Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon

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Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon Infection à virus varicelle-zona du système nerveux central dans un centre de soins tertiaires au Liban H. Tabaja a,1 , S.L. Sharara b,1 , Y. Abi Aad a,b,1 , N. Beydoun b,1 , S. Tabbal c , A. Makki c , R. Mahfouz d , S.S. Kanj a,∗ a Infectious Diseases Unit, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon b The School of Medicine, American University of Beirut Medical Center, Beirut, Lebanon c The division of Neurology, American University of Beirut Medical Center, Beirut, Lebanon d The division of Diagnostic Molecular Pathology, Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon

a r t i c l e

i n f o

Article history: Received 17 June 2018 Received in revised form 20 August 2018 Accepted 27 August 2019 Available online xxx Keywords: Encephalitis Meningitis Meningoencephalitis Varicella zoster virus

a b s t r a c t Objective. – To describe the clinical manifestations and treatment outcomes of patients with VZV meningitis and encephalitis consulting at two medical centers in Lebanon. Methods. – Retrospective study of patients with VZV meningitis and/or encephalitis confirmed by positive cerebrospinal fluid (CSF) VZV PCR. Results. – Twenty patients were identified (13 males). The average age was 49.7 ± 22.2 years. The most common complaint was headache (n = 17/20). Common comorbidities included hypertension (n = 7/20) and diabetes mellitus (n = 5/20). Immunosuppression was reported in two patients. Vesicles were only observed in eight patients. Altered mental status, focal neurological deficits, and fever were documented in six, two, and four patients respectively. All patients had CSF leukocytosis with lymphocytic predominance, normal CSF/serum glucose ratio, and high CSF protein. Eighteen patients had brain CT scans showing no relevant findings. Two of 12 patients with brain MRI had focal abnormalities. Unilateral temporal slow waves were observed in three of four patients who underwent electroencephalograms. Four patients had encephalitis and 16 had meningitis. Eighteen patients received an antiviral therapy. Treatment either included intravenous acyclovir or oral valacyclovir. The encephalitis and meningitis groups had comparable mean duration of treatment (13.5 ± 6.6 vs. 12.2 ± 5.4, respectively). All admitted patients showed clinical cure with no reported neurological sequelae. Conclusion. – VZV infection should be suspected in any patient with signs and symptoms of viral meningitis or encephalitis, irrespective of age, immune status, presence or absence of vesicles, fever, or neck stiffness. © 2019 Elsevier Masson SAS. All rights reserved.

r é s u m é Mots clés : Encéphalite Méningite Méningoencéphalite Virus varicelle-zoster

Objectif. – Décrire les manifestations cliniques et les résultats thérapeutiques des patients atteints de méningite ou d’encéphalite à VZV dans deux centres médicaux libanais. Méthodes. – Étude rétrospective de patients atteints de méningite et/ou d’encéphalite à VZV confirmées par PCR dans le liquide cephalorachidien. Résultats. – Vingt patients ont été identifiés, dont 13 hommes. L’âge moyen était de 49,7 ± 22,2 ans. Le symptôme le plus commun était les céphalées (n = 17/20). Les comorbidités incluaient l’hypertension (n = 7/20) et le diabète (n = 5/20). Deux patients étaient immunodéprimés. L’éruption cutanée était

∗ Corresponding author. E-mail address: [email protected] (S.S. Kanj). 1 H. Tabaja and S.L Sharara have contributed equally as primary authors while Y. Abi Aad and N. Beydoun have contributed equally as secondary authors on this paper. https://doi.org/10.1016/j.medmal.2019.08.005 0399-077X/© 2019 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Tabaja H, et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.08.005

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présente chez huit patients. Des symptômes psychiatriques, des déficits neurologiques focaux et une fièvre ont été documentés respectivement chez six, deux et quatre patients. Tous les patients avaient une leucocytose du LCS avec une prédominance lymphocytaire. Dix-huit patients avaient des résultats de tomodensitométrie cérébrale normaux. Parmi les 12 patients ayant passé une IRM cérébrale, deux présentaient des anomalies. L’électroencéphalogramme de trois patients sur les quatre ayant bénéficié de cet examen montrait des ondes lentes temporales. Quatre patients avaient une encéphalite et 16 une méningite. Dix-huit patients ont rec¸u un traitement antiviral par acyclovir par voie intraveineuse ou par valacyclovir pour une durée moyenne de traitement comparable (13,5 ± 6,6 jours contre 12,2 ± 5,4, respectivement). Tous les patients admis ont montré une guérison clinique sans séquelle. Conclusion. – L’infection à VZV doit être suspectée chez tout patient présentant une image de méningite ou d’encéphalite virale, indépendamment de l’âge, du statut immunitaire, de l’absence d’éruption vésiculaire, de fièvre ou de raideur cervicale. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv

