Man presents with right-sided headaches, ocular pain and vesicular rash
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A 64-year-old man presented to the emergency department at Lahey Hospital with a 6-day history of right-sided headaches, right ocular pain and vesicular rash.
He had a medical history of psoriatic arthritis on Humira (adalimumab, AbbVie), diabetes type 2 with peripheral neuropathy and left toe amputation, cirrhosis secondary to hepatitis C, lumbar disc degeneration with multiple surgeries, obesity, hyperlipidemia, and polysubstance abuse and active tobacco use (10-pack years). He attributed the pain to a recent decrease in oxycodone for his chronic back pain, which subjectively improved with an increase in prednisone for arthritis. He was seen 3 days before his visit to the emergency department with an unremarkable exam. In addition, he was hospitalized 1 month prior due to non-ST-elevation myocardial infarction and influenza infection. He denied a history of trauma or previous sinonasal or orbital surgery.
Source: William Binotti, MD, and Sarkis H. Soukiasian, MD
Examination
The patient had a vesicular rash on the right side of his forehead and brow, partially involving the periocular region (Figure 1). Uncorrected visual acuity was 20/60 in the right eye and 20/40 in the left eye, IOP was within normal limits in both eyes, pupils were symmetric, round and reactive without afferent pupillary defect, and confrontation visual fields and extraocular movement were full in both eyes. There was trace conjunctival injection in the right eye with a small cluster of pseudodendrites on the peripheral superior cornea, with no signs of uveitis, retinitis or papillitis. The patient was diagnosed with herpes zoster dermatitis and keratitis, and he was admitted to the hospital for further cardiac workup and started on intravenous acyclovir, bacitracin ointment and artificial tears as needed in the right eye. Prior to discharge, he improved on antivirals, the pseudodendrites resolved, and visual acuity improved to 20/50 in the right eye.
The patient returned to the clinic 10 days later with excruciating ocular pain and ptosis in the right eye. There were crusting lesions in V1 distribution with resolving vesicular rash. Vision was 20/100 in the right eye, there was a right relative afferent pupillary defect with a mydriatic, round and nonreactive pupil, there was no nystagmus, and there was a right eyelid ptosis with adduction, supraduction and infraduction deficits of the right eye (Figure 2). There was also 1+ anterior chamber cell reaction, no pseudodendrites and an unremarkable dilated fundus exam.
What is your diagnosis?
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Ophthalmoplegia, ocular pain
In a patient with acute ophthalmoplegia and ocular pain in the setting of a recent herpes zoster virus (HZV) infection, one should consider Tolosa-Hunt syndrome in the differential diagnosis. However, it is a diagnosis of exclusion, and a thorough workup is necessary to rule out vascular and ischemic diseases such as ischemic mononeuropathy, cavernous sinus thrombosis, carotid cavernous aneurysm, carotid cavernous fistula or arteriovenous malformation; an ongoing infection such as meningitis, syphilis, HZV, invasive fungal sinusitis or orbital cellulitis; inflammatory and autoimmune diseases such as sarcoidosis, lupus, granulomatosis with polyangiitis, giant cell arteritis, orbital inflammatory pseudotumor, thyroid orbitopathy or myasthenia gravis; and neoplastic disease such as neurofibroma, meningioma, glioma, schwannoma, lymphoma and leukemia. Other causes may be traumatic, including penetrating, nonpenetrating or orbital apex fracture; iatrogenic from previous sinonasal, orbital or facial surgery; or ophthalmoplegic migraine.
Management
The patient was readmitted to the hospital for further workup and started empirically on intravenous acyclovir. Brain MRI with and without contrast showed an avidly enhancing mass involving multiple locations, including the extension via the right rotundum canal and superior orbital fissure to the orbital apex (Figure 3). There were no signs of acute vascular changes on MRI. Infectious and inflammatory workups were negative, including HIV testing, QuantiFERON Gold, serum Lyme antibodies, Aspergillus antigen, serum protein electrophoresis, treponemal antibodies, ACE and 1-3-beta-D-glucan. Complete blood count, platelets and C-reactive protein were within normal limits. The presumed diagnosis was HZV infection (dermatitis and keratitis) complicated with orbital apex syndrome with cranial nerve VII and possibly cranial nerve VIII involvement, secondary to Tolosa-Hunt syndrome. Because one cannot exclude an active HZV underlying process, acyclovir was maintained for at least 24 hours before considering steroids.
There was a concern that the enhancing mass, which was typical for meningioma, could be the culprit of the acute symptoms with focal compression and involvement of the right orbital apex. However, the meningioma was present in previous brain scans in the patient’s records, and neurosurgery was not convinced that it had significantly increased to the point to consider resection, especially given its location. Further, neurosurgery declined a biopsy of the mass for the same reason. The neurology team performed a lumbar puncture, which showed a white blood cell count of 12 with lymphocytic predominance and red blood cell count of 193. The total protein count was 193, glucose was 86 mg/DL, LDH was normal, and bacterial and fungal cultures and cryptococcal antigen were negative. There was a positive HZV IgM with negative HZV PCR and negative herpes simplex virus in the cerebrospinal fluid. Cytology showed no carcinoma, and flow cytometry showed no abnormal lymphocyte population. Thus, intravenous dexamethasone 10 mg was initiated, for which the patient had a rapid and good pain response and partial recovery of ophthalmoplegia.
