Disease Entity

Disease
Gradenigo Syndrome (GS) is classically described as a clinical triad of otitis media, facial pain,
and abducens palsy that in the past most commonly developed from infection in the petrous
temporal bone (i.e., petrous apicitis) [1]. The full triad of GS however may not always be present
especially in the post-antibiotic era.

Etiology
GS is rare in the post antibiotic era. First described in 1904 [1], it typically arose from a
progression of untreated or partially treated otitis media. With appropriate antibiotic use, it is now
becoming increasingly rare [2]. In the preantibiotic era, intracranial complications secondary to ear
infection occurred in 2.3-6.4% of cases [3]. With the introduction of more potent and effective
antibiotics, and later with more refined surgical techniques, intracranial complications decreased
to 0.04-0.15% of cases [3].
The abducens nerve originates from the sixth nerve nucleus in the dorsal pons, ventral to the
fourth ventricle (Figure 1). The fibers exit the nucleus and leave the brainstem at the
pontomedullary groove, generally located medial and caudal to facial and vestibulocochlear
nerve. The nerve then courses through subarachnoid space to reach the upper edge of the tip of
the petrous bone (part of the temporal bone) towards the clivus. This portion of the petrous bone
is where the nerve is most susceptible to mastoiditis, otitis or bone infection of any sort. Passing
the clivus, the abducens nerve is then surrounded by a fibrous bone-less sheath, known as
Dorello's canal, where the nerve is sensitive to stretching with changes in intracranial pressure.
After exiting Dorello’s canal, it then enters the cavernous sinus and follows the internal carotid
artery before entering the orbit through the superior orbital fissure to innervate the lateral
rectus [4].

Figure 1. Diagram of the abducens nerve pathway. Note that the trigeminal nerve (gray nerve
exiting the pons) and the abducens nerve (red line) run together adjacent to the petrous bone.
Image obtained from AAO.org.

Risk Factors
Patients who have extensively pneumatized petrous apices are more at risk of developing the
symptoms of GS. In these patients, ear infections can spread into air spaces within the temporal
bone, increasing the risk of compromising nearby nerve structures [5]. Patients with
cholesteatomas and chronic osteomyelitis are also at higher risk [6][7]. Diabetics, patients on high
dose steroids, and immunosuppressed individuals may be at higher risk of GS because of a
weakened ability to limit the spread of infection [8].
 General Pathology
GS may progress from untreated otitis media when the infection spreads to the petrous apex of
the temporal bone. Infection is commonly caused by Streptococcus pneumoniae, Haemophilus
influenzae, Pseudomonas, and Staphylococcus aureus [9]. Tuberculosis and fungal infection is
another less likely cause of infection[10].

Pathophysiology
Bacteria travels from the middle ear to the mastoid air cells, which contain highly vascular
marrow and are susceptible to infection [5]. It can then spread to the adjacent petrous temporal
bone, around which are located many key structures. These structures include the trigeminal
ganglion and abducens nerve, which are separated from the petrous bone only by dura
mater [9]. Inflammation in this region can damage these nerves, causing facial pain and horizontal
diplopia secondary to unilateral esotropia.

Primary prevention
The administration of antibiotics upon diagnosis of otitis media helps prevent the progression to
GS. [9].

Diagnosis
GS is diagnosed by the clinical triad:

1. Otitis media
2. Pain in distribution of ophthalmic and maxillary branches of trigeminal nerve
3. Abducens nerve palsy

History
Otorrhea and otalgia typically precedes diplopia and facial pain.
The timing of presentation of diplopia and facial pain varies with patients, and due to the rarity of
GS it is difficult to determine a typical timeline of presentation for the clinical triad of symptoms.
Furthermore, it is difficult to distinguish between facial pain that arises from trigeminal nerve
lesion and a radiating headache that develops from a different cause also associated with
infection and illness.
In four GS cases, diplopia was observed within a week of otorrhea [1][6][11][9]; in two cases, it was
observed within two weeks [12][13]; in another two cases, within a month of otorrhea [14]; in one case,
within two months [14]; and in one case, a year after presentation of chronic otorrhea. Notably, the
delayed development of diplopia (after at least one month) was found in four of the five cases of
prolonged otorrhea (at least one-month history of otorrhea).

Physical examination
The tympanic membrane should be examined for discharge. Extraocular muscle function,
especially the lateral rectus, should also be tested.

Signs
The three classic signs of GS are: otorrhea, facial pain, and horizontal diplopia.
 Figure 2: Image showing right sixth nerve palsy. Patient is attempting to gaze to the right. Image
obtained from AAO.org.

Symptoms
Patients may complain of earache, tenderness, fever, ear discharge, deep unilateral facial pain,
headache, diplopia, dizziness, nausea, vomiting, and confusion [1][13].

Diagnostic procedures
 CT imaging of the petrous temporal bone is the exam of choice to identify lesions and has a low
false-positive rate. It can evaluate the extent of pneumatization of the temporal bone and marrow
formation [5].
 MRI imaging of the petrous temporal bone provides more information about the composition of
the lesion that CT scans are not able to identify. This is important because it can differentiate
between petrous apicitis, osteomyelitis, cholesteatoma, and neoplasms, and therefore guide to
appropriate treatment [5].

