Meningoencefalitis por virus Varicella-Zóster posterior a infección por SARS-CoV2: Reporte de dos casos / Meningoencephalitis caused by Varicella-Zoster virus after SARS-CoV2 infection: Two cases report

RESUMEN La meningoencefalitis por el VZV es una patología poco frecuente que se presenta con la reactivación del virus dentro del organismo. OBJETIVO: Describir la presentación clínica de dos pacientes con neuroinfección por VZV posteriormente a infección por SARS-CoV-2. REPORTE DEL CASO: El primer caso corresponde a un hombre de 59 años con antecedente de neumonía moderada por SARS-CoV-2 que después cursó con meningoencefalitis por VZV y, además, desarrolló un síndrome de Ramsay Hunt. El segundo caso es el de una mujer de 37 años con antecedente de infección leve por SARS CoV-2 con un cuadro de cefalea con signos de alarma, en quien se documentó neuroinfección por VZV

ABSTRACT Meningoencephalitis caused by varicella zoster virus is a rare pathology that presents due to the reactivation of the virus in the organism OBJECTIVE: To describe the clinical presentation of two patients with VZV neuroinfection presented after a SARS CoV-2 infection. CASE REPORT: The first case is a 59 year old male with previous moderate SARS CoV-2 infection who presented meningoencephalitis and was diagnosed with Ramsay Hunt's Syndrome. The second case is a 37 year old female with previous SARS CoV-2 infection who presented with an acute onset headache and was documented with VZV neuroinfection.

Herpesvirus encephalitis diagnosed by polymerase chain reaction at the National Institute of Neurology of Mexico.

The frequency of central nervous system infections due to herpesvirus have been studied in various populations; however, studies in Mexican mestizo patients are scant. This paper documents the frequency of herpesvirus encephalitis in Mexican mestizo patients from the National Institute of Neurology and Neurosurgery (NINN) of Mexico. To study the frequency of herpetic viral encephalitis at the NINN in the period from 2004 to 2009. We reviewed clinical records from patients with clinically suspected encephalitis; polymerase chain reaction assays were done for detection of herpesviruses in cerebrospinal fluid (CSF) samples. The total number of patients studied was 502; in 59 (12%), the diagnosis of herpetic encephalitis was confirmed by PCR-based testing of CSF. Of them, 21 (36%) were positive for herpes simplex virus type 1, 15 (25%) for Epstein-Barr virus, 10 (17%) for varicella zoster virus, 8 (14%) for cytomegalovirus, 3 (5%) for human herpesvirus 6, and 2 (3%) for herpes simplex virus 2. Our results show a varied frequency of viral encephalitis in mestizo patients due to herpesviruses in a tertiary neurological center and point out the importance of modern molecular technology to reach the etiological diagnosis in cases of encephalitis.

RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections.

In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine.

Recurrent Herpes Simplex Virus Encephalitis After Neurologic Surgery.

BACKGROUND: The herpes simplex virus (HSV) is the most common cause of sporadic encephalitis worldwide. Even with proper treatment, this infection is associated with a mortality rate of 19%-30% and with potential neurologic sequelae. Recurrences of encephalitis are rare and limited to a few cases in the literature. Although the mechanism of reactivation has not yet been clarified, in our patient, the surgery might have acted as a precipitating factor. CASE DESCRIPTION: The case involved a female 10-year-old patient with a history of type 1 HSV encephalitis since 24 months of age. Secondarily, the patient developed postherpetic epilepsy in the following years. At 10 years old, she was referred to the epilepsy surgery service, and an elective right temporal lobectomy was performed. After surgery, the patient experienced severe clinical deterioration characterized by fever, severe headache, and altered state of consciousness. Encephalitis was diagnosed based on a positive polymerase chain reaction for HSV in the cerebrospinal fluid. The symptoms remitted after 8 weeks of treatment with acyclovir. The histopathologic diagnosis was a chronic encephalitic process with late secondary parenchymal changes without specific viral cytopathic findings. The only limitation that persisted was related to fine movements of the left hand. One year after surgery, the patient rejoined her school activities and is currently free of seizures. CONCLUSIONS: HSV encephalitis is a rare but serious complication that should be suspected in cases of unexplained postoperative fever with altered consciousness, especially in patients with histories of encephalitic states.

