Herpes simplex virus infection, with particular reference to the progression and complications of primary herpetic gingivostomatitis


Corresponding author and reprint requests: A. Kolokotronis, Dental School, Aristotle University of Thessaloniki, Oral Medicine/Pathology, Thessaloniki, Greece
E-mail: kdeod@cieel.gr


Primary herpetic gingivostomatitis (PHGS) represents the clinically apparent pattern of primary herpes simplex virus (HSV) infection, since the vast majority of other primary infections are symptomless. PHGS is caused predominantly by HSV-1 and affects mainly children. Prodromal symptoms, such as fever, anorexia, irritability, malaise and headache, may occur in advance of disease. The disease presents as numerous pin-head vesicles, which rupture rapidly to form painful irregular ulcerations covered by yellow–grey membranes. Sub-mandibular lymphadenitis, halitosis and refusal to drink are usual concomitant findings. Following resolution of the lesions, the virus travels through the nerve endings to the nerve cells serving the affected area, whereupon it enters a latent state. When the host becomes stressed, the virus replicates and migrates in skin, mucosae and, in rare instances, the central nervous system. A range of morbidities, or even mortality, may then occur, i.e., recurrent HSV infections, which are directly or indirectly associated with PHGS. These pathological entities range from the innocuous herpes labialis to life-threatening meningoencephalitis.


Primary herpetic gingivostomatitis (PHGS) represents the most commonly observed clinical manifestation of primary herpes simplex virus (HSV) infection, occurring in 25–30% of affected children [1]. Approximately 90% of cases are caused by HSV-1, although detection of HSV-2 has also been reported. The overwhelming majority of primary HSV infections are asymptomatic, so that PHGS is considered the exception rather than the rule. Indeed, in a study of 4000 children seropositive for HSV-1, only 12% had evident signs and symptoms of infection [2,3].

Epidemiologically, there are two peaks with respect to the age at which PHGS occurs. The first peak occurs in children aged between 6 months and 5 years, and the second peak occurs in young adults in their early 20s [4]. In rare cases, PHGS can occur in neonates, in adults, and even in the elderly [5–7]. Geographical location and socio-economic status also influence the incidence of HSV-1 infections. Hence, individuals in developing countries with a lower socio-economic status become seropositive for HSV-1 at an earlier age than their counterparts in developed countries [8].

Clinical symptoms

In terms of pathology, it is accepted generally that HSV-1 gains access through disruptions of skin integrity or mucous membranes. This procedure is mediated via ligand–receptor interactions (see below). Following an incubation period of 1–26 days, prodromal, non-pathognomonic signs and symptoms occur, including fever, chills, nausea, anorexia, irritability, malaise and headache [3,9–11]. The onset of the acute phase is abrupt, and is usually accompanied by pain in the mouth, salivation, fetor oris, refusal to drink and sub-mandibular lymphadenitis [12]. The affected mucosa develops numerous pin-head vesicles (rarely seen), which break down rapidly to produce numerous small, red lesions. These initial lesions enlarge slightly and develop central ulcerations covered by yellow–grey membranes. Adjacent lesions may coalesce to form irregular ulcerations. Lesions may involve buccal mucosa, tongue, posterior pharynx, and any gingival and palatal mucosae. Moreover, the affected gingivae often exhibit discernible erosions along the mid-facial free gingival margins, and these may precede the appearance of the mucosal vesicles [3,12]. Finally, lesions localised to the vermilion and the adjacent perioral skin are not uncommon. Mild lesions usually heal within 5–7 days without scar formation, but healing may require 2–3 weeks in severe cases [3,10,13–16]. It has been postulated that PHGS is the clinical pattern of the primary HSV infection occurring in children, whereas pharyngotonsillitis, or mononucleosis-like disease, is the primary HSV infection in adults [3].

