An Ancient Case of Horner Syndrome?

An Ancient Case of Horner Syndrome?

by Maggioni, Umberto; Maggioni, Ferdinando via North American Neuro-Ophthalmology Society

Recurrent Facial Nerve Paralysis : Melkersson–Rosenthal syndrome (7.5%),Neurosarcoidosis(3.7%),Traumatic neuroma (1.9%), Ramsay Hunt syndrome (1.9%),Granulomatosis with Polyangiitis (1.9%), and Neoplastic causes (5.7%) cases [Facial Nerve Schwannoma (n = 2; 3.7%),Metastatic Squamous Cell Carcinoma to the deep lobe of the Parotid Gland (n = 1; 1.9%)]; ultimately, 77.4% of cases were deemed idiopathic.

Diagn Interv Radiol. 2016 Jan; 22(1): 40–46.

Published online 2015 Nov 2. doi: 10.5152/dir.2015.15060

PMCID: PMC4712896

PMID: 26712680

Imaging of facial nerve schwannomas: diagnostic pearls and potential pitfalls

Pravin Mundada, Bela Satish Purohit, Tahira Sultana Kumar, and Tiong Yong Tan

Author information Article notes Copyright and License information Disclaimer

From the Department of Radiology (P.M. moc.liamg@nivarp.adadnum, T.S.K., T.Y.T.), Changi General Hospital, Singapore; Department of Radiology (B.S.P), National Neuroscience Institute, Singapore.

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Abstract

Schwannomas are uncommon in the facial nerve and account for less than 1% of tumors of temporal bone. They can involve one or more than one segment of the facial nerve. The clinical presentations and the imaging appearances of facial nerve schwannomas are influenced by the topographical anatomy of the facial nerve and vary according to the segment(s) they involve. This pictorial essay illustrates the imaging features of facial nerve schwannomas according to their various anatomical locations and also reviews the pertinent differential diagnoses and potential diagnostic pitfalls.

Facial nerve schwannomas (FNSs) are rare slow-growing tumors, accounting for less than 1% of all temporal bone tumors. They are typically solitary, unilateral, and sporadic in nature. FNSs may be bilateral as part of neurofibromatosis-2 spectrum (1, 2). Rarely, multiple schwannomas may involve peripheral branches of the facial nerve (FN) (3). The age of presentation varies from 5 to 84 years. No gender or side predilection is seen (4, 5).

Histologically, FNSs are neuroectodermal in origin. They are encapsulated, benign tumors arising from the Schwann cells. They may show intratumoral cystic change and hemorrhage (3, 4, 5). Malignant schwannoma of the FN is extremely rare (6). FNSs commonly present with peripheral facial neuropathy and/or various otologic symptoms including sensorineural and conducting hearing loss (2–5). Facial paralysis is often seen at a later stage or may not be seen at all. The reasons for this are thought to be neuronal tolerance induced by the extremely slow growth of the tumor, abundant tumor vascularity, and commonly associated dehiscence of adjacent bone (7). Occasionally, FNSs may present as an intraparotid mass or as an intracranial lesion (2–5).

The clinical presentations and the imaging appearances of FNSs are influenced by the topographical imaging anatomy of the FN and vary according to the segment(s) they involve (8). Here, we briefly describe the anatomy of the FN, followed by general imaging features of FNSs on computed tomography (CT) and magnetic resonance imaging (MRI), and appropriate imaging protocols. Tumor involving each segment is reviewed in relation to its characteristic clinical presentations emphasizing diagnostic pearls and potential pitfalls. The imaging examples of FNSs illustrated in this pictorial review are all histopathologically proven cases.

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Segmental anatomy of the facial nerve

The course of the FN is divided into six segments and two genua which are as follows: 1) cerebellopontine cistern (CPC) segment; 2) internal acoustic canal (IAC) segment; 3) labyrinthine segment; 4) geniculate ganglion (GG)/anterior genu; 5) tympanic segment; 6) posterior genu; 7) intramastoid segment; 8) extracranial segment. Each segment of the FN is closely related to several important structures, which may get affected by the expansion of the FN canal caused by the FNS (Figs. 11–5). The FN gives several branches along its course which are as follows: the greater superficial petrosal nerve (GSPN), muscular branches to the stapedius, posterior belly of digastric and stylohyoid, the chorda tympani, the posterior auricular nerve, and five terminal branches (temporal, zygomatic, buccal, marginal mandibular, and cervical) (9, 10).

Figure 1 a–c.

Anatomy of the right facial nerve (FN) on axial (a, b) and sagittal (c) high-resolution heavily T2-weighted images. The cerebellopontine cistern (CPC) segment of FN (a, dotted arrow) is related to the vestibulocochlear nerve posteriorly (a, arrow). The internal acoustic canal (IAC) segment of FN (b and c, dotted arrow) is related to the cochlear nerve inferiorly (c, arrowhead) and the superior vestibular nerve posteriorly (b and c, arrow).

Figure 2 a, b.

Anatomy of the right FN on axial (a) and coronal (b) HRCT images. The labyrinthine segment of FN (a, black arrow) is related to the cochlea anteromedially and slightly inferiorly (a, arrowhead) and to the semicircular canal posterolaterally (a, dotted black arrow), and ends at the geniculate ganglion (GG) (a, white arrow). The greater superficial petrosal nerve (GSPN) exits through the facial hiatus (a, short black arrow). The GG/anterior genu (b, white arrow) is related to tensor tympani inferiorly (b, dotted arrow) and cochlea posteromedially (b, arrowhead). It has a bony roof, which can be deficient in up to 18% of cases.

Figure 3 a–d.

Anatomy of the right FN on axial (b, d), coronal (a), and sagittal (c) HRCT. The tympanic segment of FN (aand b, white arrow) is related to the lateral semicircular canal superiorly, labyrinthine segment of FN and cochlea medially (a, dotted white arrow and white arrowhead, respectively), the cochleariform process (a,short arrow) and the oval window inferiorly, the vestibule medially (b, black dotted arrow), and the incus laterally (b, black arrowhead). The posterior genu (c, black arrow) is related to the lateral semicircular canal superiorly (c, black arrowhead), fossa incudis superolaterally and the ponticulus superomedially. The intramastoid segment of FN (c and d, white arrow) is related to the facial recess anterolaterally (d, black dotted arrow), the pyramidal eminence anteriorly and the sinus tympani anteromedially (d, dotted white arrow and black arrow, respectively).

Figure 4

Anatomy of the right FN on axial postcontrast CT. The extra cranial segment of FN cannot be visualized on CT or MRI. Its course is marked by a line drawn from the stylomastoid foramen (black arrowhead) to the lateral aspect of the retromandibular vein (white arrowhead) where it enters in the parotid gland (dotted line).

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Figure 5 a–c.

Schematic representation of axial section through IAC (a) shows anatomical context of facial nerve schwannoma (FNS), involving the IAC segment, the labyrinthine segment, the GG, the GSPN, and the tympanic segment of the left FN (a, 1 to 5, respectively). Schematic representation of the coronal section (b)through left IAC shows anatomical context of the FNS involving the IAC segment, the labyrinthine segment and the GG of the left FN and its extension to middle cranial fossa through the roof of the GG (b, 1 to 3, respectively). Schematic representation of the coronal section through the mastoid (c) shows anatomical context of FNS involving the mastoid and the intraparotid segments of the left FN.

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Imaging protocols and general imaging features of facial nerve schwannomas

The commonly performed imaging protocol for the evaluation of FNS includes high-resolution CT (HRCT) scan of the temporal bone with multiplanar reconstructions and pre- and postcontrast multiplanar MRI sequences centered on the IAC (axial 2 mm T1-weighted imaging, three-dimensional 0.6 mm heavily weighted T2-weighted imaging (CISS), axial 2 mm T2-weighted fat-saturated imaging, coronal 2 mm postcontrast T1-weighted fat-saturated imaging, and postcontrast isovoxel VIBE). A simultaneous MRI of the brain (5 mm axial T2-weighted and 5 mm postcontrast T1-weighted sequences) is also routinely performed. Contrast-enhanced CT has no role in the imaging of FNS (2, 4).

FNSs usually involve more than one segment of the FN. Like schwannomas occurring elsewhere, FNSs are typically fusiform solid tumors with well-circumscribed smooth margins. They usually grow along the path of least resistance. They appear iso- to hypointense to brain parenchyma on T1-weighted images and hyperintense on T2-weighted images. On diffusion-weighted imaging, there is usually no restriction. They generally show homogeneous postcontrast enhancement; however, cystic degeneration may result in heterogeneous enhancement (2, 4). FNSs can show a "target sign" on T2-weighted images; however, this feature is nonspecific, and may be seen in other benign and malignant neurogenic tumors (3). Small FNSs cause smooth, fusiform expansion of the FN canal, best seen on HRCT images. Large FNSs can cause pressure erosion of the adjacent bony labyrinth and ossicles. Bony erosions caused by FNSs are smooth and sharply marginated, in keeping with long-standing bony compression rather than aggressive pathology (4, 5, 7).

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Pearls and pitfalls in imaging of schwannomas according to involved facial nerve segment(s)

Schwannomas involving the CPC segment and/or the IAC segment of the FN cannot be differentiated from a vestibular schwannoma unless the tumor extends to the labyrinthine segment of the FN (Fig. 6). Other signs like erosion of superior part of the internal auditory canal and eccentricity of tumor in relation to porus acousticus are not reliable. Hence, it is imperative to include the FNS in the differential diagnosis of vestibular schwannoma during preoperative planning and counseling (2, 4, 5).

Figure 6

Contrast-enhanced axial T1-weighted image at the level of left IAC shows an intracanalicular enhancing mass (arrow). The CPC segment (arrowhead) and the labyrinthine segment (not shown) of the FN appear uninvolved. This mass, although proven to be an FNS on surgery, cannot be differentiated from a vestibular schwannoma on imaging.

FNS may acquire a "dumbbell" shape when it shows multisegmental involvement. The relatively narrow labyrinthine segment forms the isthmus of the dumbbell between the globular tumor components at the IAC and the GG (Fig. 7). Occasionally, the GG component of a dumbbell-shaped FNS erodes into the cochlea and thus mimics a transmodiolar acoustic schwannoma. However, unlike FNS, a transmodiolar schwannoma expands the cochlear nerve canal but not the FN canal (11).

Figure 7

Contrast-enhanced coronal T1-weighted image through pons, at the level of the left IAC shows a dumbbell-shaped FNS. The isthmus of dumbbell is formed by the narrow labyrinthine segment of the FN (bent arrow), which connects the globular components in the IAC (dotted arrow) and those at the GG (arrow). The CPC segment of the FN (arrowhead) is not involved.

The GG fossa is the most common location for the occurrence of FNS. FNSs in this location often show extension to the tympanic and/or the labyrinthine segments. Isolated involvement of the GG at the time of presentation is very rare (Fig. 8). This location is also common for the occurrence of FN hemangiomas. In about 50% cases, FN hemangiomas may not show their characteristic amorphous honeycomb appearance and/or internal bony spicules on CT. However, FN hemangiomas show poorly defined margins on HRCT, which differentiate them from FNSs with smooth margins (12, 13).

Figure 8

Contrast-enhanced axial T1-weighted image through the pons at the level of left internal auditory canal shows FNS involving the GG with no extension to other segments. This mass shows smooth scalloping of the adjacent bone on CT (not shown), which is compatible with FNS and excludes the possibility of a facial nerve hemangioma.