1. Introduction Varicella zoster virus (VZV) causes a wide spectrum of disorders including chickenpox, herpes zoster, and central nervous system (CNS) infections. It has the ability to remain latent in neurons of the cranial nerves, dorsal root ganglia, and autonomic ganglia after primary infection and can reactivate later in life [1]. During reactivation, VZV can cause various CNS infections, including meningitis and encephalitis [2]. Significant morbidity and mortality can be associated with these conditions despite antiviral therapy [2]. Such infections are thought to mainly affect the elderly and immunocompromised individuals; however, disease involvement in young and immunocompetent patients has been increasingly reported [3–6]. Furthermore, while VZV reactivation is usually associated with vesicles, a significant number of VZV CNS infections present without any skin manifestations [2–4,6]. Early diagnosis could thus be challenging due to the lack of clear clinical signs. VZV is currently recognized as the second or third most common cause of aseptic meningitis in adults [4,7–10], and as the second most common infectious etiology of encephalitis [6,10–13]. Nevertheless, VZV meningitis and encephalitis have not been extensively reported in the literature. More importantly, treatment guidelines are based on low-level evidence derived from few descriptive studies and expert opinion [4,14]. Our study describes the clinical manifestations, laboratory and radiographic abnormalities, treatment outcomes, and complications of patients with VZV meningitis and encephalitis consulting at two medical centers in Lebanon. 2. Methods 2.1. Study design We performed a retrospective study between January 1, 2008 and November 11, 2016 at the American University of Beirut Medical Center (AUBMC) and its affiliate, the Keserwan Medical Center (KMC). The study was approved by the Institutional Review Boards of both AUBMC and KMC. Adult patients ≥ 18 years of age were recruited from the database of the Molecular Diagnostics Laboratory of AUBMC if they had a positive VZV PCR in cerebrospinal fluid (CSF). Molecular detection of VZV, which became available at AUBMC in 2008, was performed using the artus VZV RG PCR Kit (QIAGEN, Cambridge, UK) on the Rotor-Gene Q platform. The analytical detection limit of the kit is 0.136 copies/␮l. 2.2. Definitions and diagnostic criteria Subjects were diagnosed with VZV meningitis or encephalitis if they had CSF leukocyte count >5 cells/mm3 , negative CSF bacterial cultures, positive VZV PCR in CSF, and at least one of the

following symptoms: headache, neck stiffness, nausea/vomiting, altered mental status, focal neurological manifestations, seizures, fever (temperature >38 ◦ C), and behavioral changes [3,15]. The diagnostic criteria outlined by the International Encephalitis Consortium for encephalitis or encephalopathy of presumed infectious or autoimmune etiology was used to distinguish between encephalitis and meningitis (Table 1) [16]. Subjects fulfilling the aforementioned criteria were classified as having probable or possible encephalitis, while all other patients were considered as having meningitis. 2.3. Data collection A medical chart review was performed to collect patients’ demographic and clinical data. 3. Results Twenty patients were included in our study; a summary of their characteristics is presented in Table 2. Most patients were males Table 1 The International Encephalitis Consortium diagnostic criteria for encephalitis and encephalopathy of presumed infectious or autoimmune etiology [16]. Critères diagnostiques du Consortium international de l’encéphalite pour l’encéphalite et l’encéphalopathie de l’étiologie présumée infectieuse ou auto-immune [16]. Major criterion (required) Altered mental statusa lasting ≥ 24 hours with no identified alternative etiology Minor criteria Documented fever (≥ 38 ◦ C) within 72 hours prior to or post hospitalization Seizure not entirely attributable to a prior seizure disorder New focal neurological deficit CSF leukocyte count ≥ 5/mm3 Acute or new onset of brain parenchyma abnormality observed on neuroimaging suggestive of encephalitis Abnormal activity on electroencephalogram (EEG) suggestive of encephalitis with no identified alternative etiologyb Interpretation “Possible” encephalitis: major criterion + 2 minor criteria “Probable” or “confirmed”c encephalitis: major criterion + ≥ 3 minor criteria CSF: Cerebrospinal fluid. a Defined as altered mental status, lethargy, or change of personality. b EEG findings are often nonspecific and may be explained by other causes including medications or metabolic disorders. Abnormalities reported in encephalitis cases vary and range from nonspecific generalized slow waves to distinctive patterns indicative of particular causes such as lateralized epileptiform activity or temporal lobe sharp wave complexes seen in herpes simplex virus encephalitis. c In addition to the above criteria, “confirmed” encephalitis requires at least one of the following: 1. brain pathology confirming inflammation; 2. pathological, microbiological, or serological testing of appropriate clinical specimen confirming infection with a pathogen strongly associated with encephalitis; 3. laboratory-confirmed autoimmune disease strongly associated with encephalitis.