Latency and reactivation of hsv

Before discussing the potential after-effects of PHGS, it is relevant to consider briefly the structure and pathogenesis of HSV (for a detailed review, see Roizman and Knipe [17]). The unique biological properties of these viruses are their neurotropism and their ability to remain latent in nerve and ganglial cells [2,18]. Their proclivity to reside in neural immune-privileged tissues, and subsequently to elude the immune system ‘reconnaissance’, is explained by the following facts: (1) the shielding of central nervous system (CNS) and peripheral nervous system by the blood–brain barrier and blood–nerve barrier; (2) the non-expression of the typical major histocompatibility complex class I; (3) the absence of regular lymphoid drainage; and (4) the lack of intra-neural lymphatic channels [19,20]. It is also known that the viral protein ICP47 contributes to immuno-evasion by inhibiting binding of viral peptides to TAP, a molecule necessary for major histocompatibility complex class I molecule presentation [20]. In addition, the viral infection protein ICP0, amongst other roles, enhances HSV resistance to interferon-α/β (IFN-α/β) [21].

HSV belongs to the α-herpesvirinae family. It has been demonstrated that there are two distinct serotypes, referred to as HSV-1 and HSV-2 [17]. Both are double-stranded DNA viruses and they have 50% homology. The HSV genome is 152 kb in size, with an unmethylated G + C content of 68% for HSV-1 and 69% for HSV-2 [22–24].

In broad terms, HSV-1 is responsible for HSV infections encountered above the waist, while HSV-2 is isolated from HSV infections below the waist, although exceptions can occur [5]. It is also believed that HSV-1 emulates HSV-2, inasmuch as individuals seropositive for HSV-1 are less susceptible to disease caused by HSV-2 [8,25].

The HSV virion comprises four elements: (1) a core, accommodating the viral DNA; (2) an icosadeltahedral capsid surrounding the core; (3) a tegument; and (4) an outer envelope with projecting spikes [17]. The envelope surrounds the capsid–tegument structure, and consists of glycosylated (gB, gD, gE, gG, gH, gI, gK, gL, gM and gJ) and several non-glycosylated (UL24, US9 and, possibly, UL24, UL43 and UL34) viral proteins, lipids, and polyamines (spermine and spermidine). Host immune responses are greatest against the structural proteins and the envelope glycoproteins [17,26]. The tegument contains several proteins, namely VP16, VP11–12, VP13–14, the virion host shut-off (vhs) protein, VP1–2 and the product of gene Us11 [17].

There are three discernable forms of capsid morphology, distinguishable by the distance sedimented in sucrose gradients [27]. ‘A’ capsids are empty, containing neither DNA nor scaffold proteins. These are thought to be capsids for which the DNA packaging process failed. ‘B’ capsids are devoid of DNA, but contain the scaffold proteins. ‘C’ capsids, which sediment furthest, contain virus DNA and are the capsids that mature into infectious virions. A fourth capsid type, which cannot be isolated from sucrose gradients, but has been observed by ultrastructural analysis of infected cells, is the procapsid, which is thought to be the earliest spherical structure formed in HSV-1-infected cells [17,27].

Finally, the 152-kb double-stranded DNA of HSV exists in three forms: linear, circular or concatemeric, depending on the stage in the virus replication cycle. ICP0 seems to regulate this process [28,29].

The replication cycle for HSV includes: (1) entry into epithelial cells; (2) replication in epithelial cells and release with concomitant cell lysis (clinically seen as PHGS); (3) entry into the nerve that serves the affected area and transport to cell nuclei (the trigeminal ganglion for PHGS, but superior cervical, sphenopalatine, vestibular or geniculate ganglia may also be affected) [18,30–33]; and (4) latency or reactivation with anterograde axonal transport and manifestation of recurrent HSV lesions in skin and, rarely, in the CNS [2].