A large FNS at the GG can cause bulbous expansion of the GG fossa, erosion of its roof, and can eventually present as an extra-axial middle cranial fossa mass (Fig. 9). Alternatively, it may extend anteriorly along the course of GSPN through the widened facial hiatus (Fig. 10). Rarely, it may involve the GSPN alone. Involvement of the GSPN by the tumor may be seen as smooth scalloping along the anterolateral margin of the petrous bone on CT (Fig. 10b). Whenever a middle cranial fossa mass is associated with facial nerve dysfunction and/or otologic symptoms, an FNS should be suspected (4, 12).

Figure 9 a, b.

Contrast-enhanced coronal T1-weighted image (a) and coronal HRCT image (b) show a dumbbell-shaped FNS on left side. The FNS is involving the CPC segment (a, curved white arrow), IAC segment (a and b, thick arrow), labyrinthine segment (a and b, dotted arrow), and the GG (a, thin black arrow). It is extending to the middle cranial fossa (a, white arrow) by eroding the roof of geniculate fossa (b, white arrows). The HRCT coronal image (b) shows smooth expansion of the facial nerve canal, and smooth erosion of the otic capsule (b,black arrowhead) and ossicles (b, white arrowhead).

Figure 10 a, b.

Contrast-enhanced axial T1-weighted image (a) and axial HRCT image (b) show a dumbbell-shaped FNS on the left side. The FNS is involving the CPC segment (a, black arrowhead), IAC segment (a and b, thick white arrow), labyrinthine segment (a and b, thin white arrow), and the GG (a and b, dotted white arrow). It is extending to the middle cranial fossa (a, white arrowhead) through the widened facial hiatus. Note its extension along the course of GSPN (a and b, curved black arrow). On HRCT axial image (b), the margins of the expanded FN canal appear smooth and well-defined without cortical destruction.

FNS of tympanic segment sometimes extends to the middle ear cavity by eroding the lateral wall of the FN canal. It can appear as a white mass behind an intact tympanic membrane on otoscopy. It can cause smooth pressure erosion of the tympanic cavity walls and of the ossicles. The ossicular chain may be disrupted (Fig. 11). FNS of tympanic segment can extend superomedially to cause smooth pressure erosion of the lateral semicircular canal and vestibule. Congenital cholesteatoma and middle ear adenoma may mimic FNS on otoscopy and CT, but the former shows no postcontrast enhancement and the latter shows no extension into the FN canal. Glomus tympanicum appears red on otoscopy and does not extend into the FN canal (4, 8, 12).

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Figure 11 a, b.

Axial HRCT (a) and postcontrast axial T1-weighted images (b) of left temporal bone through the IAC show fusiform-shaped FNS causing smooth erosion of the tympanic segment of FN, extending in the middle ear cavity (a and b, black arrow) and displacing the ossicle laterally (a, thin white arrow). It also causes smooth expansion of GG and the facial hiatus (a and b, white curved arrow).

FNS involving the mastoid segment can cause smooth expansion of the vertical FN canal and can erode into the external auditory canal (Fig. 12). Occasionally, FNS of the mastoid segment may mimic aggressive bony lesions (like lymphoma or metastasis) when it breaks through the thin-walled adjacent mastoid air cells or shows irregular shape and margins on HRCT and postcontrast MRI (Fig. 13). Perineural spread of parotid gland malignancy along the FN may mimic a mastoid segment FNS, when it is contiguous with the primary tumor or seen as a skip lesion. History of known parotid gland malignancy should suggest the diagnosis (4, 8, 12, 13).

Figure 12 a, b.

Axial (a) and coronal (b) HRCT images of the right temporal bone through posterior part of the mastoid show an FNS of the mastoid segment (a and b, white arrow) which is causing smooth erosion of the bony wall and protruding in the external auditory canal (a and b, star). Normal stylomastoid foramen (b, black arrowhead), middle ear cavity (b, white arrowhead), and lateral semicircular canal (b, black arrow) are seen.

Figure 13 a, b.

Axial HRCT (a) and postcontrast coronal T1-weighted image (b) of the left temporal show FNS of the mastoid segment (a and b, thick white arrow), which breaks through adjacent mastoid air cells and shows irregular margins (a and b, thin black arrows), and thus appears aggressive. Tumor extends to the posterior genu (a,white arrowhead) and the tympanic segment is normal (a, thin white arrow). Differential diagnosis includes aggressive lesions like metastasis or sarcoma.

Intraparotid FNS can mimic a pleomorphic adenoma clinically, as well as on imaging (Fig. 14). Extension to the stylomastoid foramen and the tumor location along the posterolateral aspect of the retromandibular vein favor the diagnosis of an FNS (Fig. 15). However, these findings are not diagnostic for the FNS since pleomorphic adenomas, albeit rarely, may show extension to the stylomastoid foramen. Presence of a target sign on T2-weighted images, if seen, excludes the possibility of a pleomorphic adenoma. Parotid malignancies often have infiltrating margins and heterogeneous appearance on T2-weighted images. Nevertheless, perineural spread of parotid malignancies should be included in the differential diagnosis of an intraparotid FNS showing extension along the stylomastoid foramen (3, 4, 14).

Figure 14

Postcontrast axial CT scan shows an intraparotid FNS on left side (white arrow). Note its relation to the retromandibular vein (black arrowhead). The stylomastoid foramen shows normal fat density, which excludes extension of mass (black arrow). FNS in this location cannot be differentiated from a pleomorphic adenoma on imaging alone.

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Figure 15 a–c.

Axial (a) and coronal (b) T2-weighted fat-saturated image through the left parotid gland shows an intraparotid FNS (a, arrow). This mass shows extension to the stylomastoid foramen (b and c, arrowhead) and along the mastoid segment of the FN (b and c, arrows). Coronal HRCT image (c) through mastoid shows smooth expansion of the stylomastoid foramen and the mastoid segment of the FN.

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Treatment options

Treatment options for FNSs include surgical resection with nerve preservation, complete resection with nerve grafting, and decompression. The use of gamma knife radiosurgery is a relatively new and promising treatment option in cases of new or residual FNSs (15, 16).

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Conclusion

Evaluation of the FNS requires a combined approach of correlating accurate clinical information with HRCT and MRI findings. Awareness of the imaging anatomy of the FN and the characteristic CT and MRI appearances of FNS involving different FN segments is crucial to arrive at the correct diagnosis. Finally, the possible imaging differentials at various locations must be borne in mind so as to avoid potential diagnostic pitfalls.

Main points

• Knowledge of the complex anatomical landscape of the facial nerve (FN) is vital in the diagnosis of facial nerve schwannomas (FNSs).
• The FNS involving the cisternal and/or internal acoustic canal segments of the FN cannot be confidently differentiated from the vestibular schwannoma on imaging. Its inclusion in the differential diagnosis of the latter has important implication in presurgical counselling.
• FNSs may present as a middle cranial fossa mass, a middle ear mass, an external auditory canal mass, or an intraparotid mass.
• Demonstration of smooth scalloping of the FN canal and adjacent bony labyrinth on HRCT differentiates the FNS from the FN hemangioma. However, FNSs of mastoid segment can sometimes mimic aggressive tumors.
• The differential diagnosis of an intraparotid mass with extension in the stylomastoid foramen includes FNS, parotid malignancy with perineural spread and, rarely, pleomorphic adenoma.

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Acknowledgements

The schematic representation of FNS in context of FN segment(s) in Fig. 5 was conceived and sketched by Dr. Bela Purohit.

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Footnotes

Conflict of interest disclosure

The authors declared no conflicts of interest.

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References

1. Fenton JE, Morrin MM, Smail M, Sterkers O, Sterkers JM. Bilateral facial nerve schwannomas. Eur Arch Otorhinolaryngol. 1999;256:133–135. http://dx.doi.org/10.1007/s004050050125. [PubMed]

2. Harnsberger HR, Glastonbury CM, Michel MA, Koch BL. Diagnostic imaging: Head and neck. 2nd ed. Vol. 6. Altona: Amirsys; 2011. pp. 14–17.

3. Shimizu K, Iwai H, Ikeda K, Sakaida N, Sawada S. Intraparotid facial nerve schwannoma: a report of five cases and an analysis of MR imaging results. AJNR Am J Neuroradiol. 2005;26:1328–1330.[PubMed]

4. Wiggins RH, 3rd, Harnsberger HR, Salzman KL, Shelton C, Kertesz TR, Glastonbury CM. The many faces of facial nerve schwannoma. AJNR Am J Neuroradiol. 2006;27:694–699. [PubMed]

5. McMonagle B, Al-Sanosi A, Croxson G, Fagan P. Facial schwannoma: results of a large case series and review. J Laryngol Otol. 2008;122:1139–1150. http://dx.doi.org/10.1017/S0022215107000667. [PubMed]

6. Hasan NU, Kazi T. Malignant schwannoma of facial nerve. J Pediatr Surg. 1986;21:926–928.http://dx.doi.org/10.1016/S0022-3468(86)80090-2. [PubMed]

7. Sunderland S. Some anatomical and pathophysiological data relevant to facial nerve injury and repair. In: Fisch U, editor. Facial nerve surgery. Amstevleen: Kugler; 1977. pp. 47–67.

8. Kertesz TR, Shelton C, Wiggins RH, Salzman KL, Glastonbury CM, Harnsberger R. Intratemporal facial nerve neuroma: anatomical location and radiological features. Laryngoscope. 2001;111:1250–1256.http://dx.doi.org/10.1097/00005537-200107000-00020. [PubMed]

9. Guinto EJ, Himadi GM. Tomographic anatomy of the ear. Radiol Clin North Am. 1974;12:405–417.[PubMed]

10. Gupta S, Mends F, Hagiwara M, Fatterpekar G, Roehm PC. Imaging the facial nerve: a contemporary review. Radiol Res Pract. 2013;248039:1–14. http://dx.doi.org/10.1155/2013/248039 [PMC free article][PubMed]

11. Salzman KL, Davidson HC, Harnsberger HR, et al. Dumbbell schwannomas of the internal auditory canal. AJNR Am J Neuroradiol. 2001;22:1368–1376. [PubMed]

12. Chung SY, Kim DI, Lee BH, Yoon PH, Pyoung J, Chung TS. Facial nerve schwannomas: CT and MR findings. Yonsei Med J. 1998;39:148–153. http://dx.doi.org/10.3349/ymj.1998.39.2.148. [PubMed]

13. Phillips CD, Hashisaki G, Vellion F. Anatomy and development of the facial nerve. In: Swartz JD, editor. Imaging of temporal bone. 4th ed. New York: Theime; 2009. pp. 444–479.