Please cite this article in press as: Tabaja H, et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.08.005

Reported symptoms (RS)/Physical exam (PE)

Brain CT scan

Brain MRI

EEG

Diagnosish

Antiviral treatment duration

1

78/M

Diabetes mellitus

16

RS: AMS, fall, eyelid swelling, rash PE: lethargy, disorientation, dysarthria, vesicular lesions on right eyelid and nasal bridge

Diffuse atrophy and periventricular small vessel ischemic disease

Mild brain atrophy and small vessel ischemic disease

MEN

15 days IV + 6 days oral

2

34/M

None

10

Normal

Normal

MEN

15 days IV

3

62/F

None

14

RS: severe headache, fever, chills, myalgia, nausea PE: no relevant findings RS: fever, AMS, rash PE: confusion, disorientation, expressive aphasia, vesicular lesions on right shoulder

Diffuse slow waves (agerelated changes) –

Normal

Hyperintense cortical signal on left temporal lobe and amygdala Meningeal enhancement of temporal lobes

Probable ENC

14 days IV

4

20/M

History of zoster episode

8

Normal

–

Slow centrotemporal waves on left hemisphere –

MEN

7 days IV + 7 days oral

5

24/F

13

Normal

Normal

Probable ENC

5 days IVd

6

74/F

–

Right facial nerve enhancement

91/M

Normal

–

–

8

80/F

Chronic ischemic changes

–

9

45/M

MD

7

RS: severe headache, nausea, vomiting, phonophobia, photophobia, rash PE: vesicular lesions on right shoulder

Moderate small vessel ischemic disease and old lacunar infarct in the left frontal white matter and right basal ganglia –

Ramsay Hunt syndrome and MEN Possible ENC MEN

14 days IV

7

Traumatic brain injury, obese DM, CAD, CAa , ISb , congenital single kidney, hyper-T AZ, HTN, DL, BPH DM, CVA, HTN, DL, PVD, OP

–

MEN

4 days oral + 15 days IVe

10

32/M

–

5

RS: severe headache, fever, nausea, vomiting, phonophobia, photophobia, rash, neck stiffness PE: neck stiffness, (+) kernig’s sign, vesicular lesions on the back

Normal

–

MEN

10 days IV

15

4 14

RS: severe headache, diarrhea, fever, photophobia, rash, neck stiffness PE: neck stiffness, (+) kernig’s sign, vesicular lesions on anterior chest RS: severe headache, vomiting, phonophobia, AMS PE: fever (38.4 ◦ C), confusion, disoriented, agitated, dorsiflexion on Babinski RS: mild headache, stiff neck, fever, chills, right ear pain, dizziness, right facial weakness, rash PE: neck stiffness, right facial weakness, dysarthria, vesicular lesions (unspecified site) RS: fever, AMS PE: fever (38.1 ◦ C), lethargy, disorientation RS: severe headache, fever, nausea, vomiting, photophobia, AMS, neck stiffness PE: lethargy, disorientation, neck stiffness

Mucosal disease of both maxillary and frontal sinuses and almost complete obliteration of the ethmoid air cells –

Right temporal slow waves –

14 days IV 8 days IVd

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Table 2 Characteristics of patients (n = 21). Caractéristiques des patients (n = 21).

3

Brain CT scan

Brain MRI

EEG

Diagnosish

Antiviral treatment duration

11

47/F

DL

17

Normal

–

–

MEN

12

26/M

–

7

Normal

–

–

MEN

14 days IV + 7 days oral 7 days IV

13

55/M

DM, HTN, psoriasis, ISc

8

Normal

–

–

MEN

14 days IV

14

26/M

–

1

Normal

Normal

–

MEN

Nonef

15

52/F

8

–

Normal

–

MEN

7 days IV

16

47/M

Previous zoster episode, HTN, AVR TBI, HTN

RS: severe headache, fever, chills, nausea, vomiting PE: no relevant findings RS: severe headache, rash, neck stiffness PE: neck stiffness, (+)kernig’s sign, (+)brudzinski’s sign, vesicular lesions (unspecified site) RS: severe headache, nausea, photophobia, phonophobia, fever, chills, rash, neck stiffness PE: fever (38.1 ◦ C), neck stiffness, vesicular lesions on left axilla and scapula RS: moderate headache, fever, chills, nausea, photophobia, left sided body numbness PE: fever (38.2 ◦ C), left lower and upper extremity decreased sensation to light and pinprick touch by 60% RS: severe headache, neck pain, nausea PE: no relevant findings