Entry of the virus into the cell is a three-step process. First, HSV attaches, mainly via gC, but also via gB, to the cell (epithelial, epidermis and neural) surface heparan sulphate [34,35]. HSV then binds to co-receptors belonging to the immunoglobulin superfamily, namely nectins 1α and 1β, previously called herpes virus entry mediators C (HveC) and herpes virus immunoglobulin-like receptor (HIgR), respectively [36]. The C-terminal domains of these receptors bind to L-afadin, a PDZ-binding protein (PDZ is the acronym of the PSD-95/Dlg/ZO-1 protein domain) that anchors these molecules to cytoskeleton actin and adherens junctions, thus facilitating cell-to-cell propagation of HSV in skin, brain and ganglia [17,37,38]. However, nectins also facilitate the ingress of HSV into cells, and some fraction of nectins must therefore also be distributed on the apical surfaces of polarised cells [39]. Tran et al.[40] consider that gG is an essential molecule for virus entry through the apical surfaces of polarised cells, i.e., keratinocytes and neurones. Mannose-6-phosphate receptors can also act as HSV receptors [41]. The third stage of virus entry comprises the fusion of the virus envelope with the cell membrane, a process referred to as de-envelopment. Virus–cell fusion requires the participation of gD, gB and the gH–gL heterodimer [17]. Overall, attachment to the apical surface of polarised cells is gC-dependent, whereas ingress through the basolateral facet (required for cell-to-cell spread as well as entry into cells after reactivation) is gC-independent. In addition, gG plays a pivotal role in post-attachment entry on the apical surface, but is not essential for basolateral entry.

Following fusion, the capsid, together with the associated tegument proteins, travels throughout the cytoplasm, and then virus DNA is released into the nucleus. Replication of HSV takes place and, following assembly of the virions and packaging of DNA, cell lysis ensues [17]. This phenomenon is seen clinically as PHGS. It is of note that virions shed into the saliva can travel to other parts of the body, or can contaminate other individuals via airborne or waterborne spread [11,42].

With respect to the fate of the newly formed virions, Scott et al.[43] have reviewed the oral shedding of HSV-1. Hill and Blyth [44] developed the ‘skin trigger’ theory, which was supported by the work of Hochmanet al.[45]. According to this theory, the oral cavity may be a reservoir of latent HSV, which is guarded by the immune system. Support for this theory comes from the rapid development of recurrent herpetic lesions, and the fact that herpes antigens could be detected in the sulcular gingival epithelium of 60% of individuals with otherwise healthy gingiva.

It is accepted universally that HSV epithelial replication is followed by transport of virus to the trigeminal or other ganglia. Thus, the newly formed virions enter the neuronal processes of the nerve that serves the infected region. This process is akin to the one described above. Transport of the de-enveloped virions to the trigeminal ganglion, at 3–5 mm/h, is accomplished via the microtubules of the neurones. Moreover, UL34 viral protein binds to the N-terminal domain of the 1α intermediate chain of the cytoplasmic neuronal dynein, and uses the microtubular network for retrograde transport of the capsid–tegument structure to the nuclear pore [46,47]. Although actin filaments and kinesins are now known to act as tracks for axoplasmic organelle motility, their role in retrograde axial transport has yet to be elucidated [46]. Once the capsid reaches the nuclear pore, an interaction between the capsid and nuclear pore complex takes place. It seems that the capsid, particularly the VP1–2 tegument protein, has nuclear localisation sequences that form a complex with nuclear localisation sequence receptors, i.e., importins or karyopherins [17,48]. Three putative mechanisms have been implicated in the transport of virus DNA into the nucleus [48].

