Disseminated herpes zoster with acute encephalitis in an immunocompetent elderly man

Abstract

Varicella-zoster virus (VZV) encephalitis typically occurs in immunosuppressed populations such as in patients with HIV/AIDS, transplantation and autoimmune disease. However, it can also occur in healthy hosts. We present the case of an immunocompetent patient who presented with a clinical picture of VZV encephalitis with the sole precipitating factor of advanced age. We want to stress the importance of including VZV in the differential diagnosis for encephalitis in healthy elderly hosts. In patients with a clinical diagnosis of encephalitis, the presence of herpes zoster rash increases the likelihood of VZV encephalitis. However, the absence of a skin rash may not exclude the diagnosis. In general, there is an elevated risk of transient ischaemic attack and stroke associated with the diagnosis of herpes zoster infection. Early treatment is essential to prevent complications, including death.

Background

Varicella-zoster virus (VZV) is a double-stranded DNA virus that belongs to the Alphaherpesvirinae subfamily.¹ VZV can manifest in different forms, including varicella infection, herpes zoster and severe disseminated disease.²

Primary infection by VZV presents as varicella, which is colloquially known as chickenpox.¹ This syndrome commonly manifests in children and presents with fever and diffusely scattered and pruritic vesicular rash that occurs most frequently on the trunk, head and face.^{3 4} The skin lesions occur in crops of outbursts, transforming from papules to vesicles and then crusting over in the span of a few days.³ It is highly contagious and usually benign.^{1 3} The primary infection presentation is often limited and usually lasts about a week.³

Herpes zoster is the reactivation of VZV which has remained latent in the dorsal root ganglia following a primary infection.¹ It classically presents with a sensation of localised burning pain that occurs prior to the appearance of a vesicular rash scattered along one or adjacent dermatomes.⁴ The risk of shingles is increased in ageing patients and immunosuppression, which is correlated with declining immune responses specific to the virus.¹

Severe disseminated disease can be defined by encephalitis, hepatitis, pneumonitis and/or diffuse rash over the body. Encephalitis may occur before or after the presentation of a rash or even without a rash.^{3 4} This complication is rare and may possibly be under-reported.³ VZV encephalitis has been documented to manifest in severely immunocompromised individuals.^{5 6}

VZV is found worldwide but is more common in temperate climates.⁴ The annual incidence of herpes zoster is about 1.5–3.0 cases per 1000 persons in the USA.¹ The lifetime risk of herpes zoster is about 10%–20%.¹ As stated above, the increase in age is associated with an increased risk of herpes zoster. In fact, the incidence of shingles among patients older than 75 years is higher than 10 cases per 1000 persons.¹ We report a case of an elderly man without previous history of zoster vaccination who presented with VZV encephalitis and diffuse herpes zoster skin rash with old age as the only precipitating factor.

Case presentation

An 86-year-old man with mild cognitive impairment who had not seen a physician for 25 years was brought to the emergency department by his wife in August 2019 with a 1-day history of altered mental status, confusion and right-sided facial swelling. At baseline, he had been fully oriented and capable of performing all activities of daily living prior to presentation. His medical history was significant for chickenpox, glaucoma and bilateral cataract surgery. Four days prior to admission he began having increased fatigue and frontal headache followed by the development of somnolence and confusion. The evening before his presentation he began speaking nonsensically, had hallucinations and developed swelling over his right eye with redness and watery discharge. He had no history of malignancy, HIV, recent steroid use or immunosuppressive medication use. He did not receive the zoster vaccine in the past.

On examination, he appeared ill and was alert and oriented to self only. He was afebrile with the blood pressure of 165/101 mm Hg, the pulse of 71 beats/min and regular, respiratory rate of 15 breaths/min and oxygen saturation of 98% on room air. Skin examination was remarkable for the vesicular, erythematous rash on the right side of his face involving the trigeminal distribution (V1, V2 and V3 dermatomes) with scattered vesicles near his lips and chin and yellow crusting (figure 1). Hutchinson’s sign was positive for a vesicle over the tip of the nose. Vesicles were also noted on the right palate with some crossing midline as well as on the trunk and extremities. Eye examination showed right conjunctival chemosis with yellow exudate and crusting along with swelling of the right eye. On neurologic examination, he was confused with poor concentration and unable to follow any commands but did not have any cranial nerve or motor deficits. Within a few hours of presentation, his vesicular rash had worsened on the trunk and extremities. Ophthalmology consult confirmed the presence of Hutchinson’s sign without corneal involvement.

