Varicella zoster encephalitis in an immunocompetent patient.

Encephalitis is inflammation of the brain parenchyma, most often caused by viruses. Historically, data have shown herpes simplex virus 1 and 2 to be the most common causes of viral encephalitis, with cases due to varicella zoster virus (VZV) more often seen in older age and immunocompromised states. However, emerging data show VZV as an increasingly common culprit of encephalitis in young, immunocompetent patients. PCR analysis of the cerebrospinal fluid is the most accurate diagnostic modality for viral encephalitis. Appropriate and complete treatment hinges on accurate identification of the cause of encephalitis, underscoring the need for comprehensive testing. We present a case of VZV encephalitis in an immunocompetent male patient in his 40s.

Varicella Zoster viral encephalitis without herpes: diagnosis by metagenomic next-generation sequencing of cerebrospinal fluid.

Acute Varicella Zoster viral encephalitis in immunocompetent adult patients without cutaneous herpes has rarely been reported. A 24-year-old female was hospitalized for a headache with a fever but without other obvious symptoms. Multiple routine examinations showed no abnormalities. Lumbar puncture indicated intracranial hypertension. The examination of cerebrospinal fluid by metagenomic next-generation sequencing demonstrated acute Varicella Zoster viral encephalitis. The patient's condition improved by treatment with acyclovir for antiviral therapy and mannitol dehydration to lower cranial pressure. Central Varicella Zoster viral infection should be emphasized as it is easily misdiagnosed and rare in clinical settings. Metagenomic next-generation sequencing of cerebrospinal fluid has significant advantages in the diagnosis of Varicella Zoster viral encephalitis.

Varicella zoster virus encephalitis: a potentially serious complication during treatment with vedolizumab.

Vedolizumab is a monoclonal antibody that has demonstrated efficacy and a good safety profile in patients with inflammatory bowel disease. Varicella zoster virus encephalitis is a potentially serious complication not previously described with its use, highlighting the importance of vaccination, as well as early diagnosis and treatment of infections in this type of patients.

Comparisons in the changes of clinical characteristics and cerebrospinal fluid cytokine profiles between varicella-zoster virus meningitis/encephalitis and other central nervous system infections. / 水痘-å¸¦çŠ¶ç–±ç–¹ç— æ¯’è„‘è†œç‚Ž/è„‘ç‚Žä¸Žå ¶ä»–ä¸­æž¢ç¥žç»ç³»ç»Ÿæ„ŸæŸ“çš„ä¸´åºŠç‰¹å¾å’Œè„‘è„Šæ¶²ç»†èƒžå› å­æ¯”è¾ƒï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Varicella-zoster virus (VZV) is one of the most common etiologies of viral meningitis/encephalitis. The early clinical manifestations and cerebrospinal fluid (CSF) changes of VZV meningitis/encephalitis lack specificity, and it is easy to be misdiagnosed as other viral encephalitides or tuberculous meningitis. This study aims to investigate whether the clinical characteristics, CSF analysis findings, and CSF cytokine levels could distinguish VZV meningitis/encephalitis from central nervous system (CNS) herpes simplex virus (HSV) and Mycobacterium tuberculosis (MTB) infections. METHODS: The medical records from 157 CNS infections, including 49 HSV (45 HSV-1, 4 HSV-2), 55 VZV, and 53 MTB infections between January 2018 and June 2021 in the Cytology Laboratory, Department of Neurology, Third Xiangya Hospital of Central South University were retrospectively reviewed. The data of 3 groups included demographic characteristics, laboratory results, radiographic findings, and outcomes. The levels of 12 cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-γ, IFN-α, and TNF-α) in the CSF of 68 patients (13 HSV, 22 VZV, and 33 MTB infection cases) were quantified. Clinical and laboratory data were compared among the 3 groups. RESULTS: The most common clinical manifestations in the 3 groups were fever, headache, vomiting, and neck stiffness. The clinical manifestations of HSV and VZV CNS disease were similar, although fever and altered consciousness were less common in the VZV group than those in the HSV and MTB groups (63.6% vs 87.8% vs 96.2%, P<0.001, and 14.5% vs 26.5% vs 47.2%, P=0.004, respectively). Seven patients (7/55, 12.7%) presented cutaneous zoster in the VZV group. CSF leukocyte count was significantly higher in the VZV group (230×106 cells/mL) and MTB groups (276×106 cells/mL) than that in the HSV group (87×106 cells/mL, P=0.002). CSF protein level was significantly higher in the VZV than that in the HSV group (1 034 mg/L vs 694 mg/L, P=0.011) but lower than that in the MTB group (1 744 mg/L, P<0.001). IL-6 (VZV vs HSV vs MTB: 2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL, P=0.029) and IL-8 (VZV vs HSV vs MTB: 4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL, P=0.046) levels were significantly different among the 3 groups and were elevated in the VZV group.Post hoc analysis revealed that IL-6 and IL-8 were significantly higher in the VZV group than those in the MTB group (P=0.002 and P=0.035, respectively), but not in the HSV group (P>0.05). CONCLUSIONS: VZV meningitis/encephalitis presents with CSF hypercellularity and proteinemia, challenging the classical view of CSF profiles in viral encephalitis. CSF IL-6 and IL-8 levels are elevated in patients with VZV meningitis/encephalitis, indicating a more intense inflammatory response in these patients.