14. Nader ME, Bell D, Sturgis EM, Ginsberg LE, Gidley PW. Facial nerve paralysis due to a pleomorphic adenoma with the imaging characteristics of a facial nerve schwannoma. J Neurol Surg Rep. 2014;75:84–88. http://dx.doi.org/10.1055/s-0034-1368149. [PMC free article] [PubMed]

15. McMonagle B, Al-Sanosi A, Croxson G, Fagan P. Facial schwannoma: results of a large case series and review. J Laryngol Otol. 2008;122:1139–1150. http://dx.doi.org/10.1017/S0022215107000667. [PubMed]

16. Madhok R, Kondziolka D, Flickinger JC, Lunsford LD. Gamma knife radiosurgery for facial schwannomas. Neurosurgery. 2009;64:1102–1105.http://dx.doi.org/10.1227/01.NEU.0000343743.20297.FB. [PubMed]

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For Whom the Bell's Toll: Recurr

ent Facial Nerve Paralysis, A Retrospective Study and Systematic Review of the Literature

by Chweya, Cynthia M.; Anzalone, C. Lane; Driscoll, Colin L.W.; Lane, John I.; Carlson, Matthew L. via Otology & Neurotology - Published Ahead-of-Print

Purpose: To examine the etiology, clinical course, and management of recurrent peripheral facial nerve paralysis. Methods: Retrospective review at a single tertiary academic center and systematic review of the literature. Clinical presentation, laboratory and imaging findings, treatment and outcome for all cases of recurrent ipsilateral, recurrent contralateral, and bilateral simultaneous cases of facial paralysis are reviewed. Results: Between 2000 and 2017, 53 patients [41.5% men, 29 median age of onset (range 2.5 wk–75 yr)] were evaluated for recurrent facial nerve paralysis at the authors' institution. Twenty-two (41.5%) cases presented with ipsilateral recurrences only, while the remaining 31 patients (58.5%) had at least 1 episode of contralateral recurrent paralysis. No cases of bilateral simultaneous facial nerve paralysis were observed. The median number of paretic events for all patients was 3 (range 2–20). The median nadir House–Brackmann score was 4, with a median recovery to House–Brackmann grade 1.5 over a mean recovery time of 61.8 days (range 1–420 d). Diagnostic evaluation confirmed Melkersson–Rosenthal syndrome in four (7.5%) cases, neurosarcoidosis in two (3.7%), traumatic neuroma in one (1.9%), Ramsay Hunt syndrome in one (1.9%), granulomatosis with polyangiitis in one (1.9%), and neoplastic causes in three (5.7%) cases [facial nerve schwannoma (n = 2; 3.7%), metastatic squamous cell carcinoma to the deep lobe of the parotid gland (n = 1; 1.9%)]; ultimately, 77.4% (41) of cases were deemed idiopathic. Facial nerve decompression via a middle cranial fossa approach was performed in three (5.7%) cases without subsequent episodes of paralysis. Conclusion: Recurrent facial nerve paralysis is uncommon and few studies have evaluated this unique population. Recurrent ipsilateral and contralateral episodes are most commonly attributed to idiopathic facial nerve paralysis (i.e., Bell's palsy); however, a subset harbor neoplastic causes or local manifestations of underlying systemic disease. A comprehensive diagnostic evaluation is warranted in patients presenting with recurrent facial nerve paralysis and therapeutic considerations including facial nerve decompression can be considered in select cases. Address correspondence and reprint requests to Matthew L. Carlson, M.D., Department of Otorhinolaryngology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; E-mail: carlson.matthew@mayo.edu The authors disclose no conflicts of interest. Copyright © 2019 by Otology & Neurotology, Inc. Image copyright © 2010 Wolters Kluwer Health/Anatomical Chart Company

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J Neurol Neurosurg Psychiatry. 2001 Aug;71(2):149-54.

Ramsay Hunt syndrome.

Sweeney CJ1, Gilden DH.

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1

Department of Neurology, Mail Stop B182, University of Colorado Health Sciences Center, SOM Room 3657, 4200 East 9th Avenue, Denver, Colorado 80262, USA.

Abstract

The strict definition of the Ramsay Hunt syndrome is peripheral facial nerve palsy accompanied by an erythematous vesicular rash on the ear (zoster oticus) or in the mouth. J Ramsay Hunt, who described various clinical presentations of facial paralysis and rash, also recognised other frequent symptoms and signs such as tinnitus, hearing loss, nausea, vomiting, vertigo, and nystagmus. He explained these eighth nerve features by the close proximity of the geniculate ganglion to the vestibulocochlear nerve within the bony facial canal. Hunt's analysis of clinical variations of the syndrome now bearing his name led to his recognition of the general somatic sensory function of the facial nerve and his defining of the geniculate zone of the ear. It is now known that varicella zoster virus (VZV) causes Ramsay Hunt syndrome. Compared with Bell's palsy (facial paralysis without rash), patients with Ramsay Hunt syndrome often have more severe paralysis at onset and are less likely to recover completely. Studies suggest that treatment with prednisone and acyclovir may improve outcome, although a prospective randomised treatment trial remains to be undertaken. In the only prospective study of patients with Ramsay Hunt syndrome, 14% developed vesicles after the onset of facial weakness. Thus, Ramsay Hunt syndrome may initially be indistinguishable from Bell's palsy. Further, Bell's palsy is significantly associated with herpes simplex virus (HSV) infection. In the light of the known safety and effectiveness of antiviral drugs against VZV or HSV, consideration should be given to early treatment of all patients with Ramsay Hunt syndrome or Bell's palsy with a 7-10 day course of famciclovir (500 mg, three times daily) or acyclovir (800 mg, five times daily), as well as oral prednisone (60 mg daily for 3-5 days). Finally, some patients develop peripheral facial paralysis without ear or mouth rash, associated with either a fourfold rise in antibody to VZV or the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva. This indicates that a proportion of patients with "Bell's palsy" have Ramsay Hunt syndrome zoster sine herpete. Treatment of these patients with acyclovir and prednisone within 7 days of onset has been shown to improve the outcome of recovery from facial palsy.

Comment in

• Increased risk of stroke after Bell's palsy: a population-based longitudinal follow-up study. [J Neurol Neurosurg Psychiatry. 2012]

PMID:

 

11459884

 

PMCID:

 

PMC1737523

Granulomatosis with polyangiitis

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Información en español

Other Names:

 

GPA; WG; Wegener granulomatosis; See More

Categories:

 

Blood Diseases; Kidney and Urinary Diseases; Lung Diseases; See More

This disease is grouped under:

 

ANCA-associated vasculitis

Summary

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Granulomatosis with polyangiitis (GPA) is a type of vasculitis or swelling (inflammation) of the blood vessels. The disease can cause swelling of the blood vessels anywhere in the body but mainly impacts the sinuses, nose, trachea (windpipe), lungs, and kidneys. The swelling can limit the flow of blood to these body parts, causing damage. Symptoms of the disease can include sinus pain, recurrent respiratory infections, joint pain, tiredness (fatigue), and skin lesions.[1][2]

The exact cause of GPA is unknown, but it is a type of autoimmune disease. Diagnosis of GPA can be made with laboratory tests such as a blood test, biopsy of affected areas, and imaging of the lungs. Treatment of GPA often includes medications such as glucocorticoids and immunosuppressants.[1] 

Last updated: 1/14/2018

Symptoms

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Granulomatosis with polyangiitis (GPA) can affect the blood vessels in any part of the body, but the most commonly affected areas include the sinuses, trachea, lungs, and kidneys. Granulomatosis with polyangiitis is the term used to describe this disease because people with this disease may have granulomas, which are areas of swelling that contain cells of the immune system. These granulomas are especially common in the lungs and airways of people with GPA. The term "polyangiitis" refers to swelling of many different types of blood vessels.[3]  

The first sign of GPA may be a recurrent respiratory infection, or a cough or runny nose that continues for longer than expected.[2] Other common symptoms of the disease include nosebleeds, joint pain, weakness, tiredness (fatigue), weight loss, or an unexplained fever.[4] In some cases, the disease can cause the bridge of the nose to collapse, resulting in a saddle-nose deformity. Some people with GPA may have blood in the urine, chest pain, or skin lesions. If the disease is not treated, symptoms can progress to include kidney failure.[1][2]More rarely, people with GPA may have symptoms affecting the eyes such as a recurrent eye infection or swelling of the eyes.[2] Most people who have GPA start to have signs and symptoms of the disease in adulthood. The disease is most common in people of northern European descent.[2] 

Last updated: 1/14/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing 62 of 62 | 

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Abnormal oral cavity morphology	Abnormality of the oral cavity	0000163
Arthralgia	Joint pain	0002829
Autoimmunity	Autoimmune disease [ more  ]	0002960
Cerebral ischemia	Disruption of blood oxygen supply to brain	0002637
Epistaxis	Bloody nose [ more  ]	0000421
Fatigue	Tired [ more  ]	0012378
Fever		0001945
Glomerulopathy		0100820
Granulomatosis		0002955
Hematuria	Blood in urine	0000790
Pulmonary infiltrates	Lung infiltrates	0002113
Recurrent respiratory infections	Frequent respiratory infections [ more  ]	0002205
Sinusitis	Sinus inflammation	0000246
Vasculitis	Inflammation of blood vessel	0002633
Weight loss		0001824
30%-79% of people have these symptoms
Abdominal pain	Pain in stomach [ more  ]	0002027
Abnormality of the hypothalamus-pituitary axis		0000864
Chest pain		0100749
Chronic obstructive pulmonary disease		0006510
Cough	Coughing	0012735
Elevated C-reactive protein level		0011227
Elevated erythrocyte sedimentation rate	High ESR	0003565
Hemoptysis	Coughing up blood	0002105
Inflammatory abnormality of the eye		0100533
Nausea and vomiting		0002017
Papule		0200034
Periorbital edema	Puffiness around the eyes [ more  ]	0100539
Proteinuria	High urine protein levels [ more  ]	0000093
Pulmonary fibrosis		0002206
Recurrent intrapulmonary hemorrhage	Recurrent bleeding into lungs	0006535
Respiratory insufficiency	Respiratory impairment	0002093
Skin rash		0000988
5%-29% of people have these symptoms
Angina pectoris		0001681
Arrhythmia	Abnormal heart rate [ more  ]	0011675
Chronic otitis media	Chronic infections of the middle ear	0000389
Cranial nerve paralysis		0006824
Diabetes insipidus		0000873
Gangrene	Death of body tissue due to lack of blood flow or infection	0100758
Gastrointestinal hemorrhage	Gastrointestinal bleeding	0002239
Headache	Headaches	0002315
Hemiplegia	Paralysis on one side of body	0002301
Hydronephrosis		0000126
Hypertension		0000822
Intestinal obstruction	Bowel obstruction [ more  ]	0005214
Meningitis		0001287
Myalgia	Muscle ache [ more  ]	0003326
Pancreatitis	Pancreatic inflammation	0001733
Pericarditis	Swelling or irritation of membrane around heart	0001701
Pleuritis	Inflammation of tissues lining lungs and chest	0002102
Proptosis	Bulging eye [ more  ]	0000520
Prostatitis	Inflammation of the prostate	0000024
Purpura	Red or purple spots on the skin	0000979
Renal insufficiency	Renal failure [ more  ]	0000083
Restrictive ventilatory defect	Stiff lung or chest wall causing decreased lung volume	0002091
Retinopathy	Noninflammatory retina disease	0000488
Seizures	Seizure	0001250
Sensorineural hearing impairment		0000407
Sensory neuropathy	Damage to nerves that sense feeling	0000763
Skin ulcer	Open skin sore	0200042
Ureteral stenosis	Narrowing of the ureter	0000071
Venous thrombosis	Blood clot in vein	0004936
Visual impairment	Impaired vision [ more  ]	0000505

Melkersson-Rosenthal syndrome

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Other Names:

 

MRS; Melkersson syndrome; MROS; See More

Categories:

 

Immune System Diseases; Skin Diseases

This disease is grouped under:

 

Orofacial Granulomatosis

Summary

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Melkersson-Rosenthal syndrome (MRS) is a rare, inherited syndrome that affects the nervous system and skin (a neurocutaneous syndrome). MRS may be characterized by three main features: recurrent facial nerve palsy, episodes of swelling of the face and lips, and fissuring of the tongue (formation of deep grooves). The majority of people with MRS only have one or two of these features, rather than all three.[1][2] The age when symptoms begin and frequency of episodes varies from person to person (even within the same family), but usually symptoms begin during childhood or early adolescence.[1][2] Recurrent episodes may lead to worsening and persistent swelling, which may become permanent.[2] MRS is more common in females than in males.[1]