0h

Normal

Normal

–

MEN

Noneg

17

31/M

–

8

Normal

–

–

MEN

6 days IV + 1 day oral

18

26/F

–

5

Normal

Normal

–

MEN

7 days IV

19

72/M

DM, TIA, HTN

16

Normal

Left temporal slow waves

Possible ENC

16 days IV + 5 days oral

20

72/M

HTN, hypo-T

5

Multiple foci of high FLAIR signal in white matter representing combination of normal brain ageing and mild form of small vessel ischemic disease –

–

MEN

7 days oral

RS: severe headache PE: no relevant findings RS: severe headache, N/V photophobia, phonophobia, neck stiffness PE: neck stiffness RS: severe headache, N/V, chills, neck stiffness PE: neck stiffness, (+)kernig’s sign, (+)brudzinski’s sign RS: mild headache, nausea, AMS PE: confusion, disorientation, expressive aphasia

RS: severe headache PE: no relevant findings

Normal

All patients had CSF leukocyte count > 5 cells/mm3 . AMS: altered mental status, AVR: aortic valve replacement; AZ: Alzheimer’s disease; BPH: benign prostatic hyperplasia; CA: cancer; CAD: coronary artery disease; CVA: cerebrovascular accident; DL: dyslipidemia; DM: diabetes mellitus; ENC: encephalitis; FMF: familial mediterranean fever; HTN: hypertension; Hyper-T: hyperthyroidism; Hypo-T: hypothyroidism; IS: immunosuppression; MD: migraine disorder; MEN: meningitis; N/V: nausea/vomiting; OP: osteoporosis; PVD: peripheral vascular disease. a Metastatic breast cancer b Chemotherapy (vinorelbine and capecitabine) c Biological agents (initially on adalimumab then switched to ustekinumab) d Treatment discontinued early due to acute kidney injury e Patient received 4 days of oral valacyclovir for vesicular rash prior to hospitalization and was switched to IV acyclovir when presenting with meningitis f Patient had rapid resolution of symptoms on IV hydration; treatment was therefore deemed unnecessary. g Left against medical advice after lumbar puncture procedure h Diagnosis of encephalitis according to Venkatesan et al. The International Encephalitis Consortium Diagnostic Criteria for Encephalitis and Encephalopathy of Presumed Infectious or Autoimmune Etiology [16].

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Table 2 (Continued)

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level was 1.6 ±1.0 g/l (median 1.3 g/l, range 0.5–3.7 g/l). One patient had CSF bacterial culture growing diphtheroids, likely representing contamination.

Table 3 Symptoms of patients (n = 20). Symptomatologie (n = 20). Symptoms

Number of patients (Count, %)

Headache Severity of headache Mild Moderate Severe Fever prior to hospitalization Nausea Vomiting Seizures Altered mental status Syncope Phonophobia Photophobia Neck stiffness Chills Zoster Dizziness Facial paralysis Other

17 (85%)

a b

5

2 (10%) 1 (5%) 14 (70%) 10 (50%) 11 (55%) 7 (35%) 0 6a (30%) 1 (5%) 5 (25%) 7 (35%) 8 (40%) 6 (30%) 8 (40%) 1 (5%) 1 (5%) 3b (15%)

Lethargy (n = 3) and confusion (n = 3). Ear pain, dizziness, unilateral body numbness, eyelid swelling and redness.

(n = 13/20). The mean age of patients was 49.7 ± 22.2 years. Nineteen patients were hospitalized, while one patient left the hospital against medical advice after lumbar puncture. The mean hospital length of stay was 9.5 ± 4.8 days (median 8 days, range 1-17 days). Common comorbidities included hypertension in 35% of patients and diabetes mellitus in 25%. Immunosuppression, history of zoster episode, and recent head trauma were each observed in only 10% of patients. Based on our defined diagnostic criteria, four patients had either “possible” or “probable” encephalitis and 16 had meningitis. 3.1. Signs and symptoms The mean duration of symptoms prior to hospitalization was 4.3 ± 2.8 days and ranged from a few hours to 10 days. Table 3 outlines the symptoms of patients. The most common symptom was headache (85% of patients, and reported as severe by 82% of them). Other less frequent symptoms were neck stiffness, photophobia, and phonophobia (<50% of patients). In addition, only 30% of patients had altered mental status and 10% had focal neurological deficit. Documentation of the physical examination was not complete for all patients (Table 4). Vital signs were recorded for all patients and only four had documented fever and tachycardia. Of the 20 patients who underwent neck examination, eight presented with stiffness. Kernig’s and Brudzinski’s signs were evaluated in 13 patients, and were positive in four and two, respectively. Babinski sign was observed in only 1 of 18 patients tested. Speech disorder was reported in four out of 18 patients. Interestingly, only 8 of the 20 patients had the characteristic vesicles. 3.2. Laboratory findings Peripheral leukocytosis was detected in only 4 of 19 patients. A lumbar puncture was performed in all 20 patients (Table 5). The average time to lumbar puncture from hospitalization was 12.5 ± 13.5 hours (median: 6 hours; range: 2-48 hours). CSF appearance was consistently clear. All patients had CSF leukocytosis with lymphocytic predominance. Mean CSF leukocyte count was 303.5 ± 467.0 cell/mm3 (median: 112.5 cell/mm3 ; range: 22–2,000 cell/mm3 ). CSF protein level was high while CSF/serum glucose ratio was normal in all patients. The mean CSF protein