Figure 1.

Right V1–V3 (trigeminal) dermatomal distribution of herpes zoster rash with Hutchinson’s sign (presence of vesicle over tip of the nose).

Investigations and diagnosis

White blood cells were 12.0×10⁹/Lon presentation with 75.2% neutrophils, 8.4% lymphocytes, 16.0% monocytes, 0% eosinophils and 0.3% basophils. CT of the head without contrast and chest radiograph were unremarkable for acute processes. Due to concern for disseminated herpes zoster and suspected meningoencephalitis he underwent a lumbar puncture which was consistent with aseptic meningitis. Total nucleated cells were 18/µL with 52% lymphocytes, 4% neutrophils and 44% monocytes/macrophages. Total protein was elevated to 119 mg/dL (normal range 15–45) and glucose 65 mg/dL (normal range 40–75). No organisms were noted on cerebrospinal fluid (CSF) gram stain, and over the next few days his CSF and blood cultures returned negative. CSF and skin lesion real-time PCR returned positive for VZV DNA. CSF was negative for herpes simplex virus 1 and 2 (HSV1 and HSV2) DNA. HIV antigen/antibody immunoassay was negative.

Treatment

He was started empirically on intravenous vancomycin, ceftriaxone, ampicillin and acyclovir after lumbar puncture. Antibiotics were discontinued after CSF analysis did not suggest bacterial meningitis and results of CSF and blood cultures were negative; however, intravenous acyclovir was continued for 7 days. Over this period, he became more awake and alert. His orientation improved to person and place. He was then transitioned to oral valacyclovir for 14 days on discharge per infectious disease recommendations, for a total of 21 days of antiviral treatment. He was discharged from hospital to a skilled nursing facility (SNF).

Outcome and follow-up

After discharge to a SNF, the patient remained oriented to person and place for more than a week before being readmitted with increased confusion, decreased orientation and altered level of consciousness. Further workup revealed complicated urinary tract infection in the setting of urinary retention due to benign prostatic hyperplasia. Despite being treated with appropriate antibiotics, his mental status did not improve. MRI revealed a small late subacute to chronic right thalamic infarct (figure 2). Electroencephalogram (EEG) did not reveal seizures but showed mild encephalopathy (figure 3). He then underwent a second lumbar puncture which again revealed aseptic meningitis. VZV PCR returned negative at this time. His wife elected to pursue comfort care and requested for withdrawal of aggressive treatment. He was subsequently discharged to hospice care 1 month after initial presentation.

Figure 2.

MRI head T2/fluid-attenuated inversion recovery (FLAIR) image showing right thalamic and left frontal hyperintense lesion (right image with white arrow). Image showing T1 (middle) and diffusion weighted image (left) of the lesions.

Figure 3.

Electroencephalogram profiles from second hospitalisation showing mild encephalopathy.

Discussion

Of the 36 cases of VZV encephalitis reported in medical literature, more than half of the patients were found to be immunosuppressed (table 1). Among the reported cases, 25 patients (69%) were found to have herpes zoster rash. The rash was more common in 76% of immunocompromised patients with VZV encephalitis. Eighteen out of 36 cases were older than 65 years, and 6 of this subset were immunocompromised. This indicates that old age alone could be an important precipitating factor for VZV encephalitis regardless of immunosuppression status.

Table 1.