Inheritance of MRS is autosomal dominant, but a consistent genetic cause has not been found. It is possible that more than one gene is responsible for MRS, and/or that environmental "triggers" may contribute to causing the syndrome in some genetically predisposed individuals.[1] In some cases, MRS may be associated with Crohn's disease or sarcoidosis.[2] MRS is diagnosed based on the symptoms present and medical history, and a biopsy of the lips may be needed to confirm the diagnosis in some cases.[3]

Treatment for MRS aims to relieve symptoms, but the effectiveness of current treatment options has not been well-established.[4] Treatment options may include medications to reduce swelling (such as nonsteroidal anti-inflammatory drugs and corticosteroids), antibiotics, immunosuppressants, surgery (to relieve pressure on the facial nerves and reduce swelling), and facial rehabilitation (which may involve physiotherapy and speech-language therapy).[2][5]

Last updated: 10/15/2018

Symptoms

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This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing 15 of 15 | 

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Cheilitis	Inflammation of the lips	0100825
Inflammatory abnormality of the skin	Skin inflammation	0011123
Mask-like facies	Expressionless face [ more  ]	0000298
Oligosacchariduria		0010471
Periorbital edema	Puffiness around the eyes [ more  ]	0100539
30%-79% of people have these symptoms
Facial palsy	Bell's palsy	0010628
Furrowed tongue	Grooved tongue	0000221
Macroglossia	Abnormally large tongue [ more  ]	0000158
5%-29% of people have these symptoms
Abnormal autonomic nervous system physiology		0012332
Fever		0001945
Lymphadenopathy	Swollen lymph nodes	0002716
Nystagmus	Involuntary, rapid, rhythmic eye movements	0000639
Percent of people who have these symptoms is not available through HPO
Abnormality of the eye	Abnormal eye	0000478
Autosomal dominant inheritance		0000006
Facial edema	Facial puffiness [ more  ]	0000282

Curr Neuropharmacol. 2011 Sep; 9(3): 429–436.

doi: 10.2174/157015911796557975

PMCID: PMC3151597

PMID: 22379457

Neurosarcoidosis

David Lacomis*

Author information Article notes Copyright and License information Disclaimer

Departments of Neurology and Pathology (Neuropathology), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA

*Address correspondence to this author at Department of Neurology, UPMC Presbyterian, HPU010806, 200 Lothrop Street, Pittsburgh, PA, USA; Tel: 412-647-1706; Fax: 412-647-8398; E-mail: ude.cmpu@dsimocal

This article has been cited by other articles in PMC.

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Abstract

Neurosarcoidosis is an uncommon but potentially serious manifestation of sarcoidosis. While the cranial nerves are most frequently affected, neurosarcoidosis can involve other nervous system tissues including the meninges, brain parenchyma (especially the hypothalamic region), spinal cord, peripheral nerve, and muscle. Diagnosis may be particularly challenging when neurosarcoidosis occurs in isolation. Diagnostic criteria usually include histologic identification of a noncaseating granuloma, supportive laboratory or imaging tests or both, and a compatible clinical course. Treatment has not been subjected to rigorous study, but corticosteroids are typically the first line of therapy and approximately half of patients have substantial benefit. For patients who are refractory to or intolerant of corticosteroid therapy, second-line agents include azathioprine, methotrexate, cyclosporine, cyclophosphamide, mycophenolate, and even cranial irradiation. The combination of infliximab and mycophenolate mofetil is under study as well. Treatment options will likely evolve as well-designed studies are undertaken.

Keywords: Neurosarcoidosis, sarcoidosis, cranial neuropathy, meningitis, neuroendocrine dysfunction, seizures, peripheral neuropathy, myopathy.

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INTRODUCTION

Sarcoidosis is a systemic granulomatous disease that is still of undetermined etiology [1, 2]. In the United States, the incidence ranges from 11 per 100,000 in Caucasians to 36 per 100,000 in African-Americans, and it tends to manifest prior to age 40. However, it occurs in people of all ages and races [1, 2]. The respiratory and lymphatic systems are most commonly affected [1]. When the nervous system is involved as it is in about 5-13% of cases, that involvement is termed "neurosarcoidosis" [3-6]. Neurosarcoidosis can occur either in isolation or along with other features of systemic sarcoidosis.

Neurosarcoidosis has protean manifestations and can masquerade as many other diseases. It can affect a combination of intracranial structures, such as leptomeninges, cranial nerves and hypothalamus, and it can affect the spinal cord and its coverings as well as peripheral nerve and muscle.

Spontaneous improvement or remissions occur in about 60% of patients with neurosarcoidosis [7]. The mortality rate in all forms of sarcoidosis is from 1-5% and is due to severe pulmonary, cardiac, or neurologic disease [8].

Most of our current knowledge of neurosarcoidosis comes from retrospective and autopsy series, and from studies involving patients with systemic sarcoidosis. The immunopathogenesis and treatments of neurosarcoidosis are similar to those of systemic disease, and they have not been subjected to placebo-controlled, double-blinded studies.

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EPIDEMIOLOGY OF NEUROSARCOIDOSIS

The typical mean age of onset is from 33 to 41 years, slightly later compared to other forms of sarcoidosis [4, 9-11]. About half of these patients have known generalized disease, and 30-70% present with neurologic symptoms [4, 6, 9]. Neurologic manifestations usually occur within the first two years of illness [4, 10]. In general, neurosarcoidosis, like systemic sarcoidosis, is more common among blacks. Women make up the majority in most, but not all, series. For example, in the large series reported by Stern, et al.,85% of patients with neurosarcoidosis were black, and 64% were female [4]. In contrast however, a French study of 35 patients reported that 91% were Caucasian [6], and a United Kingdom study reported that 29 of 30 patients were Caucasian, and 53% were male [9].

Risk factors specific to neurosarcoidosis have not been identified. Research involving the immunopathogenic aspects of neurosarcoidosis is lacking, and it is currently felt that the inflammatory response in the nervous system is similar to that seen in other organs, including the lung. The immunopathogenesis of sarcoidosis will be discussed later.

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CRANIAL NEUROSARCOIDOSIS

Symptoms of cranial neurosarcoidosis are varied and commonly include headache, ataxia, visual disturbances, fatigue, nausea and vomiting. Others include weakness, sensory disturbances, seizures, cognitive dysfunction, eye pain, depression, aphasia, and tremor [9]. The combination of symptoms present in an individual depends on the localization of the inflammatory process.

Cranial Neuropathies

Cranial neuropathies are the most common manifestation of neurosarcoidosis (see Table 11) [3-7, 9, 10, 12]. Any cranial nerve (CN) may be affected, and multiple cranial nerve involvement is common. In older series, the most frequently affected CN is VII, and sometimes bilateral facial neuropathies are present [10]. In the more recent series, optic neuropathy (discussed below) is more common [9]. Involvement of CN VIII (uni- or bilaterally) can cause auditory or vestibular dysfunction [4], but it may be asymptomatic and detected by brainstem auditory-evoked responses [10]. Nerves involved in eye movement (CN III, IV, and VI) may also be affected. Olfactory involvement is somewhat uncommon and causes anosmia and impaired taste [10, 13].

Table 1

Neurologic Manifestations of Sarcoidosis

	Zajicek et al. [20] N=68	Joseph and Scolding [9] N=30	Pawate et al.[11] N=54	Delaney, et al. [5] N = 23	Stern, et al.[4] N = 33	Chapelon, et al. [6] N = 35	Oksanen [10] N = 50	Lower, et al.[3] N = 71	Wiederholt, Siekert [7] N = 28
Cranial neuropathy % (N)	34 (23)	28 (8)	23 (12)	48 (11)	73 (24)	34 (12)	42 (21)	70 (50)	64 (18)
Optic neuropathy	38 (26)	37 (11)	35 (19)	30 (7)	12 (4)	3 (1)	10 (5)	10 (7)	21 (6)
Endocrine/hypothalamic dysfunction	3 (2)	17 (5)	2 (1)	26 (6)	15 (5)	11 (4)	10 (5)	8 (6)	25 (7)
Other intracranial mass	--	--	--	35 (8)	0 (0)	--
Seizures	--	10 (3)	17 (9)	22 (5)	0 (0)	14 (5)	18 (9)	7 (5)	18 (5)
Meningitis	12 (8)	22 (7)	--	26 (6)	18 (6)	40 (14)	8 (4)	40 (28)	--
Myelopathy	28 (19)	15 (5)	19 (10)	9 (2)	6 (2)	0 (0)	10 (5)	--	4 (1)
Peripheral Neuropathy	--	--	2 (1)	4 (1)	6 (2)	40 (14)	18 (9)	4 (3)	14 (4)
Myopathy	--	--	--	9 (2)	12 (4)	26 (6)	10 (5)	--	7 (2)

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Cranial neuropathies may occur because of basilar meningitis, but infiltration or compression of nerves along their course can cause their dysfunction. For example, olfactory nerve dysfunction can occur from olfactory bulb involvement as well as from involvement of the nasal mucosa [13]. In the latter instance, it can be diagnosed by nasal biopsy. In addition, some facial neuropathies probably occur from basilar meningitis, while other cases may be due to granulomatous involvement of the extracranial portion of the nerve.

Optic Neuropathy

Optic neuropathy is uncommon in some series but more common in others (Table 11), and it may be serious. Bilateral involvement sometimes occurs [11]. Symptoms and signs may include decreased or blurred vision, papilledema, optic nerve atrophy, retrobulbar pain, visual field defects, and pupillary abnormalities [5, 11]. There may be local granulomatous involvement of the optic nerve, but papilledema can also be caused by increased intracranial pressure from hydrocephalus or meningeal involvement. Overall, optic neuropathy is less frequent than other common ocular features of sarcoidosis including anterior uveitis, conjunctival granulomas, scleritis, episcleritis, keratitis, posterior segment disorders, and lacrimal involvement with sicca symptoms [14].

Acute or Chronic Meningitis

Meningeal infiltration preferentially involves the basal leptomeninges. It has been reported in up to 40% of patients (Table 11). It may manifest with cranial nerve palsies. It can lead to hydrocephalous from cerebrospinal fluid outflow obstruction, ventricular system granulomas, or choroid plexus infiltration [5]. Cerebrospinal fluid (CSF) studies --discussed in detail later-- reveal mononuclear inflammatory cells with an elevated protein. Occasionally, the glucose is low. Magnetic resonance imaging (MRI) with contrast usually reveals leptomeningeal enhancement. The course can be monophasic, chronic, or relapsing, and is usually associated with a good outcome [8].

Hypothalamic Dysfunction, Intracranial Masses, and Encephalopathy

Hypothalamic and pituitary dysfunction are relatively common (Table 11), usually due to subependymal granulomatous infiltration in the region of the third ventricle. Diabetes insipidus and hyperprolactinemia are the two most common endocrine manifestations along with hypogonadism [15].

Encephalopathy can occur from neuroendocrine disturbances, leptomeningeal infiltration, mass lesions, seizures, and small vessel vasculitis. Rarely, central nervous system (CNS) sarcoidosis causes arterial and venous infarcts or transient ischemic attacks [6, 16, 17].

Granulomas in or adjacent to the brain parenchyma may mimic gliomas or meningiomas [18]. Some can also cause cerebellopontine angle masses mimicking schwannomas. Masses may be asymptomatic, but they can obstruct the ventricular system and cause hydrocephalus. Others may cause seizures [15].