The fate of HSV following entry into the nucleus is determined by virus and host immune system responses, but latency is established in the vast majority of cases. During latency, only latency-associated transcripts (LATs) are present in the nucleus, although low levels of lytic viral gene mRNAs have also been detected[49–51]. Theil et al.[19] demonstrated that the latter may trigger a chronic inflammatory response, including CD8+ T-cells, CD68+ macrophages, natural killer cells, and interleukins IFN-γ and tumour necrosis factor-α, which are attracted by the chemokines RANTES and IP-10[19,52,53]. Mogensenet al.[54] showed that the activation of macrophages results from mitochondrial stress, with subsequent nuclear factor kappa B activation inducing development of a Th1 response by releasing interleukin-12 [20,54,55]. It has also been postulated that the immune system adopts a non-cytolytic profile during latency rather than a lytic profile, and that IFN-γ can prevent HSV reactivation from latency [56]. On the other hand, HSV tries to prolong its stay in the cell nucleus by adopting mechanisms of immuno-evasion and neuronal survival. Two models by which this can be accomplished have been suggested. The first suggests that LATs downregulate virus expression; hence, the viruses escape from immunosurveillance [48,57]. The second suggests that LATs possess anti-apoptotic properties. Moreover, the 2.0-kb LAT intron inhibits both exogenous caspase-8 (rendering the neural cells refractory to IFN-γ, tumour necrosis factor-α and T-cell granzymes B) and endogenous mitochondrial caspase-9 apoptotic pathways [33,48,58,59]. It should be noted that ICP4, ICP27, viral glycoproteins gD and gJ and protein kinase Us3 also have anti-apoptotic properties [17].

Reactivation of the virus and re-initiation of the productive cycle may sometimes occur spontaneously, but this is more often secondary to infection with human immunodeficiency virus, cancer, exposure to UV light, organ transplantation, pregnancy or menstruation, fever, cold, X-ray irradiation, chemotherapy, fractures, tooth extraction, sideropenia, gastrointestinal upset, surgery or other stress-inducing states [4,43,60,61]. Moreover, it is believed that human immunodeficiency virus enhances HSV virulence, and vice versa [8,62]. Cancer induces HSV reactivation by altering immune responses from Th1 to Th2 [63]. The same alteration results from exposure of keratinocytes to UV light, through release of interleukin-10. The latter can downregulate Th1 responses, thus facilitating the development of Th2 responses [64]. In all other cases, HSV reactivation may be a consequence of corticosteroid and adrenaline release caused by stress-inducing stimuli [65]. Finally, the 5′ exon of LAT has been implicated in HSV reactivation, although Thomas et al.[66,67] proposed that the 2.0-kb intron region of the LAT open reading frame is responsible for HSV-1 reactivation [33,49]. In addition, Halford and Schaffer [68] have demonstrated that ICP0 is required for HSV reactivation.

During lytic infection with HSV, virus genes are expressed in a cascade-like fashion, including the transcription of initiator element genes, followed by transcription of the early genes, replication of virus DNA and, finally, transcription of the late genes, although the transcription of some late genes, referred to as β1 genes, occurs before DNA replication [69]. Transcription of initiator element genes is stimulated by VP16, a tegument protein that is transported into the nucleus, with positive and negative feedback loops [17,70]. Both transcription and replication are performed in the cell nucleus, whereas translation is carried out in the endoplasmic reticulum. The completion of these processes implies either the usurpation–recruitment of host-cell mechanisms or the inhibition–abrogation of others. Hence, the vhs protein shuts down host protein production and coordinates viral gene expression, whereas the γ34.5 gene product and the Us10–12 gene products block protein synthesis by inhibiting protein kinase R [71]. Likewise, HSV recruits host-cell RNA polymerase II for viral gene expression [17]. Once the early genes are expressed, several of these proteins are aggregated into the nucleus and assemble on parental virus DNA molecules, in structures termed pre-replicative sites, close to nuclear domain 10, the domain where virus DNA replication takes place [17].

Tang et al.[72] demonstrated that ICP24–ICP27 interaction plays a key role in localisation of virus DNA to nuclear domain 10. Virus DNA replication is accomplished by viral (DNA polymerase, accessory protein, origin-binding protein, the ICP8 single-stranded DNA-binding protein and the helicase-primase proteins) and host-cell (DNA polymerase α-primase, DNA ligase and topoisomerase II) enzymes in the replicative site at nuclear domain 10 [17,73]. DNA replication is followed by capsid assembly: initially procapsid, and eventually capsid B, formation. After DNA cleavage and packaging, encapsidation of virus DNA, or insertion into capsid B, takes place. Virus DNA enters through a portal, whereas scaffolding proteins are extracted, resulting in capsid C formation [17,27,74–77]. These processes, along with other cellular events, produce the characteristic appearance of the so-called intra-nuclear inclusion bodies seen under the light microscope [17]. The fully formed virion leaves the nucleus and travels through the cytosol to the nerve endings, which in turn lead to skin or mucosa, and rarely to the CNS. The replication of HSV is accompanied by nerve cell death [78].