Published cases of VZV encephalitis

References	Patient age (years)	Sex	Medical history	Immune status	Rash location	Diagnosis	Treatment	Outcome
Edgar19	36	F	AIDS	Compromised	None	Brain biopsy	N/A	N/A
Gilden20	54	M	AIDS	Compromised	None	CSF	Acyclovir, foscarnet	Expired 2 weeks after admission
Gilden20	34	M	AIDS	Compromised	None	CSF	Acyclovir	Improved
Nakane21	71	M	N/A	N/A	None	CSF	N/A	N/A
McKelvie22	67	F	NHL, breast and colon cancer	Compromised	Present	CSF	Acyclovir	Expired 15 days after onset
Toledo23	37	M	AIDS	Compromised	R trunk	CSF	Acyclovir	Improved
Hackanson24	53	M	IgG kappa plasma cell leukaemia, stem cell transplant, GVHD	Compromised	Several thoracic dermatomes and oropharynx	CSF	Acyclovir	Expired 2 days later
Hackanson24	72	F	AML, stem cell transplant 3 months prior, GVHD	Compromised	R sided S1 and S2 segments	CSF	Acyclovir	Expired 24 days after presentation
Fukuno25	35	M	Myelodysplastic syndrome, overt leukaemia, transplant	Compromised	L thoracic region	CSF	Acyclovir for 40 days	4 months with incomplete resolution
Chuang26	34	M	Renal transplant	Compromised	Head and ears, face, neck trunk, extremities	Serum: positive IgM, positive IgG. Brain MRI: tiny infarcts of L pon	Acyclovir for 12 days, Valacyclovir for 2 weeks	Full recovery on HOD 7
Braun-Falco27	90	F	N/A	N/A	V1	CSF	Acyclovir, steroids	Improved with mild focal deficits
Braun-Falco27	83	F	Stroke	Competent	V1	CSF	Acyclovir, steroids	None
Braun-Falco27	82	F	Dementia	Competent	V1	No CSF growth	Acyclovir, steroids	None
Braun-Falco27	79	F	DM, kidney insufficiency	Competent	C3–4, T2–4	CSF	Acyclovir, steroids	Improved with mild focal deficits
Eskiizmir28	19	M	None	Competent	L cymba concha of auricle	CSF	Acyclovir	Improved with mild focal deficits
Buccoliero29	38	F	Psoriatic arthritis, treatment with Adalimumab	Compromised	Trunk	CSF	Acyclovir	Full recovery at 2 months
Klein30	53	F	DM2, asthma, bipolar	Competent	None	CSF	Valacyclovir for 21 days	Full recovery in 1 week
Cunha31	75	F	None	Competent	L forehead	CSF	Acyclovir	Full recovery
Kangath32	30	F	Previous varicella infection	Competent	L lumbar	CSF	Acyclovir for 7 days, valacyclovir for 2 weeks	Full recovery
Elwir33	71	M	Ulcerative colitis, varicella	Compromised	R upper extremity, L chest	CSF	Acyclovir	Full recovery
Saxena34	40	M	None	Competent	Abdomen	CSF	Acyclovir	Full recovery
Alonso35	41	M	HTN, smoker	Competent	None	CSF	Acyclovir	Full recovery
Nabi36	73	F	Kidney transplantation, Recent CMV infection	Compromised	N/A	CSF	Acyclovir	Full recovery
Ellis7	85	F	Alzheimer’s, recent UTI	Competent	R upper extremity	CSF	Valacyclovir for 21 days	Full recovery after 21 days
Halling37	22	M	Previous varicella infection	Competent	None	Brain biopsy	Valacyclovir	Full recovery at 1 year
Teodoro38	72	M	None	Competent	L ophthalmic distribution	CSF, temporal artery biopsy	Valacyclovir, then acyclovir 3 weeks	N/A
Chai39	33	F	Homeless, HIV	Compromised	Diffuse	Skin biopsy	Acyclovir	Full recovery at 1.5 years
Issa40	66	F	MS	Compromised	None	CSF	Acyclovir for 11 days, continued due to worsening mental status for unknown time	N/A
Afsrikordehmahin F41	40	F	HIV	Compromised	Bilateral eyelids and lose, bilateral lower extremities	CSF	Acyclovir, steroid for 21 days	Expired in 46 days
Bradshaw MJ42	57	F	Renal transplant	Compromised	Arm, L ear pinna	CSF	Acyclovir	Full recovery
Bennett L43	68	F	None	Competent	None	CSF	Acyclovir	Improved with mild focal deficits
Fujisato S44	69	M	Amiodarone associated ILD, steroid use. DM2, CKD	Compromised	Genital region, Left thigh, abdomen	CSF	Acyclovir	Expired due to aspiration pneumonia
Yamashiro N45	90	M	N/A	N/A	R ear	CSF	Acyclovir	Expired after melena
Sullivan NL46	19	F	None, recent corticosteroid use	Compromised	L axillary	CSF	N/A	Full recovery at 3 months
Cao DH47	66	M	HTN	Competent	None	CSF	Acyclovir for 21 days	Improved with mild focal deficits
Quan SC48	70	M	None	Competent	Thoracic dermatome	CSF and aqueous humour	Acyclovir	Full recovery

AIDS, acquired immunodeficiency syndrome; AML, acute myeloid leukemia; CKD, chronic kidney disease; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DM, diabetes mellitus; GVHD, graft versus host disease; HIV, human immunodeficiency virus; HOD, hospital day; HTN, hypertension; ILD, interstitial lung disease; L, left; MS, multiple sclerosis; N/A, not available; NHL, non-Hodgkin's lymphoma; R, right; UTI, urinary tract infection; VZV, varicella-zoster virus.