MENINGOENCEPHALITIS DUE TO VARICELLA ZOSTER VIRUS IN AIDS PATIENTS. REPORT OF ELEVEN CASES AND REVIEW OF THE LITERATURE / Meningoencefalite pelo vírus varicela-zoster em pacientes com AIDS. Relato de onze casos e revisão da literatura

Neurological complications of varicella-zoster virus (VZV) are infrequent and include various clinical pictures. The reactivation of VZV in patients with AIDS is generally associated with an acute and severe meningoencephalitis. We report the epidemiological, clinical and virological data from 11 consecutive patients with diagnosis of HIV/AIDS and central nervous system (CNS) involvement due to VZV. All patients were male and seropositive for HIV. The primary risk factor for HIV infection was unprotected sexual contact. The median of CD4 T cell count was 142 cells/µL. All of them presented signs and symptoms of meningoencephalitis. Six patients (54.5%) presented pleocytosis; they all showed high CSF protein concentrations with a median of 2.1 g/dL. Polymerase chain reaction of cerebrospinal fluid specimen was positive for VZV in all of them and they were treated with intravenous acyclovir at doses of 30/mg/kg/day for 21 days. Overall survival was 63% (7 of 11 patients). The four dead patients had low cellular counts in CSF, below the median of this parameter. VZV should be included among the opportunistic pathogens that can involve CNS with a diffuse and severe meningoencephalitis in patients with advanced HIV/AIDS disease.

As complicações neurológicas do vírus varicela-zoster (VVZ) são pouco frequentes e incluem vários quadros clínicos. A reativação do VVZ em pacientes com AIDS é geralmente associada com meningoencefalite aguda e grave. Nós relatamos os dados epidemiológicos, clínicos e virológicos de onze pacientes consecutivos com diagnóstico de HIV/AIDS e comprometimento do sistema nervoso central (SNC) devido ao VVZ. Todos os pacientes eram do sexo masculino e soropositivos para HIV. O principal fator de risco para a infecção pelo HIV foi o contato sexual sem proteção. A mediana da contagem de células CD4 T foi de 142 cel/µL. Todos apresentavam sinais e sintomas devido à meningoencefalite. Seis pacientes (54,5%) apresentaram pleiocitose; todos apresentaram hiperproteinorraquia com mediana de 2,1 g/dL. A reação em cadeia da polimerase de amostra do líquido cefalorraquidiano foi positiva para VVZ em todos eles. Todos os pacientes foram tratados com aciclovir por via intravenosa em doses de 30 mg/kg/dia durante 21 dias. A sobrevida global foi de 63% (sete de 11 pacientes). Os quatro pacientes mortos tiveram uma escassa resposta celular no LCR abaixo da mediana para este parâmetro. O VVZ deve ser incluído entre os patógenos oportunistas que podem comprometer o SNC com meningoencefalite difusa e grave em pacientes com doença avançada por HIV/SIDA.

Psychiatric aspects of herpes simplex encephalitis, tick-borne encephalitis and herpes zoster encephalitis among immunocompetent patients.

The psychopathological symptoms occurring in the course of diseases associated with infections are often initially isolated and non-characteristic, and may cause diagnostic difficulties. Moreover, such disorders tend to be less responsive to psychiatric management. Among possible causes such as trauma, neoplasm and vascular changes, inflammatory changes of the brain as a result of a viral infection should also be considered. There were 452 registered cases of viral encephalitis in Poland in 2010, and although not very prevalent they remain a severe and life-threatening condition. What is more, the frequently occurring neurological and psychiatric complications of viral encephalitis often result in permanent disabilities, causing a significant decrease in the quality of life. This article presents the three types of encephalitis that are most prevalent among immunocompetent patients in Poland, i.e. herpes simplex encephalitis (HSE), tick-borne encephalitis (TBE) and herpes zoster encephalitis (HZE). The psychopathology of the acute phase of the infection, the residual symptoms, features apparent in imaging studies and some neuropathological aspects are also presented. The paper also focuses on psychiatric aspects of the diagnostics and treatment of the described conditions. The clinical pictures of these infections are quite specific, although they cover a wide range of symptoms, and these characteristic features are described. The aim of this review is also to show the significance of thorough diagnostics and a multidisciplinary approach to patients with viral CNS infections.

Varicella zoster virus encephalomyelitis as a late complication following haematopoietic stem cell transplantation.

Varicella zoster virus (VZV) causes the primary infection manifesting as varicella or chickenpox, with possibility of reactivation later in life. A 71-year-old man presented with headache and lower extremity weakness. There was no evidence of skin lesions to suggest a recent zoster infection. The patient had a history of multiple myeloma diagnosed 2 years earlier, treated with chemotherapy and autologous stem cell transplant. Antimicrobial prophylaxis was discontinued 12 months after the transplant. MRI of the brain demonstrated areas of T2/fluid-attenuated inversion recovery hyperintensity in bilateral cerebral white matter and MRI of the spine demonstrated enhancement along the cauda equine. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis and VZV DNA was detected by PCR in the CSF. The patient was treated with 8 weeks of antiviral therapy with complete resolution of symptoms. VZV should be considered in patients with haematopoietic stem cell transplantation presenting with similar neurological manifestations even in the absence of dermatological signs.