Seizures

Seizures occur in 7-22% of patients with neurosarcoidosis (Table 11). They are the presenting manifestation in about 10%, and may be generalized or focal [19]. Their etiologies include leptomeningeal infiltration with cortical irritation, parenchymal masses, metabolic disturbances related to hypothalamic dysfunction, and possibly small vessel vasculitis associated with granulomatous angiitis. Cerebrospinal fluid and electroencephalography results may correlate poorly with clinical findings [5]. The overall prognosis can be poor because of the severity of CNS disease [5]. The seizures are usually well-controlled with anticonvulsants [19].

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SPINAL CORD AND ITS COVERINGS

Neurosarcoidosis can cause arachnoiditis, cauda equina dysfunction, extra- and intra-dural, extra-medullary and intra-medullary lesions. The incidence in modern studies utilizing MRI is 15-28% [9, 11, 20]. Junger, et al., reported 16 patients with intra-medullary lesions studied retrospectively. MRI and clinical findings were noted. Five patients had sarcoidosis isolated to the spinal cord, while ten had systemic disease. The median age of onset was 35. Patients had myeloradicular symptoms. MRI showed spinal cord enlargement in seven patients, atrophy in four, and focal regions of increased T2 signal in two. One patient had diffusely increased T2 signal throughout the spinal cord. There was multifocal or focal enhancement in 50% and diffuse enhancement in 1 of 12 [21].

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PERIPHERAL NEUROPATHY

Peripheral neuropathy occurs in 4-20% of patients with neurosarcoidosis (Table 11). Subtypes include chronic sensorimotor axonal polyneuropathy, multiple mononeuropathies, sensory polyneuropathy including small-fiber neuropathy, acute inflammatory demyelinating polyneuropathy (AIDP) and chronic inflammatory demyelinating polyneuropathies [22-26]. The overall incidence of neuropathy in Oksanen's series was relatively high at 40% due to a relatively large number of mononeuropathies. The ulnar and peroneal nerves were most commonly affected [10]. Neuropathy can occur at various stages of sarcoidosis, and it can be the initial feature. Cranial neuropathies are more commonly encountered with the AIDP and multifocal mononeuropathy forms.

The presentation depends on the type of neuropathy. Diagnosis is typically confirmed by nerve biopsy, which shows the characteristic noncaseating granulomas, (Fig. 11). In some biopsy specimens, there is also evidence of necrotizing vasculitis or microvasculitis [24]. The mechanism of the neuropathy is often uncertain but could be due to compression by granulomas and immune factors with either axonal loss or demyelination. Vasculitis can also cause ischemic axon loss. Electrodiagnostic studies in patients with an AIDP presentation are similar to those seen in Guillain-Barré syndrome. CSF pleocytosis is more likely to be present in the patients with sarcoidosis rather than in typical AIDP, though a pleocytosis with an elevated CSF protein can also be present in HIV-associated AIDP for example [27]. A low CSF glucose would favor sarcoidosis.

Fig. (1)

A hematoxylin- and eosin-stained paraffin section of a superficial peroneal sensory nerve biopsy specimen reveals a granuloma consisting of epithelioid histiocytes surrounded by a rim of lymphocytes. Giant cells are not seen and may not be readily apparent in most nerve granulomas. The granuloma is in the epineurium adjacent to the endoneurium (E).

Evaluation of intraepidermal nerve fiber density may be useful in confirming a diagnosis of small-fiber neuropathy when suspected and when electrodiagnostic studies do not show large-fiber neuropathic dysfunction. Subclinical involvement may also be identified by either test [28].

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MYOPATHY

Muscle involvement is commonly noted in autopsy and clinical series, and it is usually asymptomatic [29,30]. It may be detected subclinically in up to 50% of sarcoidosis patients who undergo muscle biopsy as part of the evaluation [29]. Symptomatic muscle involvement is present in less than 1% of patients with systemic sarcoidosis. It is somewhat more common in conjunction with other features of neurosarcoidosis (Table 11), in post-menopausal women, [31] and in the presence of erythema nodosum [29]. Its onset tends to occur later with other organ involvement [31]. Presentations include acute myopathy with a polymyositis-like presentation and chronic myopathy with muscle wasting [30]. Patients may have muscle tenderness, and sometimes nodules may be palpated [32, 33]. Diaphragm involvement is rare [34].

The serum creatine kinase is sometimes elevated. EMG reveals "myopathic" motor unit potentials with or without fibrillation potentials [35]. Diagnosis is confirmed by identification by noncaseating granulomas in muscle tissue. They are usually located in the perimysium, and sometimes occur in the endomysium but do not typically infiltrate myofibers distant to the granuloma (Fig. 22).

Fig. (2)

A photomicrograph of a hematoxylin- and eosin-stained paraffin section from a skeletal muscle biopsy specimen reveals a granuloma containing giant cells. It is located in the perimysium. Some lymphocytes course outside the granuloma, but the adjacent muscle fibers are mostly unaffected.

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DIAGNOSIS

The criteria for diagnosis of neurosarcoidosis usually include a compatible clinical scenario, histologic identification of a noncaseating granuloma in any tissue, and imaging or laboratory tests supportive of the diagnosis. Zajicek et al. proposed diagnostic criteria with levels of certainty, and these criteria are now commonly used [20]. All categories include a clinical presentation suggestive of neurosarcoidosis and exclusion of other diagnoses. These are the criteria for possible neurosarcoidosis. For a definite diagnosis, there should also be "positive" nervous system histology. For a diagnosis of probable neurosarcoidosis, laboratory support (CSF or MRI) is required as well as evidence of systemic sarcoidosis (histological, Kveim test, and/or two or more indirect indicators: suggestive Gallium scan, chest imaging, or serum ACE) [20].

The approach to diagnosis is dependent on the presumed localization of the neurologic lesion and whether or not the patient has known evidence of systemic sarcoidosis [2]. Since intrathoracic disease is most common, screening for systemic sarcoidosis usually starts with a chest x-ray. Chest x-rays are abnormal in up to 90% of sarcoidosis patients, and hilar adenopathy is the most common finding. High resolution chest CT is more sensitive, especially for detecting nodules along the bronchovascular bundle and subpleural regions [36]. In addition, skin lesions should be sought. The presence of Löfgren syndrome (erythema nodosum, bilateral hilar adenopathy, fever and arthritis) is practically diagnostic of sarcoidosis. Ophthalmologic evaluation, including slit lamp exam for uveitis and other ocular findings, should also be performed. An endocrine evaluation should be undertaken if hypothalamic or pituitary dysfunction is suspected.

A minority of patients may have an elevated erythrocyte sedimentation rate. Elevations in serum alkaline phosphatase and calcium are uncommon. The serum angiotensin converting enzyme (ACE) level may be elevated in up to 65% of patients, usually in the setting of active disease, but it is insensitive [6]. The Kveim test, which utilizes intradermal injection of a single antigen from a spleen removed in 1981, is very sensitive [20], but it is not readily available.

Bronchoalveolar lavage may reveal a lymphocytosis with a high CD4:CD8 ratio, but this finding is also insensitive and non-specific [36]. Gallium-67 scanning is cumbersome and findings are nonspecific, but it may be useful in detecting a site for biopsy [6, 36]. Whole-body flourodeoxyglucose positron emission tomography may be more sensitive and useful in identifying occult granulomas, but a positive finding by itself is not diagnostic and such scanning is expensive and not widely available. Its utility has not been compared against Gallium-67 imaging [12].

Ultimately, a tissue diagnosis is required in the vast majority of patients. Common methods of biopsy would include transbronchial or endobronchial biopsies, lymph node biopsy, as well as biopsy of skin lesions [37]. Peripheral nerve, muscle, and sometimes CNS tissues are biopsied in patients with isolated neurosarcoidosis. Intraepidermal nerve fiber density analysis with punch skin biopsy may reveal reduced density scores [28], consistent with a small fiber neuropathy. Non-caseating granulomas are not expected on normal appearing skin of biopsy sites for nerve fiber density analysis.

In patients already diagnosed with sarcoidosis, additional recommended evaluations include pulmonary function testing, complete blood count, serum chemistries with calcium, liver enzymes and renal function tests, urinalysis, an electrocardiogram, and tuberculin skin test [1, 36].

Neurosarcoidosis

Computed tomographic (CT) scans may show hydrocephalus, intracranial calcification, and enhancing nodules, [4] but they are less sensitive than MRI. MRI is very sensitive in detecting abnormalities in neurosarcoidosis, [20, 38-40] but it is nonspecific. It can detect evidence of meningeal inflammation, diencephalic involvement and parenchymal lesions in about 40%. Non-specific white matter changes are most common. In particular, periventricular T2-hyperintense lesions are often seen [11, 41, 42] and may mimic multiple sclerosis, also affecting the corpus callosum [43]. Optic nerve enlargement and enhancement also occurs in some [20]. In contrast to multiple sclerosis, linear enhancement along Virchow-Robin spaces may be more typical of neurosarcoidosis and stem from granulomatous vasculitis; nonspecific leptomeningeal and parenchymal enhancement occurred in 19% in one series [11]. In addition, parenchymal or meningeal enhancement may last longer (more than a few weeks) with neurosarcoidosis than with multiple sclerosis [20].

In patients with leptomeningeal involvement, the CSF findings are as follows: 40-70% exhibit pleocytosis; 40-73% has an elevated protein; and 10-20% has a low glucose [4, 5, 20, 44]. The mean number of CSF lymphocytes reported in the patients with pleocytosis in one series was 78, with a range from 8-300 per mm3 [5]. Oligoclonal bands and an elevated IgG index are encountered in up to 53% [20, 45]. The oligoclonal bands are usually accompanied by an elevation in protein [9]. Cultures for bacteria, fungi, and mycobacteria must be sterile, and cytology should be negative for neoplasm. CSF is often normal with isolated facial palsies [8]. From subsets of retrospectively studied patients, it has been found that CSF ACE levels are elevated in 24-55%, and thus insensitive, but they may be highly specific (94-95%) [46].

Electroencephalography may reveal focal or generalized slowing, but it is usually normal unless patients are having seizures [4]. Electrodiagnostic testing may be useful in patients with suspected neuropathy or myopathy.

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PATHOGENESIS

The cause remains uncertain. Observations of outbreaks and clustering of disease suggests a common environmental exposure, infectious agent, or genetic predisposition in some [2, 47, 48]. A single gene has not been identified as being causative. However, familial clustering in 19% of affected African-American families and in 5% of Caucasian families as well as associations with class I HLA-A1 and -B8 and class II HLA-DR 3 in Caucasians [49, 50] and HLA-DRB1 and DQB1 [2] suggest a genetic predisposition. There may also be a role for vitamin D deficiency, which is more prevalent in African-Americans [51].

As mentioned, the histopathologic lesion is the non-caseating granuloma. It is thought that granuloma formation begins with exposure to an antigen and is followed by T-cell and macrophage activation via a classic major histocompatibility complex (MHC) II-mediated pathway. It is further mediated by T-helper cells and activated T cells. Macrophages and dendritic cells release cytokines and chemokines, including interferon γ, tumor necrosis factor ∝, and interleukin (IL) including IL-2, IL-6, IL-12, IL-15, IL-16, and IL-18. Other cells are then recruited to the site of granuloma formation and become activated [51].