Available literature reveals that VZV encephalitis is rare. Only 0.1%–0.2% of patients with disseminated varicella-zoster have been reported to have manifestations of encephalitis.⁷ In a retrospective study of adult patients with positive herpes simplex or varicella zoster PCR from CSF samples, only 5 out of 98 adults (5.1%) were identified to have VZV encephalitis in Houston, Texas, from 2004 to 2014 and New Orleans, Louisiana, from 1999 to 2008.⁸ In another study of 514 consecutive HIV patients with neurological disease, 13 patients (2.5%) had VZV DNA positive in the CSF and only four patients (0.7%) had encephalitis or meningoencephalitis.⁹ In a retrospective observational study of 238 567 patients hospitalised for encephalitis in the USA from 2000 to 2010, VZV encephalitis was estimated to account for 0.4% of the hospitalisation. Total deaths recorded were 44, and the mortality of encephalitis hospitalisation was calculated to be 4.6 per 100 persons for VZV encephalitis.¹⁰

Although coined VZV encephalitis, this disease is actually a vasculopathy affecting both small and large arteries. VZV large vessel arteritis, also known as granulomatous arteritis, typically affects the anterior circulation (carotid, anterior and middle cerebral arteries) in elderly immunocompetent adults and presents as focal neurologic deficit weeks to months after shingles in the contralateral trigeminal distribution. Pathology of these arteries has shown multinucleated giant cells and Cowdry bodies similar to those seen in HSV. In small vessels, symptoms include headache, fever and altered mental status and typically occur in immunocompromised individuals.^{11 12} Parenchymal infiltration with or without demyelination can also occur in areas contiguous with impaired cerebral vasculature or blood-brain barrier.^{2 11 12} In the case of our patient’s initial presentation, the symptoms of headache, altered mental status and confusion suggest a mixed vasculitis picture. However, since his central nervous system (CNS) complication occurred in a small window of time with the zoster, it is more likely to be diagnosed as encephalitis. His second presentation with increased confusion and the MRI revealing the lesion at the grey–white matter junction in the frontal lobe is more consistent with small vessel vasculopathy.

In a 2018 meta-analysis, herpes zoster infection was found to be associated with a 1.5-fold increased risk of stroke (95% CI: 1.46 to 1.65) within 4 weeks of onset of zoster. A sub-analysis found a higher risk of stroke in younger individuals presenting with herpes zoster, patients presenting with ophthalmic zoster and patients not prescribed antivirals. Stroke risk within 4 weeks of ophthalmic zoster was found to be 1.77 (95% CI: 1.53 to 2.05) compared with 1.44 (95% CI: 1.46 to 1.65) following zoster in any other presentation. Antiviral use appeared to decrease the stroke risk in two out of three studies; however, this difference was not statistically significant.¹³ Similarly, a 2019 meta-analysis found higher risk of cerebrovascular events in patients younger than 40 years of age and noted that individuals had 1.3-fold to 4-fold increased risk of stroke with exposure to herpes zoster.¹⁴ This markedly increased risk of stroke can be explained by the fact that younger populations already have a low risk of stroke and thus the increased risk with zoster appears relatively large.¹³

In the largest US study to date on herpes zoster (n=69 717), the incidence rate ratio (IRR) of transient ischaemic attack (TIA) in the 4 week prodromal period prior to diagnosis of zoster to the 52 weeks afterwards was 5.12 (p=0.02) in adults aged 18 through 49. For adults older than 50 years, the IRR was 1.4 (p=0.05). In all age groups combined, the IRR was 1.56 (p=0.007). No statistically significant increased risk of stroke was found in any of these subsets within this 56-week span.¹⁵ For our patient, the thalamic infarct seen on MRI was thought to have occurred 1 week after the diagnosis of zoster and therefore attributable to VZV.