Factors Predictive of Varicella Zoster Virus Encephalitis/Meningitis: A Single-Center, Retrospective Study.

BACKGROUND The outcomes of varicella zoster virus (VZV) encephalitis/meningitis vary from complete recovery to severe complications. This study aimed to investigate the predictive factors of encephalitis and meningitis caused by VZV reactivation. MATERIAL AND METHODS VZV encephalitis/meningitis patients (n=39) who were treated between January 2019 and December 2021 were included. Patients were followed up for 3 months after discharge and divided into a favorable outcome group (FO, n=18; 46.2%) and an unfavorable outcome group (UO, n=21; 53.8%) according to whether it affects quality of life. The clinical data were retrospectively analyzed and compared between groups. RESULTS As compared to the FO group, patients in the UO group were more likely to have higher body temperature (>38°C) at admission, longer interval from onset of CNS symptoms to initial of antiviral therapy, higher white blood cells (WBC) and adenosine deaminase (ADA) in the cerebrospinal fluid (CSF) and higher CRP in the blood (P<0.05 or P<0.01). Univariate logistic regression analysis showed CSF ADA (OR=1.279, 95% CI: 0.996~1.642) and interval from onset of CNS symptoms to initial of antiviral therapy (OR=1.299, 95% CI: 1.011~1.669) were independent risk factors for unfavorable outcomes (P<0.05). The sensitivity and specificity of combined CSF ADA and time interval from onset of CNS symptoms to initial of antiviral therapy were 78.8% and 95.2%, respectively, in predicting outcomes. CONCLUSIONS Higher CSF ADA and longer interval from onset of CNS symptoms to initial of antiviral therapy predict an unfavorable outcome, and the combination of both factors can achieve better performance.

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.

Neurological complications of varicella zoster virus reactivation: Prognosis, diagnosis, and treatment of 72 patients with positive PCR in the cerebrospinal fluid.

BACKGROUND: VZV infection can involve every level of the neurologic system: from the central nervous system (CNS) to the peripheral nervous system (PNS), including aseptic meningitis. Prognosis seems to differ between these neurological involvements. Prognostic factors remain unknown. METHODS: This is a retrospective multicenter study including all patients with a positive VZV polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) from eight centers in Paris (France) between 2011 and 2018. Unfavorable outcome was defined as mortality linked to VZV or incomplete recovery. Modified Rankin Scale (mRS) evaluated disability before and after the infection, with the difference designated as Rankin Delta. RESULTS: Seventy-two patients were included (53% male, median age 51 years, median mRS 0). Immunosuppression was reported in 42%. The clinical spectrum included 26 cases of meningitis, 27 instances of CNS involvement, 16 of PNS involvement, and 3 isolated replications (positive PCR but no criteria for neurological complications from VZV). Antiviral treatment was administered to 69 patients (96%). Sixty-two patients completed follow-up. Death linked to VZV occurred in eight cases. Unfavorable outcome (UO) occurred in 60% and was significantly associated with a higher prior mRS (Odd-ratio (OR) 3.1 [1.4-8.8] p = .012) and the presence of PNS or CNS manifestations (OR 22 [4-181] p = .001, OR 6.2 [1.3-33] p = .03, respectively, compared to meningitis). In the CSF, higher protein level (p < .0001) was also significantly associated with a higher Rankin Delta. CONCLUSIONS: Neurological complications of VZV with evidence of CSF viral replication are heterogeneous: aseptic meningitis has a good prognosis, whereas presence of CNS and PNS involvement is associated with a higher risk of mortality and of sequelae, respectively.