Complications and recurrent infections

The complications of PHGS range from indolent cold sores to life-threatening encephalitis. The most common cause of morbidity following PHGS is dehydration. Amir et al.[1] found that 89% of patients drank less than normal, and that two of 36 patients were unable to drink. In severe cases, hospitalisation and parenteral fluid intake are recommended. Bacteraemia caused by the Gram-negative bacillus Kingella kingae has been observed [1,79], but this complication subsided uneventfully after the administration of antibiotics.

An innocuous morbidity of PHGS is herpes labialis (also known as ‘cold sores’ or ‘fever blister’). This represents the most common manifestation of HSV reactivation in trigeminal ganglia, with an incidence among adults of 20–40%[80]. Two or three recurrences annually are normal, but as many as 12 may occur. HSV-1 infections recur more often than HSV-2 infections. The vermilion border and adjacent skin of the lips are the sites affected most frequently, although the skin of the nose, chin or cheek may also be involved. Pain, tingling, burning sensation, itching, fever (fever blisters) or upper respiratory tract infection (cold sores) usually precede the onset of the disease [3,81]. Herpes labialis is characterised by multiple small, erythematous papules that develop and form clusters of fluid-filled vesicles that rupture within 2 days. The total area involved is usually less than 100 mm2, and the lesions progress to being pustular or ulcerative, with crusting within 3–4 days [5]. Pain is intense at the outset, but resolves over 4–5 days. Shedding of virus from lesions continues, with progressive healing over 2–3 days. Healing is rapid and is complete within 10 days. Remission of herpes labialis can occur; inciting factors are fever, stress and exposure to UV light [5].

‘Herpetic geometric glossitis’, characterised by linear fissures on the dorsum of the tongue, with branching dendritic lesions, represents an HSV-1 infection in immunocompromised patients [82], whereas recurrent herpetic stomatitis presents in immunocompetent individuals. The latter differs from PHGS in that it has a more confined enanthema. Tabaee et al.[83] described an oral recurrent HSV infection presenting as an immense tongue mass in a patient who underwent cardiac transplantation. Paradoxically, this lesion was first encountered 10 months after transplantation, although most recurrent oral HSV infections occur within the first month post-transplant [83,84]. The lesion was initially considered to be a squamous carcinoma, so a 0.5-cm free margin excision was performed. Later, following immunostaining, the final diagnosis of HSV infection was established [83].

An even more unusual clinical entity is a recrudescent HSV infection identical to PHGS. Use of laboratory screening tests is mandatory in such cases in order to make the differential diagnosis [85].

Finally, there is a single report [60] postulating that recurrent HSV infection affecting the oral cavity may even manifest as a dry socket, since HSV was isolated from the socket. However, there are reservations concerning the acceptance of this pathology.

A less common presentation of HSV is herpetic whitlow (herpetic paronychia). This may occur as a result of auto-inoculation in children with orofacial herpes (i.e., children sucking their hands), and in adults in association with genital herpes [3,86]. In the past, before the use of protective gloves, dental personnel could come into contact with HSV during the treatment of patients suffering from HSV infection. Whitlow is a noxious pathology characterised by prodromal symptoms, namely pain and burning, during the 2–20-day incubation period. Herpetic whitlow usually manifests with local swelling, erythema, and one or more small, tender vesicles. Fever and malaise may be present, especially in infants. The lesions typically contain clear fluid in the initial stages, but the fluid can become cloudy after a week by virtue of the presence of white blood cells. In contrast, bacterial paronychia presents with suppuration from the onset of the disease. The site affected most commonly is the digital pulp space, but infections of the nail folds or lateral aspects of the fingers can also be encountered. The disease subsides completely within 3 weeks [87].