3.3. Neuroimaging and electroencephalogram findings Brain computed tomography (CT) scan was performed in 18 patients, none of which had abnormal findings. Twelve subjects had brain magnetic resonance imaging (MRI), with only two patients showing relevant abnormalities (Table 2). Of the six patients with altered mental status, five underwent brain MRI and four underwent electroencephalogram (EEG). One patient had temporal hyperintense signals on MRI, and three patients had unilateral temporal slow waves on EEG (Table 2). 3.4. Management Eighteen patients received an antiviral therapy. An empirical treatment was initiated in 15 treated patients, two guided by the presence of a vesicular rash alone, six by an elevated CSF leukocyte count, five by the presence of both rash and an elevated CSF leukocyte count, and two by unspecified reasons. Three patients received an adapted therapy after positive VZV PCR. Treatment regimens either included oral valacyclovir, intravenous (IV) acyclovir, or a sequential combination of both (Table 2). IV acyclovir was uniformly given at a dose of 10 mg/kg every 8 hours, while oral valacyclovir was uniformly given at a dose of 1 g every 8 hours. The mean time between symptom onset and treatment was 5.1 ± 3.5 days (median: 5 days; range: 0–14 days). Overall, the mean total duration of antiviral therapy was 12.5 ± 5.5 days (median: 14 days; range: 5–21 days). Patients with encephalitis had a comparable mean duration of treatment as those with meningitis (13.5 ± 6.6 vs. 12.2 ± 5.4, respectively). As for the remaining patients, one left against medical advice and was lost to follow-up. The second experienced symptom resolution with IV hydration and painkillers, and was discharged one day after admission. He had no relapse on clinic follow-ups.

Table 4 Physical exam results. Résultats de l’examen physique. Physical exam results Temperature 36.0 ◦ C < t ≤ 37.5 ◦ C 7.5 ◦ C < t ≤ 38.0 ◦ C 38.0 ◦ C < t ≤ 38.5 ◦ C 38.5 ◦ C < t ≤ 39.0 ◦ C Heart rate ≥ 100 Altered mental status Confusion Lethargy Neck stiffness Kernig’s sign Brudzinski Babinski Dorsiflexion Plantar flexion Motor weakness/paralysis Sensory deficits Visual field defect Changes in speech Hallucination Vesicular lesions

Number of positives/number documented [count/total (%)] 16/20 (80%) 0/20 (0%) 4/20 (20%) 0/20 (0%) 4/20 (20%) 3/20 (15%) 3/20 (15%) 8/20 (40%) 4/13 (31%) 2/13 (15%) 1/18 (6%) 17/18 (94%) 1/20a (5%) 1/20b (5%) 0/20 (0%) 4/18c (22%) 0/14 (0%) 8/20 (40%)

a

Right-sided facial paralysis. Significant decrease in sensation to light and pinprick touch on left upper and lower body. c Expressed as dysarthria in two patients and expressive aphasia in two patients. b

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6 Table 5 Laboratory results. Résultats de laboratoire.

Laboratory results

Number of positivesf /number documented (%)

N < 4,000 4,000 ≤ N ≤ 11,000 11,000 < N ≤ 15,000

1/19 (5%) 14/19 (74%) 4/19 (21%)

15,000 ≤ N ≤ 450,000

19/19 (100%)

N < 130a 130 ≤ N < 135 135 ≤ N ≤ 145 BUN > 25 mg/dl GFR < 60 ml/min

1/19 (5%) 3/19 (16%) 15/19 (79%) 0/19 (0%) 0/19 (0%) Number of positives/number documented (%)

Leukocytes (cells/mm3 )

Platelets (cells/mm3 ) Serum sodium (mEq/l)

BUN > 25 mg/dl GFR < 60 ml/min Lumbar puncture studies Contraindication to lumbar puncture Time from hospitalization to lumbar puncture (hours)

CSF appearance Leukocyte count (cell/mm3 )

CSF neutrophil (% WBC) CSF lymphocytes (% WBC)