Laboratory test
 Fluid from otorrhea is cultured for antibiotic selection

 Complete blood count

 C-reactive protein

Differential diagnosis
 Cholesteatoma, or implantation of epithelium by trauma to the tympanic membrane, can grow to
a size that puts necrotic pressure on the petrous bone. [5]
 Petrous effusion is fluid that drains into the air cells of the petrous temporal bone. This may be
asymptomatic but can also form cysts. [5]
 Cholesterol granuloma occurs when red blood cells and other tissue break down, releasing
cholesterol to form crystals that induce an inflammatory response. These can form granulomas
that destroy portions of the temporal bone. [5]
 Osteomyelitis may develop following chronic infection of the external ear, middle ear, mastoid, or
petrous apex. [5]
 Neoplasms such as meningioma, intracranial plasmacytoma, chondroma and chondrosarcoma of
the petrous temporal bone are very rare [5][15]
Management
Antibiotics are given for an extended period. In more serious cases, other procedures such as
myringotomies, placement of ventilation tubes, and surgery may be performed. There is no
current guideline for determining when to move from conservative treatment, which risks
deterioration of the cranial nerves, to more invasive surgical procedures [11][9].

General treatment
High dose antibiotic therapy is the primary form of treatment. In cases where inflammation puts
key structures at risk, surgery is performed, most commonly mastoidectomies and
petrosectomies [9].

Medical therapy
High-dose antibiotic treatment is the most common form of medical therapy. Multiple reported
cases of GS involved infection by Staphylococcus or Streptococcus bacteria [1][11][16].
Cephalosporins were the most common antibiotics prescribed, in addition to penicillin, ampicillin,
and vancomycin. In other cases, metronidazole was prescribed [12].
Other forms of treatment may be used in atypical cases to address the underlying illness. One
case of non-Hodgkin’s lymphoma with associated GS was administered chemotherapy, with
partial improvement to nerve functions [7].
GS may need to be treated aggressively with antibiotics and the major morbidity is hearing
loss.[11] .

Surgery
Patients who fail, are intolerant of, or noncompliant with maximal medical therapy may require
mastoidectomy or petrosectomy which removes granulation tissue and necrotic bone that results
from infection in either the mastoid cells or the petrous portion of the temporal bone [2][17][18]. A
mastoidectomy is performed by making a retroauricular incision to access the mastoid antrum
and the mastoid cells deep to it [18]. Using an electric burr and curette, mastoid cells lining the
sigmoid sinus and the middle and posterior cranial fossas are removed [18]. A petrosectomy is a
similar surgery involving the petrous portion of the temporal bone. It is also performed to remove
diseased tissue and reduce further risk of bone erosion and inflammation at the petrous temporal
bone [2].
Another related surgical method is an infralabyrinthine bony dissection, in which a burr is used to
access the infralabyrinthine air cell tract and then the petrous apex of the temporal bone [11].
Purulent secretions can then be drained and the cavity irrigated with saline and hydrogen
peroxide [11]. A tube may be placed to avoid recurrence [11].
Myringotomy, an incision at the tympanic membrane, can be performed to drain fluid. Ear
ventilation tubes may also be placed into the ear for the same long-term function [11][2].

Surgical follow up
Otolaryngology should see the patient if surgical treatment is necessary.

Complications
Complications may arise from the spread of infection in several pathways: directly through the
temporal and mastoid bone; through the labyrinth via the round window and oval window; or via
the bloodstream or thrombophlebitis [19].
 Complications include:

 Meningitis [8]
 Intracranial, prevertebral or parapharyngeal abscess [8]
 Spread of infection to cavernous sinus [19]
 Spread to skull base (Vernet's syndrome) [8]
 Hearing loss [11][18]
 Epidural or subdural empyema [19]
 Sigmoid sinus thrombosis [19]
 Hydrocephalus [19]
 Death [13]

Prognosis
GS is rare and becoming even more rare since the advent of better medical and surgical
treatment. Documented case reports suggest that in serious cases, treatment with antibiotics and
surgery resolves symptoms of otorrhea, horizontal diplopia, and facial pain. However, some
patients may not fully recover complete nerve function [8][6][10]
Most cases of GS have full resolution of signs and symptoms after conservative antibiotic
treatment, but some cases required surgery [9][16].
If untreated GS can be fatal especially in resource limited nations. One pediatric case from
Zimbabwe described a 9-year-old female admitted for discharge in right ear and a year-long
history of chronic suppurative otitis media. Upon declination of surgery, the patient developed the
clinical triad of Gradenigo’s at day 14, and on day 25, she was declared brain dead [13].

