This is the largest series of patients reported in the literature on HSE in immunocompromised patients and the first to directly compare the presentation in immunocompromised and immunocompetent states. Despite the retrospective nature of our study, there are several important observations. 1) Immunocompromised patients may present with less prodromal symptoms, and focal deficits. 2) Immunocompromised adults have more extensive involvement of the brain and abnormalities may involve the brainstem, cerebellum, and atypical regions including scattered lesions in the cerebrum, in the absence of temporal lobe involvement. 3) Absence of CSF pleocytosis was not uncommon in immunocompromised patients. 4) The morbidity and mortality of HSE were substantially higher in the immunocompromised group. 5) Immunocompromised state, lower CSF pleocytosis, and delayed acyclovir administration were associated with poor outcomes.
The extensive and contiguous areas of brain involvement in the immunocompromised patients may reflect a wider spread of HSV due to hosts’ ineffective immune response to control the infection. This is further reflected in the frequent absence of pleocytosis in the CSF of immunocompromised patients as seen in this and other reports.10–14
However, the absence of pleocytosis may be also be seen, albeit rarely, in immunocompetent patients, particularly if CSF is evaluated early in the course of the illness.10,15
Additionally, in CSF, polymorphonuclear predominance was noted in some immunocompromised patients. These atypical features can make the diagnosis of HSE in immunocompromised patients challenging. Recurrence of herpes encephalitis may occur despite adequate antiviral therapy in the immunocompromised patients, likely because the antiviral drugs only prevent viral replication and the immune system is needed to eliminate the replicating virus or to maintain it in the latent state.
Sporadic HSE is the most common form of nonepidemic encephalitis in adults and the majority of cases (94%–96%) are caused by HSV-1.11
Latent HSV-1 infections of the trigeminal ganglia, by retrograde axonal transportation from a primary infection of the lip or buccal mucosa, were found in 65% of normal individuals.12
HSV-1 genomic sequences were also detected in the medulla, pons, olfactory bulbs, and gyrus rectus in 28%–34% of normal individuals.12,13
Although HSV-1 reactivation may occur by immunosuppression, the mechanism underlying the reactivation resulting in HSE is not well understood.
One hypothesis is that local breach of immune surveillance in the instance of cranial irradiation leads to reactivation of the latent virus in the ganglia and the brain14
; and likewise, in a systemic immunocompromised state, reactivation of the virus may occur due to the breakdown of immune surveillance. Recent evidence suggests that HSV-1 may not achieve a true stage of latency and immune surveillance is critical in preventing its spread.16
The findings of a recent Swedish nationwide retrospective study examining the incidence, morbidity, and mortality did not suggest an overrepresentation of immunocompromised hosts in the cohort.2
Some, however, have argued that the atypical presentation of HSE in immunocompromised individuals might have led to an underestimation of the incidence in immunocompromised hosts.7
Immunosuppression alone is probably not enough to cause reactivation, but may enhance reactivation in conjunction with other factors.17
Our literature review yielded 28 articles reporting HSE in immunocompromised hosts (table e-2). Overall, 49 cases were reported, 27 cases predating the widespread use of MRI and HSV PCR in the diagnosis of HSE. Cases in which diagnoses were confirmed at autopsy provided histopathologic characterization. There is a broad spectrum of immunocompromised conditions associated with HSE.
Atypical clinical manifestations have been previously reported in HIV-infected patients. HSE may present as a diffuse non-necrotizing encephalitis involving the hemispheres and brainstem.18,19
In earlier series, about one-sixth of the patients (4 out of 24) had mild or atypical disease characterized by the absence of focal findings and slower progression, regardless of CD4+ T-cell counts.20
In another series of 8 patients with HIV infection/AIDS, the speed of disease progression and lack of inflammation were proportional to the degree of immunocompromised states. Patients with advanced AIDS had chronic neurologic dysfunction and diffuse leukoencephalopathy on autopsy.21
Typical neuroimaging abnormalities involve the medial temporal lobes, either unilaterally or bilaterally, and spread along limbic pathways to involve the orbital frontal lobe and insular cortex. With further spread, cingulate gyri, parietal lobes, occipital lobes, brainstem, and internal capsules may be involved.22
Atypical neuroimaging abnormalities have been reported frequently in the literature, although this may represent a reporting bias. Some of the earlier case series and reports only utilized CT brain scans. Unremarkable CT and MRI were reported in some,7,20,23,24
while widespread signal abnormalities throughout the brain, involving cortex, basal ganglia, thalamus, brainstem, and cerebellum, were reported in the others.7,25,26
The extensive and rapid spread of the infection may explain the lesser prodromal presentations and a shorter delay between onset of symptoms and presentation to the hospital in immunocompromised patients.