CSF glucose (mg/dl)c

CSF protein (g/l)d

Qualitative VZV PCR in CSF Time from hospitalization to VZV PCR result (hours)

CSF HSV 1/2 PCR CSF enterovirus PCR CSF bacterial culture

0/20 (0%) Average Median Range Clear > 5 cells/mm3 Average Median Range < 10% > 10% N < 50% 50 < N ≤ 70% 70 < N ≤ 80% 80 < N ≤ 90% 90 < N ≤ 100% N < 35 35 < N ≤ 80 N > 80 N < 0.10 0.10 ≤ N ≤ 0.50 N > 0.50 Positive Average Median Range Negative Negative Positive Negative

12.5 ± 13.5 6 2-48 18/18 (100%) 20/20 (100%) 303.5 ± 467.0 112.5 22-2,000 19/20 (95%) 1/20 (5%)b 0/20 (0%) 1/20 (5%) 0/20 (0%) 3/20 (15%) 16/20 (80%) 1/20 (5%) 17/20 (85%) 2/20 (10%) 0/20 (0%) 0/20 (0%) 20/20 (100%) 20/20 (100%) 61.8 ± 52.1 54 9–240 16/16 (100%) 10/10 (100%) 1/20 (5)e 19/20 (95%)

The definition and diagnostic criteria of viral CNS infection was described previously [Glaser et al., 2003; Persson et al., 2009]. Briefly, a case of meningitis was defined as CSF white blood cell (WBC) count > 5 cell/mm3 and negative bacterial culture from CSF without acute signs of parenchymatous brain dysfunctions and with two or more of the following findings: headache, nausea/vomiting, photophobia, neck stiffness, and fever > 38 ◦ C. A case of encephalitis was defined as encephalopathy (de-pressed or altered level of consciousness lasting 24h, lethargy, or change in personality) and one or more of the following findings: fever, seizure, focal neurologic findings, CSF WBC count > 5 cell/mm3 , and abnormal electroencephalogram or neuroimaging report consistent with encephalitis. Cranial nerve affection was diagnosed if a patient had peripheral facial paralysis and positive VZV DNA in CSF or had eighth cranial nerve complications with disturbance in hearing and balance [Persson et al., 2009]. CSF: Cerebrospinal fluid. a Sodium level of 119 mg/dl. b 14%. c Reference range (35–80 mg/dl). d Reference range (0.10–0.50 g/l). e Diphtheroids from thiol broth. This patient’s CSF had 240 eukocyte cells/mm3 with a lymphocytic predominance (96%), normal glucose (43 mg/dl), and high protein (1.9 g/l) suggestive of a viral cause. f One patient left against medical advice after lumbar puncture and had no blood tests performed; therefore, the “number documented” for peripheral blood tests is 19. In addition, some CSF tests were not uniformly performed for all of our patients; hence, the “number documented” for those tests is < 20.

3.5. Outcomes All patients achieved clinical cure. None required admission to the intensive care unit and there were no reported neurological sequelae. Two patients developed acute kidney injury (AKI) secondary to antiviral drugs and had premature discontinuation of therapy. One of these patients was a young female whose treatment was discontinued five days after initiation. The patient’s symptoms resolved with no relapse. The second patient was an elderly female whose treatment was discontinued eight days after initiation. Her symptoms relapsed five days later. A repeat lumbar puncture showed persistent lymphocytic pleocytosis but negative

VZV PCR. She developed AKI again on IV acyclovir and was switched to oral valacyclovir for a total duration of 21 days. Her symptoms resolved and she was subsequently switched to a one-month suppressive valacyclovir therapy (500 mg orally and daily). 4. Discussion This study elucidates important findings about the natural course of VZV meningitis and encephalitis, as well as the variation between the various patient populations. All patients with encephalitis were not immunocompromised nor immunosuppressed. Varying rates of immunosuppression are reported in the