Incidence, risk factors, and implemented prophylaxis of varicella zoster virus infection, including complicated varicella zoster virus and herpes simplex virus infections, in lenalidomide-treated multiple myeloma patients.

In the era of high-dose chemotherapy and novel antimyeloma agents, the survival of multiple myeloma (MM) patients has substantially improved. Adverse effects, including infections, may however arise in the era of combination antimyeloma therapies. In general, MM patients have shown a risk of varicella zoster virus (VZV) infection of 1-4 %, increasing with bortezomib treatment or transplants, but whether immunomodulatory drugs also bear a risk of VZV/complicated herpes simplex virus (HSV) (e.g., VZV-encephalitis [VZV-E], disseminated VZV-infection [d-VZV-i], or conus-cauda syndrome [CCS]) has not been elucidated. We here assessed VZV, VZV-E, d-VZV-i, and CCS in 93 lenalidomide-treated MM patients, consecutively seen and treated in our department. Patients' data were analyzed via electronic medical record retrieval within our research data warehouse as described previously. Of the 93 MM patients receiving lenalidomide, 10 showed VZV or other complicated VZV/HSV infections. These VZV patients showed defined risk factors as meticulously assessed, including suppressed lymphocyte subsets, substantial cell-mediated immune defects, and compromised humoral immune response. Due to our findings-and in line with an aciclovir prophylaxis in bortezomib and stem cell transplant protocols-we introduced a routine aciclovir prophylaxis in our lenalidomide protocols in May 2012 to minimize adverse events and to avoid discontinuation of lenalidomide treatment. Since then, we have observed no case of VZV/complicated HSV infection. Based on our data, we encourage other centers to also focus on these observations, assess viral infections, and-in those centers facilitating a research data warehouse-advocate an analogue data review as an appropriate multicenter approach.

Longitudinally extensive varicella-zoster virus myelitis in a patient with multiple sclerosis.

STUDY DESIGN: Case report. OBJECTIVE: To report this rare varicella-zoster virus (VZV) complication in a patient with multiple sclerosis. SUMMARY OF BACKGROUND DATA: Longitudinally extensive transverse myelitis is a spinal cord lesion that extends over 3 or more vertebral segments. A common feature in neuromyelitis optica, longitudinally extensive transverse myelitis can also occur in several other diseases. METHODS: A 15-year-old boy with relapsing-remitting multiple sclerosis, who has been treated with immunomodulators for 6 months, developed a subacute left brachiocrural hemiparesis with ipsilateral decreased sensation in the trunk and limbs. This was interpreted as a new relapse and was treated consequently. During the evolution, the patient developed a cutaneous rash in the left C8 metameres, followed by asymmetric tetraparesis. RESULTS: Magnetic resonance imaging demonstrated an extensive cervical-thoracic myelopathy. Cerebrospinal fluid analysis revealed 17 leukocytes per microliter (95% mononuclear), protein 41 mg/dL, and negative VZV-DNA by polymerase chain reaction, but elevated anti-VZV immunoglobulin G cerebrospinal fluid/serum index, with a normal albumin cerebrospinal fluid/serum index, all of which were consistent with intrathecal synthesis of anti-VZV antibody. We were able to rule out all other causes included in the differential diagnosis, namely, vascular disease, tumor, and autoimmune conditions, especially those associated with neuromyelitis optica spectrum disorders. CONCLUSION: Awareness of the potentially varied presentation of VZV myelitis can enable earlier recognition and specific treatment.

Fatal varicella-zoster virus vasculopathy associated with adalimumab therapy.

OBJECTIVE: To describe the case of a patient who had been receiving adalimumab for rheumatoid arthritis and died of varicella-zoster virus vasculopathy with multifocal cerebral hemorrhage. DESIGN: Case report. SETTING: Hanyang University Hospital, Seoul, Republic of Korea. PATIENT: A 66-year-old woman with adalimumab therapy for rheumatoid arthritis followed by stuporous mental changes. RESULTS: Magnetic resonance imaging scans showed multifocal parenchymal lesions and hemorrhage in the brainstem and supratentorial areas. Polymerase chain reaction analysis of the cerebrospinal fluid was positive for varicella-zoster virus. The patient died of multifocal vasculopathy despite intensive antiviral and antibacterial medication. CONCLUSIONS: Varicella-zoster virus multifocal vasculopathy with encephalitis may be associated with adalimumab therapy. Clinicians should be aware of the possibility of fatal varicella-zoster virus vasculopathy with encephalitis in patients undergoing adalimumab therapy for rheumatoid arthritis.