Another dermatosis caused by HSV is herpes gladiatorum or ‘scrumpox’. This usually affects individuals participating in contact sports, e.g., wrestling or rugby football, or parents who have kissed areas of dermatological injury in children [3,80].

Eczema herpeticum (also known as Kaposi's varicelliform eruption) is a skin infection affecting children and adults, in which HSV is implicated. Habif [81] considers that eczema herpeticum is an association of atopic dermatitis with HSV infection. The disease is most common in areas of active or recently healed atopic dermatitis, particularly on the face, but it can also develop in areas with pre-existing dermatoses, such as are seen in atopic dermatitis, Darier's disease, mycosis fungoides, pemphigus folliaceous and Sezary's syndrome, and even on normal skin. In one-third of paediatric patients with eczema herpeticum, there is a history of herpes labialis in a parent. The disease is characterised by the eruption of numerous vesicles, which gradually become pustular, and finally are rendered umbilicated. New groups of vesicles may appear during the following weeks. High fever and adenopathy become apparent 2–3 days after the eruption of vesicles. The fever resolves in 4–5 days in uncomplicated cases, and the lesions evolve in the typical manner. The prognosis is usually good, but the patient may succumb when viraemia occurs along with visceral involvement [8,81].

Erythema multiform is another dermatosis in which HSV is implicated. Indeed, HSV may precede erythema multiform, and post-herpetic erythema multiform is thought to be the sequel of perivascular immune complex deposition of immunoglobulin, herpes virus antigen and complement [88].

An even more severe complication of PHGS is ocular involvement. This can be caused by auto-inoculation from PHGS or herpes labialis, or via the nerve route [5,17,89]. HSV infection of the eye is the most frequent cause of corneal blindness in the USA [17]. Herpetic keratoconjunctivitis is associated with acute onset of pain, blurring of vision, characteristic dendritic lesions of the cornea, injection, chemosis, photophobia, lacrimation and eyelid oedema. Less commonly, advanced disease can result in ‘geographical’ or ‘amoeboid’ ulcer of the cornea. The visual acuity declines in the presence of the ulcers after several bouts of infection and, with progressive stromal involvement, opacification of the cornea may occur. Repeated individual attacks may take place for several weeks or even months. Progressive disease can result in visual loss or even rupture of the globe [5,89].

Herpetic stromal keratitis caused by HSV appears to be related to T-cell-dependent destruction of deep corneal tissue. The UL6 viral protein mimics the corneal antigens, so an autoreaction with corneal antigens targeting T-cells has been postulated to be a factor in this infection [90]. Recently, Lundberg et al.[24] proposed a model for herpetic stromal keratitis pathogenesis in which the unmethylated CpG dinucleotides, released by degenerate stromal cells infected previously by HSV, bind to Toll-like receptor 9 of macrophages, which in turn orchestrate the Th1 response with release of cytokines and recruitment of autoreactive T-cells [24].

Herpetic oesophagitis and herpetic infection of the lower respiratory tract may result from direct extension of oropharyngeal infection, including PHGS [18]. The former may also represent the consequence of de-novo reactivation of HSV and propagation to the oesophageal mucosa via the vagus nerve. HSV oesophagitis may manifest even in immunocompetent patients, but it is more likely to occur in patients who have undergone kidney or liver transplantation, or in patients suffering from AIDS. The predominant symptoms of HSV oesophagitis are odynophagia, dysphagia, substernal pain and weight loss, while bleeding or even stricture formation may complicate the disease [91]. Clinically, there are multiple oval ulcerations on an erythematous base, which may or may not have a patchy white pseudomembrane. The distal oesophagus is involved most commonly, although disseminated disease may occur when the immune system is deranged [18,92].