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literature among patients with VZV encephalitis. Studies from Austria and France reported 15% of immunosuppression among 13 and 20 patients with encephalitis, respectively [17,18]. Comparable rates were reported in publications from Sweden, Korea, and Israel [3,15,19]. However, previous studies from the United States and Switzerland reported that 45% and 50% of patients with encephalitis were immunosuppressed, respectively [5,20]. Conversely, in our meningitis cohort, 12.5% of patients were immunocompromised. This is consistent with previous case series, where reported immunosuppression rates among patients with meningitis were 0%, 12%, and 23% in Switzerland, Austria, and the United States, respectively [5,17,20]. The mean age of patients with encephalitis in our study was 62.25 ± 28.2 years, with 75% of them aged > 50 years. Similarly, the mean age of patients with VZV encephalitis in the literature ranges from 56 to 75 years [5,17,18,20]. Old age has previously been associated with more severe presentations of VZV infections and worse outcomes [21–23]. For example, patients with encephalitis tend to be older than those with meningitis [5,10,15,17,24]. In one study, the mean age of patients with VZV meningitis was 26 years versus 72 years for patients with encephalitis [5]. The mean age of patients with encephalitis included in our study was also higher than those with meningitis (62.25 ± 28.2 years vs. 46.6 ± 20.3 years). Considering this age distribution and that a large proportion of these patients can be immunocompetent, “immunosenescence” may play a role in determining disease severity. Immunosenescence was reported in 50–92% of patients with encephalitis in previous series [5,17,18,20]. However, most of our patients with meningitis (62.5%) were aged below 50 years (average: 46.6 ± 20.3 years). Similarly, the median age of 34 patients with VZV meningitis in Sweden was 40 years [15]. The mean age reported from other countries range from 25 to 50.5 years [5,17,20]. This newly emphasizes that meningitis may predominate in younger patient populations. Only 25% of patients with encephalitis in our study had vesicular rash. This finding contradicts prior studies where higher rates of rash were reported among encephalitis patients ranging between 50% and 84.6% [5,15,17,18,20]. Similar to our encephalitis group, a large proportion of our meningitis patients did not present with skin lesions. The characteristic vesicular rash was only observed in 43.8% of patients. The prevalence of zoster in patients with VZV CNS infections varies in the literature. Some studies reported a rash in more than 70% of patients [7,19,22,25–27], while other studies reported lower rates at 27–50% [5,6,13,17,20,28–30]. Subanalyses performed in some of these studies suggested a higher prevalence of rash among encephalitis cohorts. However, this was not reflected in all publications. For instance, three studies reported the following rash prevalence in encephalitis vs. meningitis cohorts: 64% vs. 23%, 68% vs. 59%, and 85% vs. 65%, respectively [5,15,17]. However, one study reported a 57% rate of rash in meningitis patients compared with 50% in those with encephalitis [20]. In the present study we observed few systemic inflammatory signs. This was also reflected in previous publications [13,20,25]. One multicenter population-based study in England reported that only 50% of patients with VZV encephalitis presented with fever [13]. Moreover, prior series reported normal peripheral leukocyte count and C-reactive protein levels in 55–85% and 55% of patients, respectively [19,20]. However, all of our patients exhibited CSF pleocytosis. This is expected with VZV CNS infections; however, normal CSF leukocyte count has been reported in rare cases, particularly in HIV-infected patients [20]. To date there is no clinical trial assessing the efficacy of antiviral therapy in VZV CNS infections. The Infectious Diseases Society of America (IDSA) published guidelines in 2008 on the management of encephalitis [2,14]. However, these recommendations are

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based on case reports and small-scale case series. There are also no guidelines on VZV meningitis. Therefore, VZV CNS infections are still managed based on the physicians’ preference. According to the IDSA, acyclovir at a dose of 10–15 mg/kg IV every 8 hours for 10–14 days is the reference regimen for encephalitis in patients with normal renal function [2,6,14]. Alternatively, the IDSA recommends the use of ganciclovir based on its efficacy in reported cases. The IDSA indicates there is no reliable data to support the use of corticosteroids in VZV CNS infections [2,14]. High-dose oral acyclovir has been suggested as a potential alternative option in VZV meningitis or encephalitis, but little data supports its use [31,32]. The low bioavailability of oral acyclovir raises some concern. Newer oral antiviral agents such as valacyclovir have better bioavailability than oral acyclovir: 55% and 10–20%, respectively [33]. Moreover, high-dose oral valacyclovir (2 g every 6 hours) has led to a plasma acyclovir area under the concentration-time curve (AUC) value similar to that caused by 10 mg/kg IV acyclovir every 8 hours in previous reports, yet the peak concentrations were less than half of those achieved with IV acyclovir [2]. Therefore, valacyclovir may be a more effective oral medication [2,32]. In a previous case series, valacyclovir was successful in treating herpes simplex virus encephalitis [27]. However, its role in VZV CNS infections is poorly evaluated and is not mentioned in the IDSA guidelines. Overall, 90% of our patients were treated with either IV acyclovir (10 mg/kg every 8 hours), oral valacyclovir (1 g every 8 hours), or a sequential combination of both. The preferred initial therapy in our series was IV acyclovir. Oral valacyclovir was used in 39% of treated patients, but it was mainly used to continue therapy at home after clinical improvement with IV acyclovir. The only exception was a patient treated with a 7-day course of oral valacyclovir alone and who experienced favorable outcome. The mean duration of therapy in our series was 12.5 ± 5.5 days, with similar mean findings in patients with encephalitis and meningitis. Complete treatment courses, not accounting for premature discontinuations, ranged from 7 to 21 days. This mirrors treatment durations from previous case series [20,30]. In our series, treatment durations were not based on a fixed criterion but on the physician’s preference and patient’s clinical response. Interestingly, one young patient had complete resolution of symptoms without receiving any therapy. All of our patients recovered without neurological sequelae. However, this could be attributed to most of our patients having VZV meningitis as opposed to encephalitis which has been shown to be associated with worse clinical outcomes. A study in Sweden reported that 50% of patients with VZV meningitis had neurological sequelae at one month of follow up, compared with 77% of patients with encephalitis [15]. A case series from France reported neurological sequelae in up to 45% of VZV encephalitis patients, with 50% having persistent moderate to severe sequelae after a three-year follow up [30]. However, studies of patients with VZV meningitis revealed conflicting results, with all or most patients recovering without neurological sequelae [17,23]. VZV encephalitis is also associated with high case fatality rates, ranging from 5% to 20%, especially among the elderly [12,17,23,30]. This has been hypothesized to be due to the neuronal damage and astrogliosis associated with encephalitis compared with meningitis [23]. The present study adds to the limited literature on VZV meningitis and encephalitis, particularly in younger and immunocompetent populations. The limitations of the study include the small number of patients and its retrospective nature, limiting the long-term follow-up of patients for neurological sequelae. Another limitation is that only patients with a positive VZV PCR in CSF were included, whereas several cases have been reported with CNS manifestations and vesicles with a negative VZV PCR [22,30].