Varicella zoster virus meningoencephalitis after allogeneic hematopoietic stem cell transplantation.

Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life-threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen-matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft-versus-host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low-dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day -7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.

Compartmentalization of acyclovir-resistant varicella zoster virus: implications for sampling in molecular diagnostics.

BACKGROUND: Acyclovir resistance of varicella zoster virus (VZV) may arise in stem cell transplant (SCT) recipients with VZV disease and is usually a result of mutations in VZV thymidine kinase (TK), which is the target protein of acyclovir. Early detection of such mutations is necessary to enable timely therapy adaptation, for example, to foscarnet. We aimed to investigate whether TK mutations arise over time, and what sample types might be the most useful for this method. METHODS: Spatially and temporally distinct samples from 3 SCT recipients with VZV disease unresponsive to acyclovir treatment were retrospectively investigated for the presence of TK mutations by polymerase chain reaction and sequence analysis. RESULTS: In all 3 patients, a mutation in the VZV TK coding region was found resulting in an amino acid substitution. TK mutations were not only temporally but also spatially compartmentalized. In particular, plasma samples frequently showed wild-type TK sequences, whereas cerebrospinal fluid or skin vesicle fluid acquired on the same day contained mutant sequences. CONCLUSIONS: This study shows the importance of careful sampling for molecular diagnostics of acyclovir resistance in VZV disease. All affected body sites should be sampled and plasma samples may not be representative for the viral mutation status.

[A case of brainstem encephalitis following multiple cranial neuropathy in a hepatocellular carcinoma patient--association with cytomegalovirus and varicella-zoster virus infection].

A 72-year-old male with liver cirrhosis and hepatocellular carcinoma experienced general fatigue. Four days later he was admitted to our hospital because of dizziness, dysbasia and left facial palsy (day 1). On day 6, a neurological examination revealed left trigeminal neuralgia, left medial longitudinal fasciculus (MLF) syndrome, skew deviation, hypacusia, tongue deviation and left limb ataxia. Magnetic resonance imaging of the brain including diffusion-weighted imaging showed previous lacunar infarctions at the left thalamus and pons. The immunological investigation for viral infection in his serum samples showed high titers of IgM antibody against cytomegalovirus (CMV). Cerebrospinal fluid (CSF) investigation revealed mononuclear pleocytosis, elevated protein levels and high titers of IgG antibody against the varicella-zoster virus (VZV). Anti-CMV antibody measurement and CMV-DNA detection by the polymerase chain reaction in CSF revealed that the central nervous system (CNS) was not infected by CMV. We diagnosed this case as brainstem encephalitis following multiple cranial neuropathy associated with CMV and VZV infections. The neurological symptoms gradually improved with aciclovir and prednisolone therapy. The titers of antibody for CMV in his serum samples normalized 4 months later after onset. Although there was no evidence of CMV infection in the CNS was obtained, parainfection or autoimmune mediated responses followed by viral infections might have led to brainstem encephalitis with multiple cranial nerve involvements in our patient.

Varicella zoster meningoencephalitis following treatment for dermatomal zoster in an alloBMT patient.

Herpes zoster infections are frequently observed after allogeneic bone marrow transplantation (alloBMT). In the majority of cases, the infection is restricted to specific dermatomes and responds to oral acyclovir, without visceral dissemination. We report the case of a 40-year-old male who developed dermatomal herpetic infection 8 months post alloBMT. The herpetic rash responded well to treatment with high-dose oral acyclovir. However, within a week of cessation of therapy, the patient re-presented with dermatomal zoster and meningoencephalitis. Although the cutaneous lesions resolved with intravenous acyclovir, clinical features of meningoencephalitis persisted, along with evidence of varicella zoster virus (VZV) DNA in cerebrospinal fluid (CSF). A satisfactory response to treatment was observed only after the addition of intravenous foscarnet to acyclovir. Based on our experience with this patient, we suggest that in a subset of alloBMT recipients, late dermatomal herpes zoster infections may respond only partially to treatment with standard oral acyclovir. The use of oral acyclovir preparations with higher bioavailability (valacyclovir) or intravenous acyclovir early on may prevent the considerable morbidity associated with disseminated zoster infection. Bone Marrow Transplantation (2000) 26, 795-796.