References
1. ↑ Jump up to:1.0 1.1 1.2 1.3 1.4 Valles JM, Fekete R. Gradenigo Syndrome: Unusual Consequence of Otitis
Media. Case Reports in Neurology. 2014;6:197-201.
2. ↑ Jump up to:2.0 2.1 2.2 2.3 Visosky AMB, Isaacson B, Oghalai JS. Circumferential Petrosectomy for Petrous
Apicitis and Cranial Base Osteomyelitis. Otology and Neurotology. 2006;27:1003-1013.
3. ↑ Jump up to:3.0 3.1 Hafidh MA, Keogh I, McConn R, Walsh M, Rawluk D. Otogenic intracranial
complications. A 7-year retrospective review. American Journal of Otolaryngology.
2006;27(6):390-395.
4. Jump up↑ Nguyen V, Dulebohn SC. Neuroanatomy, Cranial Nerve 6, Abducens (CN VI,
Abducent) [Updated 2017 May 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls
Publishing; 2017 Jun-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430711
5. ↑ Jump up to:5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Jackler RK, Parker DA. Radiographic Differential Diagnosis of Petrous
Apex Lesions. The American Journal of Otology. 1992;13(6):562-573.
6. ↑ Jump up to:6.0 6.1 6.2 Taklalsingh N, Falcone F, Velayudhan V. Gradenigo’s Syndrome in a Patient with
Chronic Suppurative Otitis Media, Petrous Apicitis, and Meningitis. American Journal of Case
Reports. 2017;18:1039-1043.
7. ↑ Jump up to:7.0 7.1 Pedroso JL, de Aquino CCH, Abrahao A, de Oliveira RA, Pinto LF, Bezerra MLE,
Silva ABG, de Macedo FDB, de Melo Mendes AV, Barsottini OGP. Gradenigo’s Syndrome:
Beyond the Classical Triad of Diplopia, Facial Pain and Otorrhea. Case Reports in Neurology.
2011;3:45-47.
8. ↑ Jump up to:8.0 8.1 8.2 8.3 8.4 Motamed M, Kalan A. Gradenigo’s Syndrome. The Postgrad Medical Journal.
2000;76:559-560.
9. ↑ Jump up to:9.0 9.1 9.2 9.3 9.4 9.5 9.6 Burston BJ, Pretorius PM, Ramsden JD. Gradenigo’s syndrome:
successful conservative treatment in adult and paediatric patients. The Journal of Laryngology
and Otology. 2005;119:325-329.
10. ↑ Jump up to:10.0 10.1 Bhatt YM, Pahade N, Nair B. Aspergillus petrous apicitis associated with cerebral
and peritubular abscesses in an immunocompetent man. The Journal of Laryngology and
Otology. 2013;127:404-407. Resulting inflammation can damage nearby nerve structures
11. ↑ Jump up to:11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Kantas I, Papadopoulou A, Balatsouras DG, Aspris A, Marangos
N. Therapeutic approach to Gradenigo’s syndrome: a case report. Journal of Medical Case
Reports. 2010;4:151-154.
12. ↑ Jump up to:12.0 12.1 Jacobsen CL, Bruhn MA, Yavarian Y, Gaihede ML. Mastoiditis and Gradenigo’s
Syndrome with anaerobic bacteria. Biomed Central Ear, Nose & Throat Disorders. 2012;12:10.
13. ↑ Jump up to:13.0 13.1 13.2 13.3 Jensen PVF, Avnstorp MB, Dzongodza T, Chidziva C, von Buchwald C. A fatal
case of Gradenigo’s syndrome in Zimbabwe and the Danish-Zimbabwean ENT collaboration.
International Journal of Pediatric Otorhinolaryngology. 2017;97:181-184.
14. ↑ Jump up to:14.0 14.1 Jensen PVF, Hansen MS, Moller MN, Saunte JP. The Forgotten Syndrome? Four
Cases of Gradenigo’s Syndrome and a Review of the Literature. Strabismus. 2016;24:21-27.
15. Jump up↑ Bourne RRA, MacLaren RE. Intracranial plasmacytoma masquerading as Gradenigo’s
syndrome. British Journal of Ophthalmology. 1998;82(4):458-459.
16. ↑ Jump up to:16.0 16.1 Janjua N, Bajalan M, Potter S, Whitney A, Sipaul F. Multidisciplinary care of a
paediatric patient with Gradenigo’s syndrome. BMJ Case Reports. Published online 2016.
17. Jump up↑ Profant HJ. Gradenigo’s Syndrome with a consideration of “petrositis.” Archives of
Otolaryngology. 1931;13(3):347-378.
18. ↑ Jump up to:18.0 18.1 18.2 18.3 Hildmann H, Sudhoff H, Dazert S, Hagen R. Manual of temporal bone
exercises. Springer. 2011:5-29.
19. ↑ Jump up to:19.0 19.1 19.2 19.3 19.4 Colpaert C, Rompaey VV, Vanderveken O, Venstermans C, Boudewyns A,
Menovsky T, de Veuster I, Van de Heyning P, Hamans E. Intracranial complications of acute
otitis media and Gradenigo’s Syndrome. B-ENT 2013;9:151-156.