Please cite this article in press as: Tabaja H, et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.08.005

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5. Conclusion VZV CNS infection should be suspected in any patient presenting with signs and symptoms suggestive of viral CNS infection irrespective of age, immune status, presence or absence of skin lesions, fever, or neck stiffness. Antiviral therapy is the current standard of care, but further randomized trials need to assess the appropriate route, dose, and duration of therapy. Disclosure of interest The authors declare that they have no competing interest. References [1] Nagel MA, Gilden D. Neurological complications of varicella zoster virus reactivation. Curr Opin Neurol 2014;27(3):356–60. [2] Grahn A, Studahl M. Varicella-zoster virus infections of the central nervous system - Prognosis, diagnostics and treatment. J Infect 2015;71(3):281–93. [3] Hong HL, Lee EM, Sung H, Kang JK, Lee SA, Choi SH. Clinical features, outcomes, and cerebrospinal fluid findings in adult patients with central nervous system (CNS) infections caused by varicella-zoster virus: comparison with enterovirus CNS infections. J Med Virol 2014;86(12):2049–54. [4] Jarrin I, Sellier P, Lopes A, Morgand M, Makovec T, Delcey V, et al. Etiologies and Management of Aseptic Meningitis in Patients Admitted to an Internal Medicine Department. Medicine (Baltimore) 2016;95(2):e2372. [5] Pahud BA, Glaser CA, Dekker CL, Arvin AM, Schmid DS. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis 2011;203(3):316–23. [6] Rottenstreich AKOZ, Oren I. Association between viral load of varicella zoster virus in cerebrospinal fluid and the clinical course of central nervous system infection. Diagn Microbiol Infecti Dis 2014;79(2):174–7. [7] Kupila L, Vuorinen T, Vainionpaa R, Hukkanen V, Marttila RJ, Kotilainen P. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006;66(1):75–80. [8] Parisi SG, Basso M, Del Vecchio C, Andreis S, Franchin E, Dal Bello F, et al. Viral infections of the central nervous system in elderly patients: a retrospective study. Int J Infect Dis 2016;44:8–10. [9] Kadambari S, Okike I, Ribeiro S, Ramsay ME, Heath PT, Sharland M, et al. Sevenfold increase in viral meningo-encephalitis reports in England and Wales during 2004-2013. J Infect 2014;69(4):326–32. [10] de Ory F, Avellon A, Echevarria JE, Sanchez-Seco MP, Trallero G, Cabrerizo M, et al. Viral infections of the central nervous system in Spain: a prospective study. J Med Virol 2013;85(3):554–62. [11] Mailles A, Stahl JP, Steering C, Investigators G. Infectious encephalitis in france in 2007: a national prospective study. Clin Infect Dis 2009;49(12):1838–47. [12] Davison KL, Crowcroft NS, Ramsay ME, Brown DW, Andrews NJ. Viral encephalitis in England, 1989-1998: what did we miss? Emerg Infect Dis 2003;9(2):234–40. [13] Granerod JAH, Davies NW, Clewley JP, Walsh AL, Morgan D, Cunningham R, et al. UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10(12):835–44. [14] Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47(3):303–27.

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Please cite this article in press as: Tabaja H, et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.08.005