Also in favor of a driving T-helper response, there is evidence of decreased expression of natural killer cell inhibitory receptors on CD8+ T cells. This scenario possibly causes impairment in controlling the cell-mediated response [51]. Following accumulation of mononuclear inflammatory cells in the affected tissues, macrophages tightly aggregate and differentiate into epithelioid histiocytes and multinucleated giant cells. CD-4 and CD-8+ lymphocytes and some B cells form a rim around the granuloma. Subsequently, the inflammatory nodule becomes encased in fibroblasts, mast cells, collagen fibers, and proteoglycans, forming a destructive region of fibrosis through an incompletely understood process.

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TREATMENT

Corticosteroids

In all forms of neurosarcoidosis, corticosteroids are typically the first line of treatment. There are no clinical trials that dictate specific doses or dosing schedules. Typically oral prednisone is dosed at 40-80 mg per day. In more severe CNS disease, intravenous corticosteroids may be administered. Benefits vary from substantial improvement – about half – to no benefit [5], and some patients succumb despite treatment [10]. Results of corticosteroid therapy from large series are summarized below.

In the study by Lower, et al., 61 patients with neurosarcoidosis received corticosteroids. Those with isolated facial nerve palsies had an excellent response. Forty-eight others were treated with corticosteroids alone. Four died, but one death was unrelated to neurosarcoidosis. Thirty went on to have subsequent therapies and fourteen (29%) were treated long-term with prednisone only [3]. Chapelon, et al., treated 31 patients with corticosteroids [6]. Ten patients completely recovered. Three required subsequent therapies with chlorambucil, methotrexate, or cyclosporine, and recovered fully. Ten patients treated with corticosteroids alone improved but had persistent deficits.

Of the 28 patients with neurosarcoidosis reported by Wiederholt, et al., corticosteroids were used in nine. One died; four improved or recovered; and four were unchanged. Of note, 14 patients were not treated with immunosuppressive agents, and two received only anticonvulsants. Of these, at least ten improved or recovered [7]. In the series of 33 patients reported by Stern, et al., 25 were known to receive prednisone. Of these, there was improvement or resolution in at least 19. One died. The response was unknown in several, and there was no improvement in at least one other. Some of the patients who benefited also had persistent deficits [4].

Zajicek et al. reported 48 patients treated for at least 18 months. Thirty-four received oral corticosteroids with or without IV methylprednisolone boluses. Twenty-nine percent improved or stabilized, while 71% worsened and then received other immunotherapy or cranial irradiation [20]. Joseph et al. treated 30 patients in a similar fashion with similar outcomes [9].

Pawate et al. treated 38 patients with either oral or IV corticosteroids followed by maintenance oral steroids. Eleven received corticosteroids alone, and the rest were offered other immunotherapies. In general, patients with bilateral optic neuropathies and those with widespread parenchymal or meningeal disease did poorly [11]. Scott et al. treated 19 patients with corticosteroids alone (60-80 mg/day). Eight of 19 were successfully weaned off in 2-3 years. Overall, 35% improved; 55% stabilized; and 10% worsened. Patients with more severe CNS involvement were treated with combination therapies (discussed in next section) [52].

The precise mechanisms of action of corticosteroids in treating neurosarcoidosis are not known, but presumably benefit is due to the known anti-inflammatory and immuno-modulating effects. These include interference with the function of leukocytes and fibroblasts, inhibiting access of leukocytes to inflammatory sites, and suppressing the myriad of humoral factors such as cytokine release involved in granuloma formation [53]. In particular, glucocorticoids antagonize the differentiation of macrophages and inhibit their functions. They block the release of cytokines such as IL-1, IL-6, and tumor necrosis factor ∝ [53]. Corticosteroids also inhibit T cell activation by binding to T cell receptors. In contrast, the immunosuppressive effects of corticosteroids affect B cells less, though they do reduce serum immunoglobulin levels, at least transiently.

Patients who are treated with corticosteroids should receive appropriate prophylaxis for osteoporosis and be monitored for hyperglycemia, cataract formation, psychiatric and infectious complications. They should eventually be treated with the lowest dose required to maintain benefit. Morning dosing should be used. Patients also need to be aware of the risk of developing cosmetic changes. Adrenal insufficiency may occur, especially if the dose is rapidly tapered or abruptly discontinued. Patients may also be at increased risk for peptic ulcer diseases, especially if they receive concomitant non-steroidal anti-inflammatory drugs [53].

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SECOND LINE TREATMENT OPTIONS

"Steroid-sparing" Immunosuppressive Drugs

Second-line treatments may include methotrexate, cyclosporine, azathioprine, cyclophosphamide, chlorambucil, chloroquines, and mycophenolate. Stern, et al., treated six patients with cyclosporine in a 12-month open label trial. They were able to lower baseline corticosteroid doses by 30-58%. It appeared that cyclosporine was beneficial in some patients, but others worsened despite a combination of cyclosporine and corticosteroid therapy [54]. Cyclosporine inhibits the CD4 cell immune response and IL-2 release. It can be started at 4 mg/kg/day in divided doses and requires careful monitoring of trough levels and for adverse events including hypertension, renal failure, hypomagnesemia, and neurotoxicity.

In the series by Lower, et al., methotrexate, a dihydrofolate reductase inhibiter, successfully treated 61% (17 of 28) at doses of 5-15 mg/week. Liver biopsies, performed in 13 patients, did not reveal hepatotoxic changes. One patient developed neutropenia, and one had refractory nausea. Patients treated with methotrexate also require monitoring for pulmonary and renal toxicity [3]. Administration of folinic acid may reduce toxicity. Intermittent IV cyclophosphamide (starting at 500-700 mg every two weeks) "controlled the disease" in 9 of 10 treated patients, and it was well-tolerated. Most were treated for six or more months and had been previously treated with prednisone and methotrexate. Some remained on low-dose prednisone [3]. Cyclophosphamide is a potent immunosuppressant alkylating agent that cross-links DNA and RNA inhibiting protein synthesis. It requires careful monitoring for infection, hemorrhagic cystitis, as well as bone marrow and other toxicities.

Agbogu, et al., reported their retrospective experience with various medications for corticosteroid-refractory neurosarcoidosis. Treatments included azathioprine (50-200 mg/day in 12 patients), cyclosporine (50-980 mg/day in 15 patients), cyclophosphamide (200 mg/day in three patients), chlorambucil (8-16 mg/day in two patients), and methotrexate (10-20 mg/week in two patients). Of 26 patients, six (23%) had improvement while receiving alternative medications, and 35% were stabilized. Fifteen percent did not respond to alternative therapies. Some patients took different drugs alone or in combination. Specific treatment recommendations cannot be made based on this study, but the authors did conclude that the choice of alternative therapy should be determined "in part, by its potential adverse effects" [55]. In the study, two patients treated with azathioprine developed neutropenia and one developed abnormal liver function tests. None had pancreatitis. Allergic reactions, which occur in 10% of patients treated with azathioprine, were not reported. One developed neutropenia with cyclophosphamide. Two developed renal dysfunction on cyclosporine. The only patient treated with chlorambucil developed leukopenia.

Scott et al. treated 26 patients with perceived severe CNS involvement with corticosteroids and steroid-sparing agents including methotrexate (n=18, 7.5-15 mg weekly), azathioprine (n=9, 150-200 mg daily), or monthly cyclophosphamide (n=9, 600-800 mg/m2 for 3-6 months). Overall, 18 (69%) improved; 4 (15%) stabilized; and 4 (15%) worsened including two deaths in patients with chronic meningitis [52].

Sharma performed a retrospective study in 12 patients with neurosarcoidosis treated with chloroquine or hydroxychloroquine for 6 to 21 months. These antimalarial drugs are used for treatment of connective tissue diseases and have an uncertain mechanism of action in sarcoidosis. Hydroxychloroquine prevents insulin degradation in the liver and suppresses gluconeogenesis, increasing peripheral utilization of glucose; so, it is particularly attractive to use in patients also treated with corticosteroids. Sharma reported that 10 of 12 patients had either stabilization or improvement in neurologic symptoms. These patients had previously failed to respond to corticosteroids or developed corticosteroid side-effects [56]. Patients must be monitored for ocular toxicity, but such effects were not observed.

Biological Agents

Based on the presence of increased cytokine activity in the inflammatory response, especially increased levels of tumor necrosis factor (TNF), treatment with TNF ∝ blockers has been utilized. Eighteen patients with ocular sarcoidosis were treated with either etanercept or placebo in a double-blind, randomized trial. No benefit was seen in this small study, and there were no severe adverse events [57].

In contrast, the results of an open label study using infliximab and mycophenolate mofetil were promising but not definitive. Patients with CNS sarcoidosis who had "failed" treatment with steroids were given infliximab, and six of seven were also treated with mycophenolate mofetil. There was no placebo group. All patients reported significant benefit, both symptomatically and with regard to reversal of neurological deficits or control of seizure activity. There was also universal benefit as detected by MRI lesion size or gadolinium enhancement. There were no serious adverse events. The TNF ∝ neutralizer was coupled with mycophenolate, based on standard practice which postulates that the combination of infliximab with an oral immunosuppressive agent prevents otherwise expected development of human anti-chimeric antibodies [58]. Hopefully, this treatment combination will be subjected to a controlled prospective study.

Infliximab treatment was also associated with improvement in small-fiber neuropathy with autonomic involvement in one patient [59]. Intravenous immunoglobulin was also thought to be beneficial in a single patient with sensorimotor axonal polyneuropathy from sarcoidosis [60].

Cranial Irradiation

There have been a few anecdotal reports of benefit from cranial irradiation [40]. Of the two patients reported by Chapelon, et al., one had chronic meningitis, psychiatric disturbances and seizures [6]. He was unresponsive to corticosteroids and methotrexate, but recovered after 200 rads. The other had hemiparesis, an extrapyramidal syndrome, and severe psychiatric features unresponsive to steroids, but improved dramatically after 6000 rads. There was also dramatic improvement in CT scan findings [6]. Radiotherapy (1.3-3.6 Gy/day for 3-24 weeks) was also said to be beneficial in one of three patients treated by Agbogu, et al. [55].

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Articles from Current Neuropharmacology are provided here courtesy of Bentham Science Publishers

Original Investigation

June 2014

The Role of Total Parotidectomy for Metastatic Cutaneous Squamous Cell Carcinoma and Malignant Melanoma

Joshua J. Thom, MD¹; Eric J. Moore, MD¹; Daniel L. Price, MD¹; et alJan L. Kasperbauer, MD¹; Sidney J. Starkman, MD²; Kerry D. Olsen, MD¹

Author Affiliations Article Information

JAMA Otolaryngol Head Neck Surg. 2014;140(6):548-554. doi:10.1001/jamaoto.2014.352

Abstract

Importance  Metastatic cutaneous malignancies of the head and neck, including cutaneous squamous cell carcinoma (cSCC) and malignant melanoma (MM), are aggressive cancers frequently involving the parotid-area lymph nodes (LNs). In such cases, controversy exists about the extent of surgical resection, with many centers choosing not to remove the parotid deep lobe LNs.

Objectives  To determine patterns of intraparotid and neck metastasis, to identify risk factors, and to report outcomes in patients with parotid superficial lobe LN metastasis from cSCC and MM.

Design, Setting, and Participants  We retrospectively reviewed 65 adults from Mayo Clinic in Minnesota who underwent total parotidectomy and neck dissection for metastatic cSCC (n = 42) or MM (n = 23) involving the parotid superficial lobe.

Interventions  Total parotidectomy and neck dissection.