On his 2-week follow-up after discharge and still on a steroid taper, the patient’s uncorrected vision improved to 20/60 with improved yet still restricted right extraocular movement. The right pupil was non-mydriatic although poorly reactive with a persistent right relative afferent pupillary defect. There were no signs of keratitis, uveitis, retinitis or papillitis.
Discussion
HZV infection can have serious complications. Approximately 10% to 20% of HZV infections involve the ophthalmic branch of the trigeminal nerve, with 20% to 70% developing ocular findings. There is a prodromal phase 1 to 4 days before infection with symptoms of fever, malaise, headaches and hyperesthesia. Formation of vesicles typically occurs around 4 days to weeks in immunocompromised patients. The varicella-zoster virus can remain dormant in the sensory ganglia of the cranial nerve or the dorsal root ganglia. The incidence of herpes zoster ranges from 1.2 to 3.4 per 1,000 persons/year in younger and immunocompetent individuals, whereas the incidence increases to 3.9 to 11.8 per 1,000 persons/year in individuals older than 65 years and immunocompromised. Recurrences are also most common in the latter population. Treatment includes antivirals for 7 to 10 days but may require hospitalization for intravenous dosing in the pediatric population and immunocompromised and severely ill patients.
Orbital apex syndrome involves a collection of cranial nerve deficits and optic nerve dysfunction similar to our patient’s presentation. The main causes include trauma, tumors including meningioma, neurofibroma, schwannoma and metastatic disease, infection such as orbital cellulitis, fungal invasive sinusitis, HZV, giant cell arteritis, orbital inflammatory pseudotumor and Tolosa-Hunt syndrome, among others.
Tolosa-Hunt syndrome is an idiopathic, sterile granulomatous inflammation of the cavernous sinus and can involve the orbital apex. It is a rare and serious entity, first described in 1954 followed by a case series in 1961. Painful ophthalmoparesis or ophthalmoplegia involves cranial nerves III, IV, VI, superior division of V, as well as sympathetic fibers of the internal carotid artery in the cavernous sinus. Recent viral infection, including HZV, is considered a risk factor for this syndrome. It is important to highlight that Tolosa-Hunt syndrome is a diagnosis of exclusion, so it is important to consider and rule out other diseases, as mentioned in detail previously. MRI is preferred in these cases as it provides greater detail of the cavernous sinus and orbital apex compared with CT and may highlight a granulomatous inflammation of surrounding tissues. A biopsy can confirm a granulomatous inflammation to aid in the diagnosis; however, obtaining a biopsy in this location can be challenging, as it was in our case. A lumbar puncture is a useful diagnostic tool that can be done to check the opening pressure and cerebrospinal fluid analysis for infection and inflammatory disease. As mentioned previously, an extensive laboratory workup may be necessary to exclude infectious and inflammatory causes. Oral steroids are the mainstay of treatment, and patients are expected to have a rapid response in most cases. The prognosis of Tolosa-Hunt syndrome is excellent with good response to steroid treatment with 3 to 4 months of taper, although the disease can relapse. In this case, extraocular movement and pupillary reaction were expected to further improve in the upcoming months. The patient continues to follow with ophthalmology and neurosurgery.
Interestingly, there is some evidence in the literature that mast cells in central nervous system tumors, such as meningiomas, could contribute to the aggressiveness of meningioma and brain inflammation. Mast cells can be found mainly in the perivascular areas of high-grade meningiomas, and there is a correlation between peritumoral edema and the number of mast cells found in the tumor. The hypothesis of a recent viral infection contributing to an increase in the meningioma size due to inflammation and further compressing the regional cranial nerves and orbital apex was entertained when discussing our case. However, the risks of a biopsy or resection of the enhancing lesion to confirm a granulomatous inflammatory process or a meningioma were considered too high at that time. Thus, once the infectious workup was negative, systemic steroids were trialed first. Fortunately, the patient responded well to the steroid treatment, and further intervention with biopsy or resection was not necessary.
- References:
- Badakere A, et al. Eye Brain. 2019;doi:10.2147/EB.S180190.
- Baumrin E, et al. J Am Acad Dermatol. 2019;doi:10.1016/j.jaad.2019.03.017.
- Chiew YR, et al. J Clin Neurosci. 2022;doi:10.1016/j.jocn.2022.03.036.
- Lee WB. Herpes zoster keratitis. In: Mannis MJ, et al. Cornea Fundamentals, Diagnosis and Management. Elsevier. 5th ed. 2021;861-872.
- Nair PA, et al. Herpes zoster. In: StatPearls [Internet]. StatPearls Publishing; 2022. Updated September 2023.
- Polyzoidis S, et al. J Neuroinflammation. 2015;doi:10.1186/s12974-015-0388-3.
- Sanjay S, et al. Curr Treat Options Neurol. 2011;doi:10.1007/s11940-010-0098-1.
- Yeh S, et al. Curr Opin Ophthalmol. 2004;doi:10.1097/01.icu.0000144387.12739.9c.
- For more information:
- Edited by William W. Binotti, MD, and Julia Ernst, MD, PhD, of New England Eye Center, Tufts University School of Medicine. They can be reached at william.binotti@tuftsmedicine.org and julia.ernst@tuftsmedicine.org.
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