Ramsay Hunt syndrome revisited–emphasis on Ramsay Hunt syndrome with multiple cranial nerve involvement

Introduction: The Ramsay Hunt syndrome is characterized by herpetic lesions combined with peripheral facial nerve palsy. The disease is caused by a reactivation of the varicella zoster virus and can be deceiving since the herpetic lesions are not always present (zoster sine herpete) and might mimic other severe neurological illnesses. This article reviews the various forms of Ramsay Hunt syndrome and how they can give rise to diagnostic and therapeutic challenges. Material and method: Studies on the assessment and treatment of Ramsay Hunt syndrome were found by conducting a thorough literature search in PubMed, Medline, The Cochrane Library database and Google Scholar using the search words «varicella», «zoster», «ramsay hunt», «oticus», «cranial nerve», «facial nerve» and combinations thereof. The bibliographies of substantial articles were subsequently assessed. Results: About 12% of all peripheral facial nerve palsies are caused by varicella zoster virus. In more than 50% pain is the initial symptom making the diagnosis difficult. Female gender, and in general age above 50 years, renders patients more susceptible to Ramsay Hunt syndrome. The main prognostic factor is the severity of the initial symptoms. The occurrence rate of associated cranial polyneuropathy has been reported to be 1.8-3.2% and cranial nerves VII, VIII, IX are the ones most commonly affected. The full recovery rate is reported to be as low as 27.3% when multiple cranial nerves are involved. Combination therapy comprising of antiviral drugs and corticosteroids is recommened and should be initiated within 72 hours. Vaccination against varicella zoster virus is an interesting new development that might reduce the incidence of varicella zoster virus associated disease altogether. Conclusion: Ramsay Hunt syndrome is a difficult and severe diagnosis with a low full recovery rate. Extensive randomized trials are urgently needed to verify the optimal treatment and the efficacy of varicella zoster virus vaccine in both naïve and herpes zoster patients.


Introduction
James Ramsay Hunt was an American physician and scientist who, in the 20 th century, described a series of cases suffering from herpetic lesions in the oral cavity or external ear, combined with facial palsy and often accompanied by other neurological disturbances [1]. Since those days, the Ramsay Hunt syndrome (RHS) has been investigated thoroughly and different classifications and definitions of the disease have been proposed [1,2]; however no single definition has been agreed upon representing a 'golden standard' . Hunt himself classified the disease into four subgroups according to the extent of the pathological processes taking place in the geniculate ganglion ( Table 1) [3]. The disease is caused by a reactivation of the varicella zoster virus (VZV) of the alpha herpes family; the symptoms are deceptive since the herpetic lesions are not always present (zoster sine herpete) and might mimic several other neurologic illnesses such as cerebral insults, Lyme disease and meningitis. This article reviews the various forms of RHS in adult immunocompetent patients as they present themselves to a broad selection of medical specialties, leading to diagnostic and therapeutic challenges.

Method
In order to evaluate earlier work with regard to the assessment and treatment of RHS, a thorough literature search was conducted in PubMed, Medline, The Cochrane Library database and Google Scholar using the search words «varicella», «zoster», «ramsay hunt», «oticus», «cranial nerve», «facial nerve» and combinations thereof. A PubMed search exclusively on «Ramsay Hunt» alone produced 431 hits; the search for «zoster oticus» produced 407 hits, thus proving the need for a more restrictive search strategy. Only articles in English published doi: 10.7243/2052-6202-2-1 since the year 2003 were included in the subsequent search; resulting in 82 hits. In order to find the original articles, the bibliographies of selected reviews were examined, expanding both the time frame and the allowed languages (English, German, Norwegian and Danish). Articles reporting solely on immune-incompetent patients were excluded. Patients suffering from diabetes mellitus were regarded as immunecompetent in this review. In some articles both immunecompetent and-incompetent patients were reported on, but for our purposes the immune-incompetent patients has been excluded. Furthermore the authors prioritized original research rather than reviews and reference articles. The search was concluded on 11 th of April 2013.

Epidemiology General data and incidence
About 12% of all peripheral facial nerve palsies are caused by VZV [4]. Female gender, and in general age above 50 years, renders patients more susceptible to Ramsay Hunt syndrome [5,6]. Epidemiological data is summarized in Table 2 [6][7][8]. The reason for female predisposition to Ramsay Hunt syndrome is unknown, but the incidence of i.e., herpes simplex infection is also higher in females [9]. Regarding the frequency of RHS and cranial nerve involvement the statements in the literature diverge substantially. This might be due to the fact that some neurological deficits are difficult to assess, especially for the untrained eye. Since RHS is a relatively rare condition, not much epidemiological data is available on which cranial nerves are most commonly affected ( Table 2). The occurrence rate of associated cranial polyneuropathy has been reported to be 1.8-3.2% [5,10,11]. We gathered information on the involvement of cranial nerves from case reports published from 2003 to 2013 on immunocompetent adults ( Table 3) .

Prognosis
The rate of full recovery was found to be 67.7% in RHS, but as low as 27.3% in patients with multiple cranial nerve involvement [10]. By contrast the data on recovery rate for individual cranial nerve involvements are not well established [10,37]. Post-herpetic neuralgia has been reported in as many as 50% of RHS patients [38]. The main prognostic factor seems to be the severity of the initial symptoms [39]. The US and Japan have now implemented varicella zoster vaccination   as part of their childrens vaccination programme and the incidence of chickenpox, herpes zoster (HZ) and sequelae has declined significantly [6,40,41]. In persons 60 years of age or older, a reduction in incidence of HZ and post-herpetic pain of more than 50% has been shown to be achievable by vaccination [42].