Main Outcomes and Measures  The presence and number of parotid deep lobe and neck LNs involved with metastatic disease were assessed. Risk factors associated with metastatic spread to the parotid deep lobe were identified, and patient outcomes are reported.

Results  Eleven of 42 patients with cSCC (26%) and 3 of 23 patients with MM (13%) metastatic to the parotid superficial lobe also had parotid deep lobe metastasis. Thirteen of 42 patients with cSCC (31%) and 6 of 23 patients with MM (26%) had positive cervical LN metastasis. Among all patients, 22% (14 of 65) had metastasis to the parotid deep lobe, and 29% (19 of 65) had metastasis to cervical LNs. By univariate analysis, neck metastasis and N2 neck disease were risk factors for metastatic cSCC spread to the parotid deep lobe. Parotid-area local control was excellent in patients with metastatic cSCC (93% [39 of 42]) and MM (100% [23 of 23]). Long-term survival remains poor because distant metastases are common.

Conclusions and Relevance  Metastatic cSCC and MM to the parotid superficial lobe also involve LNs in the parotid deep lobe and neck in a significant and almost equal number of patients. Parotid deep lobe metastasis from cutaneous malignancies portends a poor prognosis. Therefore, patients with superficial parotid gland metastasis should be considered for management with not only neck dissection and adjuvant therapy but also deep lobe parotidectomy.

The embryological development of the parotid gland and its relationship with the facial nerve (FN) pose important considerations and challenges in parotid surgery. During development, the FN migrates anteriorly from the stylomastoid foramen and becomes surrounded by the parotid gland. The separation of the parotid gland into superficial and deep lobes by the FN is a surgical division and not an embryological or fascial one.¹ Therefore, no barrier exists to malignant spread between the superficial and deep lobes directly or via lymphatic channels traversing the gland. In addition, as the parotid gland becomes encapsulated by fascia, a variable but significant number of lymph nodes (LNs) are incorporated into the gland superficial and deep to the FN.² Studies^3-5 have reported mean totals of 6 to 9 (range, 2-22) parotid superficial lobe LNs and 1 to 2 (range, 0-9) parotid deep lobe LNs.

The parotid-area LNs are a common location for the development of metastasis from high-risk cutaneous malignancies of the head and neck originating from the frontotemporal scalp, face, and ear.^6-8 Patients with palpable or confirmed parotid-area LN metastasis from cutaneous squamous cell carcinoma (cSCC) or malignant melanoma (MM) generally undergo a superficial parotidectomy and often an accompanied neck dissection. Controversy exists about the need to remove the parotid gland tissue deep to the FN. Despite aggressive multimodality treatment, including surgery and irradiation with or without chemotherapy, patients with metastatic cSCC or MM to the parotid gland have high rates of parotid-area local recurrence, distant metastasis, and poor outcomes.^9-14 The aim of this study was to determine the presence and quantity of parotid deep lobe LNs and ipsilateral cervical LNs involved with metastatic cSCC or MM when metastasis has developed in the parotid superficial lobe LNs. Risk factors associated with metastatic spread of cSCC and MM to the parotid deep lobe and patient outcomes are discussed.

Methods

Institutional review board approval was obtained from Mayo Clinic in Minnesota. Written informed consent was obtained from all participants through Mayo Clinic's tumor registry. A retrospective review from January 1, 1994, through December 31, 2010, was performed among all adult patients undergoing a superficial parotidectomy with concomitant deep lobe parotidectomy and neck dissection for cSCC or MM metastatic to the parotid superficial lobe LNs at a tertiary referral center. An en bloc deep lobe parotidectomy is defined as removal of all remaining parotid gland after superficial parotidectomy and includes the tissue deep to the FN.^1,2 The FN was preserved in most cases (total parotidectomy with FN preservation). However, any FN branches directly invaded by tumor were resected with negative margins using frozen section pathological techniques. Branches not directly involved by tumor were preserved (total parotidectomy with partial FN sacrifice). Last, if the main trunk of the FN was invaded by tumor or if no FN branches could be spared because of tumor involvement, the main trunk was sacrificed (total parotidectomy with complete FN sacrifice). The FN function was assessed in patients who underwent FN preservation procedures, and the weakest scores documented within the first month following surgery and at 1 year after surgery were recorded using the grading system by House and Brackmann.¹⁵ Pathology reports were reviewed, and patients were included in the study if the final pathological examination demonstrated parotidectomy specimens positive for metastatic cSCC or MM. The total numbers of LNs involved by metastatic disease in each lobe of the parotid gland, superficial and deep, and in the neck dissection were recorded. Patients were excluded if the cutaneous tumors had directly invaded the parotid gland and did not represent metastatic disease or if a massive metastatic tumor focus involved both the parotid superficial and deep lobes such that the origin within the parotid gland could not be determined. Also, any patient in whom a total parotidectomy or neck dissection was not performed was excluded.

Standard statistical analysis was used to summarize the data. Comparisons of cSCC and MM mean numbers of LNs in parotidectomy specimens were made using unpaired t test. Risk factors for metastatic spread of cSCC to parotid deep lobe LNs were identified by univariate analysis. Associations were summarized using odds ratios and corresponding 95% CIs calculated with the parameters estimated in the models. The following outcomes were estimated using the Kaplan-Meier method: disease-free survival (survival free of any recurrence), disease-specific survival (survival from disease), overall survival (survival from all causes), local control (survival free of any parotid-area recurrence), locoregional control (survival free of any parotid-area and neck recurrence), and distant control (survival free of any distant metastasis). Risk factors for poor outcomes were identified using hazard ratios (HRs) and corresponding 95% CIs calculated with the parameters estimated in the models. P ≤ .05 was considered statistically significant. Analyses were performed using a software program (JMP, version 9.0; SAS Institute Inc).

Results

Patients With cSCC and MM, Tumor Characteristics, and Treatments

Sixty-five adults were included who underwent deep lobe parotidectomy and ipsilateral neck dissection following superficial parotidectomy with frozen section pathological confirmation of metastatic cSCC (n = 42) or MM (n = 23) to the parotid superficial lobe LNs. Patient demographics and treatments are listed in Table 1. Sixty patients were male, including 38 of 42 patients with cSCC (90%) and 22 of 23 patients with MM (96%). The mean ages at the time of parotidectomy were 74.7 and 67.5 years for patients with cSCC and MM, respectively. The median follow-up times were 36.4 and 30.6 months for patients with cSCC and MM, respectively. Most patients underwent total parotidectomy with FN preservation, including 32 patients with cSCC (76%) and 21 patients with MM (91%). In patients undergoing total parotidectomy with FN preservation, the median early postoperative House-Brackmann score was 3 (range, 1-6). At 1 year after surgery, the median House-Brackmann score was 1 (range, 1-3). The remaining patients had direct FN invasion with metastatic tumor requiring partial or total FN sacrifice. Most patients also underwent adjuvant therapy in the form of irradiation or chemoradiotherapy, including 36 patients with cSCC (86%) and 14 patients with MM (61%).

Tumor, staging, and pathological characteristics are listed in Table 2. Most cutaneous primaries originated from the face, scalp, or ear. All patients had metastatic spread to the parotid superficial lobe LNs. Eleven of 42 patients with cSCC (26%) and 3 of 23 patients with MM (13%) had separate metastasis to both the superficial and deep parotid lobe LNs. No cases were observed of isolated parotid deep lobe metastasis in which the superficial lobe was absent of tumor. Thirteen patients with cSCC (31%) and 6 patients with MM (26%) had positive cervical LN metastasis following neck dissection. Pathological staging was performed, including the parotid staging system (P stage) by O'Brien et al¹² and the seventh edition of the American Joint Committee on Cancer Cancer Staging Manual.¹⁶

The means and ranges of positive and total LNs from each parotid lobe specimen are listed in Table 3. When comparing metastatic cSCC and MM, similar means of positive and total LNs were observed in the parotid superficial and deep lobes. The cSCC and MM superficial lobe specimens contained 1.7 and 1.8 mean positive LNs (P = .76) out of 5.9 and 6.3 mean total LNs (P = .75), respectively. The cSCC and MM deep lobe specimens contained 0.4 and 0.4 mean positive LNs (P = .76) out of 1.8 and 2.6 mean total LNs (P = .14), respectively. The total numbers and ranges of LNs in the parotid superficial and deep lobes are similar to those reported previously.^3-5

Risk Factors for cSCC and Patient Outcomes

Features associated with metastatic spread of cSCC to the parotid deep lobe were identified and are listed in Table 4. By univariate analysis, risk factors that reached statistical significance included positive neck metastasis and N2 neck disease. Sex, age, FN invasion, extracapsular spread, location of cutaneous primary, and size of parotid superficial lobe metastasis did not correlate with an increased risk of parotid deep lobe metastasis.

Three of 42 patients with cSCC (7%) developed local recurrence within or adjacent to the parotid bed following total parotidectomy, neck dissection, and postoperative irradiation. Two patients developed recurrence adjacent to the parotid bed, one within the masseter muscle and the other along the skull base adjacent to the parapharyngeal space. One patient developed intradermal recurrence in the skin overlying the parotid bed. The cSCC 5-year local control rates in patients without parotid deep lobe metastasis and with parotid deep lobe metastasis were 92% (24 of 26) and 89% (8 of 9), respectively (P = .69) (Figure 1A). Two patients with cSCC developed regional recurrence in the neck following total parotidectomy, neck dissection, and adjuvant irradiation. The cSCC 5-year locoregional control rates in patients without parotid deep lobe metastasis and with parotid deep lobe metastasis were 88% (23 of 26) and 78% (7 of 9), respectively (P = .35) (Figure 1B). Nine of 42 patients with cSCC (21%) developed distant metastasis. Freedom from distant metastasis at 5 years was significantly improved in patients who did not have parotid deep lobe metastasis (76%) compared with those who had parotid deep lobe metastasis (36%]) (P < .01)(Figure 1C). Patients who had parotid deep lobe metastasis also had statistically significant decreases in disease-free survival (P < .01), disease-specific survival (P < .02), and overall survival (P < .01) compared with patients who did not have deep lobe metastasis (Figure 2).

In the final model, cSCC parotid deep lobe metastasis was a significant risk factor for several variables. It was a significant predictor of distant metastatic disease (HR, 5.35; 95% CI, 1.30-20.65; P = .02), disease recurrence (HR, 3.49; 95% CI, 1.15-9.85; P = .03), death from disease (HR, 3.73; 95% CI, 1.07-12.07; P = .04), and death from all causes (HR, 2.89; 95% CI, 1.19-6.69; P = .02).

Risk Factors for MM and Patient Outcomes

For metastatic MM, 0 of 23 patients (0%) developed parotid-area local recurrence. However, 6 of 23 patients (26%) developed regional recurrence in the neck. In addition, 11 of 23 patients (48%) developed distant metastatic disease. The 3 patients with deep lobe metastasis all had regional recurrence in the neck within 10 months following surgery, and deep lobe metastasis was a significant risk factor for locoregional failure (P < .001). One patient with parotid deep lobe metastasis developed distant metastasis to the liver and adrenal gland. Two of 3 patients with parotid deep lobe metastasis died of their disease, while the third was alive with disease at the last follow-up date. Analysis of possible risk factors for metastasis to the parotid deep lobe was not performed because there were only 3 such cases.