HSV pneumonitis is uncommon unless an individual is immunocompromised, and may result from extension of herpetic tracheobronchitis into lung parenchyma, whereupon focal necrotising pneumonitis usually ensues. The mortality rate in immunosuppressed patients is high (>80%) [18]. Bogger-Goren [93] reported a case of acute epiglottitis in a child aged 16 months that was caused by HSV, and involvement of the peripheral nervous system or the spinal cord may also be complications resulting from PHGS. Nasatzky and Katz [94] reported a case of Bell's palsy associated with HSV gingivostomatitis. It has been postulated that Bell's palsy results from the replication of HSV in geniculate ganglia, and that axonal spread and multiplication of the reactivated virus leads to inflammation, demyelination and palsy, which usually resolve within 6–8 weeks, although sequelae may occur in some patients. It has also been suggested that the anatomical structure of the Fallopian canal may be responsible for nerve compression secondary to oedema, which can lead finally to nerve degeneration and severe facial paralysis.

Galanakis et al.[95] reported a case of transverse myelitis associated with PHGS in which the patient exhibited the typical signs and symptoms of transverse myelitis, such as acute weakness, acute pain in the lower extremities, lower back and abdomen, weak leg muscles and bladder dysfunction, but retained deep sensation. The patient's history revealed that he had suffered from herpetic gingivostomatitis, and lumbar puncture, magnetic resonance imaging and serology were all consistent with transverse myelitis caused by HSV-1.

Herpetic meningoencephalitis is the most fatal complication of HSV infection. In general, herpetic encephalitis (HSE) is attributed mainly to HSV-1, whereas meningitis is ascribed to HSV-2 [96]. HSE is considered to be the most common cause of sporadic, fatal encephalitis in the USA, and probably worldwide, as it accounts for 10–20% of all cases of viral encephalitis [97,98], either primary or secondary. There are three patterns of viral propagation to brain parenchyma: (1) exogenously acquired virus entering the CNS via the olfactory epithelium and olfactory bulb; (2) reactivation of latent HSV in ganglia, followed by spread via trigeminal and autonomous nerve roots; and (3) blood-borne spread, especially in neonates or immunocompromised individuals [5,18]. However, only Ito et al.[97] have reported HSE associated directly with PHGS. The clinical signs and symptoms of HSE depend on the location of the lesion. Typically, HSE produces focal haemorrhagic necrosis of temporal and frontal lobe structures, including limbic mesocortices, amygdala and hippocampus, although the involvement of other sites cannot be excluded [2,98–102]. The clinical hallmark of HSE is the triad of fever, headache and altered consciousness [103]. Concomitant signs and symptoms include confusion, lethargy, seizures and mental aberrations, but other symptoms may also become apparent, depending on the location of the lesion [99]. The presence of neurological symptoms, e.g., altered sensorium or other focal neurological findings, distinguish HSE from HSV meningitis [103]. Mortality rates reach 60–70% and, even after adequate medication, permanent neurological deficits will remain, with only 2.5% of surviving patients recovering normal neurological function [98,104].

In terms of pathogenesis, it should be emphasised that, although HSE has been associated with necrotic cell death resulting from virus replication and inflammatory changes/cerebral oedema secondary to the virus-induced immune response, the role of virus-induced nerve cell apoptosis should not be overlooked [98,105]. Indeed, Perkins et al.[98] demonstrated HSV-1-induced apoptosis mediated by c-jun N-terminal kinase. Likewise, Anglen et al.[65] showed that CD8+ T-cells, which are probably the most efficient cell population active against HSV, may enhance or eliminate brain injury when they infiltrate brain tissues before or after HSV infection, respectively.

In contrast, meningitis is ascribed generally to HSV-2. Headache, asthenia, high fever, neck stiffness, nausea/vomiting, photophobia, muscle pain and radiculalgia are some of the symptoms indicative of meningitis [106]. Mommeja-Marinet al.[106] reported no cases of visceral involvement, and considered that meningitis did not result from blood-borne spread of viraemia, but probably from spread through the nerve tract, starting from sacral ganglia. Cerebrospinal fluid analysis is suggestive of viral meningitis if high levels of white blood cells, especially lymphocytes (lymphocytic pleocytosis), are detected, the protein level is normal or slightly elevated, and the glucose level is normal. PCR is necessary to establish the final diagnosis.