In view of the above discussion, it is important to include VZV in the differential diagnosis for encephalitis in both immunocompromised and immunocompetent hosts even in the absence of rash. Old age is a precipitating factor for VZV encephalitis even in the absence of immunosuppression. Given that this virus is the second most common cause of encephalitis in developed countries behind HSV and can have devastating complications, a lumbar puncture must be performed promptly to rule out meningoencephalitis and early treatment is vital. Furthermore, MRI of the brain with T1, T2 and fluid-attenuated inversion recovery (FLAIR) sequences is the first-line imaging with CT with and without contrast as an alternative if emergent MRI cannot be performed.¹⁶ In our case, MRI was not performed on initial admission as CT had already been performed in the emergency department prior to the patient being transferred to the internal medicine service and an alternative brain imaging modality would not have changed management in view of confirmed diagnosis and initial clinical improvement.

Based on available studies, there is an increased risk of TIA or stroke around the diagnosis of herpes zoster infection. The use of antiviral may decrease this risk, but the effect is not statistically significant.^{13 15} During the second admission, our patient was found to have a small late subacute to chronic right thalamic infarct on MRI, raising suspicion for the correlation of the infarction with his previous diagnosis of VZV meningoencephalitis. However, MR angiography was not pursued due to family wishes to have patient in hospice, and therefore, the infarction seen is likely due to zoster but not proven. MR angiography would have been helpful to diagnose CNS vasculitis during the admission and to evaluate for segmental vessel constriction or post stenotic dilatation.

In addition, estimation of sedimentation rate (ESR), C-reactive protein and systemic autoimmune antibodies would have been helpful to help exclude systemic autoimmune vasculitis but these tests were not collected during the second admission due to family’s wishes to pursue hospice.

The question that arises from this case is why our otherwise healthy patient presented with disseminated VZV infection involving the CNS. Recent evidence shows a link between individuals with mutations in RNA polymerase III coding and severe VZV infection in the CNS. In a study of four cases, healthy children that developed severe VZV infection in the CNS or lungs were found to be heterozygous for a rare missense mutation in POLR3A, POLR3C or both, which are genes coding for RNA polymerase III.¹⁷ These individuals had impaired induction of interferons, which is important for antiviral activity, due to the rare missense mutation.¹⁷ The VZV strains isolated from these four individuals had little sequence variability, which suggest that single-gene inborn errors can predispose otherwise healthy individuals to specific viral infections. In another study, monozygotic female twins experiencing recurrent CNS vasculitis due to VZV reactivation were found to have a rare mutation in the subunit POLR3F of RNA polymerase III.¹⁸ These individuals likewise had impaired antiviral and inflammatory responses.¹⁸ Our patient did not have a known immunodeficiency or autoimmune disorder, but we cannot exclude the heterozygous state for a mutation in his RNA polymerase III leading to decreased antiviral and inflammatory responses, thus causing a severe presentation of VZV involving the CNS.

Finally, little is known about the current epidemiology of VZV encephalitis. Therefore, we suggest conducting further epidemiological studies to know the true prevalence of herpes zoster infection, including VZV encephalitis. This will have an impact on future strategies on primary and secondary prevention of VZV infection and its complications.

Patient’s perspective.

As the wife of an 86-year-old patient presenting with VZV encephalitis, I remember that I thought it was the influenza without all of the influenza symptoms at that time. I did not think it was a brain infection at all. I told my husband to see a doctor from the very beginning, but he refused continuously to see a doctor. Now I see that people should not be able to refuse going to see a doctor. When he started getting worse, that is when I brought him to the emergency room. He did not develop a rash until an hour or so after arriving to the emergency room. I wish they told us that he had the virus infection sooner. I do think he received good medical care though. I think the doctors have done what they could. After he left the hospital, I was not pleased when he went to the skilled nursing home. I am concerned about whether he had received all of his oral medications or proper care at the facility because he came back so quickly to the hospital for a urinary infection after he was hospitalised for the VZV encephalitis.

Learning objectives.

• Varicella-zoster virus (VZV) encephalitis is rare and may present with or without a herpes zoster rash.

• Immunosuppression is a known risk factor for disseminated VZV and encephalitis, however; it may also be seen in immunocompetent patients.

• Old age can be the only triggering factor for VZV encephalitis.

• Herpes zoster infection can be a precipitating factor for transient ischaemic attack or stroke.

• Patients suspected to have VZV encephalitis should be started on empiric treatment as soon as possible to prevent complications.