Discussion

Metastatic cutaneous malignancies of the head and neck, including cSCC and MM, are aggressive cancers frequently involving the parotid-area LNs.^6-8 In such cases, controversy exists about the extent of surgical resection. Many centers routinely perform superficial parotidectomy and neck dissection with postoperative irradiation in patients with metastatic cSCC or MM to the parotid superficial lobe. Some surgeons may not remove the parotid deep lobe because few LNs lie in the deep lobe and irradiation can be used to treat any deep lobe metastasis. This argument to leave the parotid deep lobe LNs at the time of surgery is in contrast to the general practice to perform neck dissection for cervical LN removal when there is metastasis to the superficial lobe of the parotid gland. At our institution, total parotidectomy with FN preservation and neck dissection is routinely performed at the same operation for patients with metastasis to the parotid superficial lobe confirmed by frozen section pathological techniques.

Approximately 20% to 25% of the parotid gland, including LNs, is contained within the parotid deep lobe.^3-5 Without a true barrier to metastatic spread from the parotid superficial lobe to the deep lobe, one may expect a 20% to 25% rate of metastasis to the deep lobe LNs when the superficial lobe LNs are involved with tumor. In this series, the finding of parotid deep lobe metastasis was consistent with the approximate proportion of deep lobe LNs, namely, 26% (11 of 42) for patients with cSCC and 13% (3 of 23) for patients with MM (22% [14 of 65] for all patients). To our knowledge, this information has not previously been reported. Most patients with tumor involving the parotid deep lobe were found to have separate foci of tumor metastasis within both the superficial and deep lobes. Our findings show that some patients with cutaneous malignancies metastatic to the parotid superficial lobe LNs will have occult metastasis in the deep lobe. No patients were found to have isolated parotid deep lobe metastasis without also having superficial lobe metastasis. Therefore, the idea of skip metastasis directly to the deep lobe and not involving the superficial lobe is unlikely or rare with cutaneous malignancies.

Patients with metastatic cSCC and MM to the parotid superficial lobe LNs had similar rates of metastatic spread to cervical LNs, namely, 31% (13 of 42) and 26% (6 of 23), respectively (29% [19 of 65] for all patients). This finding is consistent with prior studies.^{9,10,12,13,17-19} Our results showed a similar finding of metastasis to the parotid deep lobe LNs, with an overall rate of 22% (14 of 65). In addition, parotid deep lobe metastasis and cervical metastasis often occurred in the same patients. Six of 11 patients with cSCC metastasis and 2 of 3 patients with MM metastasis to the parotid deep lobe had cervical LN metastasis. The data from this series suggest that the pattern of spread for many metastatic cutaneous malignancies of the head and neck is from the first LN echelon within the parotid superficial lobe to second LN echelons within the parotid deep lobe and neck. Metastatic spread to the parotid deep lobe and neck occurred at similar frequencies and often occurred together, with both representing a more advanced and aggressive cancer. As such, we recommend considering total parotidectomy with ipsilateral neck dissection in patients with parotid superficial lobe LN metastasis.

The treatment approach described has allowed for excellent parotid-area local control, 93% (39 of 42) for patients with cSCC and 100% for patients with MM. Ideally, a comparison group of patients with metastatic cSCC or MM to the parotid superficial lobe who did not receive a parotid deep lobe removal would be used to analyze the benefit of deep lobe parotidectomy. Unfortunately, a comparison group was not available at our institution. However, our low parotid-area recurrence rate is better than the rates among other studies^{9,11,12,14,19,20} in the literature (range, 11%-44%). The low local recurrence rate in this series is likely attributable to the routine resection of the entire parotid gland, both superficial and deep lobes, in patients with parotid superficial lobe LN metastasis. The parotid deep lobe can be safely removed en bloc with FN preservation as has been described in earlier studies.^1,2 In addition, the long-term FN outcomes are not significantly different compared with superficial parotidectomy, with a median House-Brackmann score of 1 at 1 year following surgery. Most patients with recurrent metastatic cSCC and MM had distant failure (21% [9 of 42] and 48% [11 of 23], respectively). In patients with cSCC, parotid deep lobe metastasis was a significant risk factor for distant metastasis and poorer survival outcomes. This information is valuable in counseling patients and physicians on the prognosis of parotid deep lobe metastasis. Despite poor distant control and overall outcomes, locoregional control is of importance in slowing disease progression and improving symptoms. Therefore, these patients should be treated with multimodality therapy, including appropriate extent of surgical resection.

Conclusions

In summary, surgical removal of the parotid deep lobe should be considered when superficial parotidectomy specimens contain metastatic cSCC or MM. The frequency of parotid deep lobe metastasis almost approaches the frequency of cervical metastasis. Removing the parotid deep lobe and treating with adjuvant therapy leads to a lower rate of parotid-area local recurrence compared with other series in which the parotid deep lobe is not routinely removed but rather the parotid superficial lobe is routinely removed and then treated with adjuvant therapy.^{9,10,12,14,20} The presence of parotid deep lobe metastasis remains a harbinger of increased risk of distant disease and poor outcomes, and this new information is useful in treatment planning and in counseling patients and physicians.

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Article Information

Submitted for Publication: December 19, 2013; final revision received February 11, 2014; accepted February 23, 2014.

Corresponding Author: Kerry D. Olsen, MD, Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic Medical School, 200 First St SW, Rochester, MN 55905 (olsen.kerry@mayo.edu).

Published Online: April 10, 2014. doi:10.1001/jamaoto.2014.352.

Author Contributions: Drs Thom and Starkman had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Thom, Moore, Price, Olsen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Thom, Moore, Price, Olsen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Thom, Starkman.

Study supervision: Thom, Moore, Price, Olsen.

Conflict of Interest Disclosures: None reported.

Previous Presentation: This study was presented as an oral presentation at the Eighth International Conference on Head and Neck Cancer; July 23, 2012; Toronto, Ontario, Canada.

References

1.

Olsen  KD, Moore  EJ.  Deep lobe parotidectomy: clinical rationale in the management of primary and metastatic cancer [published online July 6, 2013].  Eur Arch Otorhinolaryngol. doi:10.1007/s00405-013-2616-8.PubMedGoogle Scholar

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Moore  EJ, Olsen  KD. Total parotidectomy. In: Myers  EN, Ferris  RL, eds.  Salivary Gland Disorders. New York, NY: Springer; 2007:247-266.

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Pisani  P, Ramponi  A, Pia  F.  The deep parotid lymph nodes: an anatomical and oncological study.  J Laryngol Otol. 1996;110(2):148-150.PubMedGoogle ScholarCrossref

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Garatea-Crelgo  J, Gay-Escoda  C, Bermejo  B, Buenechea-Imaz  R.  Morphological study of the parotid lymph nodes.  J Craniomaxillofac Surg. 1993;21(5):207-209.PubMedGoogle ScholarCrossref

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McKean  ME, Lee  K, McGregor  IA.  The distribution of lymph nodes in and around the parotid gland: an anatomical study.  Br J Plast Surg. 1985;38(1):1-5.PubMedGoogle ScholarCrossref

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Vauterin  TJ, Veness  MJ, Morgan  GJ, Poulsen  MG, O'Brien  CJ.  Patterns of lymph node spread of cutaneous squamous cell carcinoma of the head and neck.  Head Neck. 2006;28(9):785-791.PubMedGoogle ScholarCrossref

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Moore  BA, Weber  RS, Prieto  V,  et al.  Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck.  Laryngoscope. 2005;115(9):1561-1567.PubMedGoogle ScholarCrossref

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Pathak  I, O'Brien  CJ, Petersen-Schaeffer  K,  et al.  Do nodal metastases from cutaneous melanoma of the head and neck follow a clinically predictable pattern?  Head Neck. 2001;23(9):785-790.PubMedGoogle ScholarCrossref

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Andruchow  JL, Veness  MJ, Morgan  GJ,  et al.  Implications for clinical staging of metastatic cutaneous squamous carcinoma of the head and neck based on a multicenter study of treatment outcomes.  Cancer. 2006;106(5):1078-1083.PubMedGoogle ScholarCrossref

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Audet  N, Palme  CE, Gullane  PJ,  et al.  Cutaneous metastatic squamous cell carcinoma to the parotid gland: analysis and outcome.  Head Neck. 2004;26(8):727-732.PubMedGoogle ScholarCrossref

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Hinerman  RW, Indelicato  DJ, Amdur  RJ,  et al.  Cutaneous squamous cell carcinoma metastatic to parotid-area lymph nodes.  Laryngoscope. 2008;118(11):1989-1996.PubMedGoogle ScholarCrossref

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O'Brien  CJ, McNeil  EB, McMahon  JD, Pathak  I, Lauer  CS, Jackson  MA.  Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland.  Head Neck. 2002;24(5):417-422.PubMedGoogle ScholarCrossref

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O'Hara  J, Ferlito  A, Takes  RP,  et al.  Cutaneous squamous cell carcinoma of the head and neck metastasizing to the parotid gland: a review of current recommendations.  Head Neck. 2011;33(12):1789-1795.PubMedGoogle ScholarCrossref

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Palme  CE, O'Brien  CJ, Veness  MJ, McNeil  EB, Bron  LP, Morgan  GJ.  Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma.  Arch Otolaryngol Head Neck Surg. 2003;129(7):750-753.ArticlePubMedGoogle ScholarCrossref

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House  JW, Brackmann  DE.  Facial nerve grading system.  Otolaryngol Head Neck Surg. 1985;93(2):146-147.PubMedGoogle Scholar

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Edge  S, Carducci  M.  AJCC Cancer Staging Manual.7th ed. New York, NY: Springer; 2010.

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O'Brien  CJ, McNeil  EB, McMahon  JD, Pathak  I, Lauer  CS.  Incidence of cervical node involvement in metastatic cutaneous malignancy involving the parotid gland.  Head Neck. 2001;23(9):744-748.PubMedGoogle ScholarCrossref

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Ch'ng  S, Maitra  A, Lea  R, Brasch  H, Tan  ST.  Parotid metastasis: an independent prognostic factor for head and neck cutaneous squamous cell carcinoma.  J Plast Reconstr Aesthet Surg. 2006;59(12):1288-1293.PubMedGoogle ScholarCrossref

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Khurana  VG, Mentis  DH, O'Brien  CJ, Hurst  TL, Stevens  GN, Packham  NA.  Parotid and neck metastases from cutaneous squamous cell carcinoma of the head and neck.  Am J Surg. 1995;170(5):446-450.PubMedGoogle ScholarCrossref

Traumatic neuroma

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Traumatic neuroma
Specialty	Neurology

A traumatic neuroma (also known as "amputation neuroma" or "pseudoneuroma"^[1]) is a type of neuroma which results from trauma to a nerve, usually during a surgical procedure. The most common oral locations are on the tongue and near the mental foramen of the mouth.^[2] They are relatively rare on the head and neck.^[3]

See also[edit]

• List of cutaneous conditions

References[edit]

1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
2. ^ Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001.
3. ^ Lee EJ, Calcaterra TC, Zuckerbraun L (1998). "Traumatic neuromas of the head and neck". Ear, nose, & throat journal. 77 (8): 670–4, 676. PMID 9745184.

External links[edit]

Classification	D ICD-10: T87.3 ICD-9-CM: 950-957 ICD-O: M9570/0

hide v t e Neurotrauma (S06, Sx4, T09.3–4, 850–854, 950–957)
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Spinal cord injury	Anterior spinal artery syndrome Brown-Séquard syndrome Cauda equina syndrome Central cord syndrome Paraplegia Posterior cord syndrome Spinal cord injury without radiographic abnormality Tetraplegia (Quadriplegia)
Peripheral nerves	Nerve injury  Peripheral nerve injury classification Wallerian degeneration Injury of accessory nerve Brachial plexus injury Traumatic neuroma