. Tan O, Atik B, Calka O. Plastic surgical solutions for MelkerssonRosenthal syndrome: facial liposuction and cheiloplasty procedures. Ann Plast Surg 2006;56(3):268e73.