Clinicohistopathologic correlations in HSE differ between immunocompromised and immunocompetent patients. In typical HSE, fever and headache preceded the development of encephalopathy and personality change by 1–5 days. During the second week, inflammation and necrosis appeared predominantly in medial temporal and olfactory stria/inferior frontal lobes, cingulate gyri, and occasionally pontine nuclei. By the third week, there was extensive necrosis, inflammation, and gliosis with scant HSV-1.17,27
In contrast, in immunocompromised hosts, there was a conspicuous lack of inflammation, necrosis, and hemorrhage on histopathology, with persistence of abundant viral antigens.7,20,24,28
This may reflect the host’s inability to mount an adequate immune response to limit the course of HSE in immunocompromised hosts, paradoxically limiting tissue damage with the lack of frank necrosis. While an intact immune system may mount an intense inflammatory response leading to significant CNS injury, the lack of it severely hampers the ability to clear the infection, leading to increased morbidity and mortality. The differing mechanistic pathogenesis may help explain the atypical clinical presentations. More recently, primary immunodeficiencies involving and related to mutations in toll-like receptors (TLR-3) have been implicated in the reactivation of HSV and HSE in children.29–31
The potential role of the innate immune response in the pathogenesis of HSE in adults needs to be more fully investigated.
HSE has been reported in 3 patients with rheumatologic disorders treated with anti–tumor necrosis factor antibody therapies.32
Whether the immunosuppressive state predisposes to HSE is pertinent in this era of increasing use of potent immunomodulatory therapies. There was a fatal case of HSE during the clinical trial for FTY720 in the treatment of multiple sclerosis (MS). In the same clinical trial, the incidence of HSV infection was reportedly twice as high in the higher dose FTY720 group as compared to the placebo group.33
There was also at least one case of HSE fatality in a patient treated with natalizumab, a monoclonal antibody against α-4 integrin for treatment of relapsing-remitting MS in postmarketing surveillance (personal communication, Biogen-Idec, 2011). In patients on immunomodulatory therapies, a more systemic analysis is required to determine if there is an increased risk of HSE. Nonetheless, a high vigilance for HSE including atypical presentations must be maintained.
We analyzed patients with different degrees, spectrum, and conditions of immunocompromised states under one group. Descriptive analyses as attempted in did not demonstrate patterns of clinical presentation, or investigation or outcome across different spectrum and severity of immunosuppression. The size of the study did not allow meaningful subanalyses and interpretation of clinical characteristics of various conditions. However, this study served to raise awareness of the potential increased risk, atypical presentations, and worse outcomes among immunocompromised patients.
A limitation of our study is its retrospective nature. In addition, HSV PCR performed in the clinical laboratory at our institution did not routinely distinguish between HSV-1 and HSV-2. Only patients who had HSV detectable by PCR were included in this study, so it is possible that cases in which the viral copy numbers were below the level of detection of the PCR assay may have been excluded. This had been reported in immunocompromised patients.34
The experience of our institute as a tertiary care center may reflect a referral bias with an over-representation of immunocompromised hosts. In addition, the high proportion of immunocompetent patients transferred from outside hospitals may reflect a sicker patient cohort and may thus underestimate the difference in outcome between the 2 groups. The literature review may also be biased in selectively reporting cases of atypical presentation of HSE in immunocompromised hosts.
Thus, the immunodeficiency state may alter the extent and magnitude of HSE-associated CNS injury. HSE with atypical clinical presentations, CSF profile of low white cell count or polymorphonuclear cells predominance, and widespread MRI abnormalities were more likely in immunocompromised hosts. HSE in immunocompromised hosts had a more rapid course of progression with increased morbidity and mortality. Immunocompromised state, lower CSF white cells, and delayed administration of acyclovir were associated with worse outcomes.