Pathophysiology Natural history of VZV
VZV, as does the herpes simplex virus, belongs to the family of alpha herpes viruses. It infects almost all humans in the form of chickenpox (varicella) and is spread by aerosolized respiratory droplets from infected individuals or by direct contact with a herpes zoster rash. The incubation period is 10-21 days and patients are contagious from 2 days before the rash appears until all elements have crusted, usually after 5-7 days. HZ is likewise contagious. VZV is a neurotrophic virus causing the classical variety of chickenpox in person's primary infected. Children usually exhibit milder symptoms than do adults, mainly manifested as an itching vesicular cutaneous rash; however severe and even fatal complications have been reported. Using the host's immune system, especially its T-cells, the virus is delivered to the skin and sensory nerves [43,44]. The virus is never cleared from the body but establishes a latent infection in the sensory ganglia and the facts that it does not spread is due to host's immune response and VZV antibodies.
In the ganglia, the virus keeps itself hidden from the host's immune system [45,46]. Later in life the virus, like other herpes  viruses, can become re-activated causing zoster (shingles) in all parts of the body [43]. The reason for the re-activation is believed to be caused by lessened immunity in the host over time [42,43,47]. For the varicella zoster life-cycle see Figure 1.

Localization of virus during zoster
Different theories have been proposed as to where exactly VZV and associated inflammation are situated during a flare up of herpes zoster, but generally it is acknowledged, that the cause is ganglionitis. Theories involving viral spread due to vasculitis or perineuritis have also been considered [34,48] and VZV has been electron microscopically observed in sensory nerves during HZ [49]. VZV is also found in the zoster elements during the vesicular phase [44]. Usually, no radiologic assessment is necessary, but Magnetic resonance imaging studies using gadolinium-diethylenetriamine penta-acetic acid often show enhancement of the intra-temporal segments of the facial nerve and internal auditive canal in patients with RHS [50].

Clinical presentation
RHS is a diverse and challenging disease, since it can be associated with neurological symptoms mimicking other diseases. Pathognomonic for the syndrome are peripheral facial nerve palsy and vesicular rash on the external ear, external auditory canal (which might only be visible by otoscopic assessment), and/or the mucosa of the ipsilateral part of the tongue or palate, usually accompanied by otalgia (Figures 2a  and 2b) [1,7]. By contrast there are also reports on facial nerve palsy and other cranial nerve palsies without herpetic lesions but with an increase of VZV antibodies, so called zoster sine herpete [51][52][53]. Pain in the affected area develops prior to a vesicular rash in 14-50% of VZV patients; the pain may mimic  acute otitis and other ear diseases [6,39]. Furthermore, facial nerve palsy might develop several days before the rash in up to 20% of RHS patients [11,39]. More than half the patients have pain as their first symptom while as few as 2% have a rash as the initial symptom [39]. The usual RHS patient and the possible associated symptoms are described in Table 4.

Diagnostic approach
The RHS diagnosis is purely clinical, but in some cases a blood test for VZV antibodies may be useful. When other cranial nerves are affected, Magnetic resonance imaging may be necessary to exclude intracerebral pathology. The House Brachmann scale should be used to assess the facial nerve function initially and at every subsequent follow-up.   the use of antiviral drugs [54,55]. According to a Cochrane review, only one randomized controlled trial was performed including 15 patients; and no significant conclusions could be drawn as the study was deemed of low quality [56]. Other studies comprising small study populations have shown increased effects of acyclovir combined with corticosteroids compared to corticosteroids alone [39,57]. A main prognostic factor on outcome, with regard to medication, seems to be the time from debut of symptoms to initiation of treatment, whether consisting of combined acyclovir and corticosteroids or corticosteroids alone ( Table 5) [58]. Some studies report on other treatment regimens like bed-rest, high protein, low sodium diet, peripheral vasodilators combined with acyclovir and corticosteroids, surgical decompression or anastomosis of the facial nerve but more extensive and randomized controlled studies are needed to define a 'golden standard' of RHS treatment [10,59]. Until those studies are available, acyclovir in combination with corticosteroids are considered the correct treatment of RHS.

Vaccination
For persons of 60 years or older, vaccinating them against VZV effectively reduces the risk of HZ and post-herpetic pain whether or not these persons had had prior exposure to VZV. The pathophysiology is ascribed to the booster effect of the cell-mediated immunity against the dormant VZV (42). In children, the course of primary varicella zoster infection (chickenpox) in unvaccinated patients is markedly milder when vaccinated within 3 days from exposure [60,61]. Vaccinations are well tolerated and result in a 2.1 fold increase in VZV antibody level in patients with a positive history of HZ [62]. To the best of our knowledge, no substantial studies on the prognosis of the clinical outcome regarding vaccination or passive immunization of immunocompetent HZ or RHS patients have doi: 10.7243/2052-6202-2-1 been carried out. In theory, while vaccination of RHS patients at initial presentation could have some effect, this effect should be compared to the efficacy of corticosteroids and acyclovir.

Conclusion
RHS is a rare but severe condition defined by herpetic rash of the ear or the mucosa of the mouth and peripheral facial nerve palsy, most often combined with otalgia. The syndrome can be associated with several other cranial nerve symptoms mimicking intracerebral disease. The full recovery rate is reported to be as low as 27.3%. Antiviral therapy combined with corticosteroids is recommended by most scientists in the field, although more randomized controlled trials are needed. Vaccination against VZV is an interesting new development that might reduce the incidence of VZV associated disease altogether. More studies regarding the potential efficacy of the VZV vaccine, given at the early sign of RHS, are urgently needed to combat this severe disease.