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

OBJECTIVE: To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE). METHODS: This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA. RESULTS: Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups. INTERPRETATION: The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.

Genetic Variants and Immune Responses in a Cohort of Patients With Varicella Zoster Virus Encephalitis.

BACKGROUND: Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases in which otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection. METHODS: We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient peripheral blood mononuclear cells were infected with VZV, and innate antiviral interferon (IFN) and cytokine responses as well as viral replication were evaluated. Data were analyzed by Mann-Whitney U test. RESULTS: We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within 2 major functional clusters: (1) innate viral sensors and immune pathways and (2) autophagy pathways. Antiviral IFN and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2 of 17 patients. CONCLUSIONS: This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. These data, taken together, suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.

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.

¿Encefalopatía o encefalitis por varicela-zóster? Una paciente con una punción lumbar engañosa / ENCEPHALOPATHY OR VARICELLA-ZOSTER ENCEPHALITIS? A PATIENT WITH A TRICKY LUMBAR PUNCTURE

La encefalopatía es un cuadro clínico característico de múltiples procesos neurológicos y sistémicos que no hay que confundir con la encefalitis, que es una inflamación cerebral, normalmente causadas por infecciones virales. Se presenta el caso de una mujer de 58 años con enfermedad renal crónica en diálisis peritoneal, que ingresa por sepsis de origen peritoneal con clínica de encefalopatía y crisis epilépticas parciales. La paciente presenta lesiones de herpes zóster en zona lumbar y se practica punción lumbar, con resultado del líquido cefalorraquídeo positivo para virus varicela-zóster, por lo que completa tratamiento con aciclovir. En la resonancia magnética no presenta ninguna alteración, y una segunda punción lumbar tras mejoría de las lesiones cutáneas es negativa. El curso de la paciente es fluctuante durante el ingreso, con mejoría significativa tras antibióticos, hemodiálisis y tratamiento antiepiléptico, y no respondiendo al aciclovir. La etiología sospechada es la debida al contexto infeccioso y metabólico de la paciente. Probablemente el resultado del líquido fue contaminado por la proximidad de las lesiones herpéticas, ya que además no es frecuente encontrar encefalitis infecciosas agudas sin alteraciones en las pruebas de imagen. La mejoría final fue debida tanto a la medicación antiepiléptica como al inicio de hemodiálisis

Encefalopathy is a clinical syndrome ocurring in multiple neurologic and systemic diseases which must not be mistaken with encephalitis, that is a cerebral inflammatory process, often caused by viral infections. We present the case of a 58-year-old woman with chronic renal failure receiving peritoneal dyalisis, who was admitted into hospital for sepsis secondary to infectious peritonitis, with encefalopathy and epileptic partial seizures. The patient presented lumbar herpetic cutaneous lesions and a lumbar punction is practiced, with a positive result in the cerebrospinal fluid for varicella-zoster virus. Treatment with aciclovir was completed. Her cerebral magnetic resonance was absolutely normal, and a second lumbar puncture when herpetic lesions got better was negative. The course is fluctuating during the stay, and a significant clinical improvement occurs after antibiotics, hemodyalisis and antiepileptic treatment. The patient did not respond to aciclovir. The suspected ethiology is the infectious and metabolic context. Positivity for the virus is thought to be a contamination from the nearby herpetic lesions. Also, it is rare for an infectious acute encephalitis to present with normal radiologic imaging. The final clinical improvement was probably due to hemodyalisis initiation and the antiepileptic treatment.

Serum and cerebrospinal fluid neurofilament light chain in patients with central nervous system infections caused by varicella-zoster virus.

Varicella-zoster virus (VZV) is a common cause of viral central nervous system (CNS) infection, and patients may suffer from severe neurological sequelae. The biomarker neurofilament light chain (NFL) is used for assessment of neuronal damage and is normally measured in cerebrospinal fluid (CSF). Novel methods have given the possibility to measure NFL in serum instead, which could be a convenient tool to estimate severity of disease and prognosis in VZV CNS infections. Here, we investigate the correlation of serum and CSF NFL in patients with VZV CNS infection and the association of NFL levels in serum and CSF with different VZV CNS entities. NFL in serum and CSF was measured in 61 patients who were retrospectively identified with neurological symptoms and VZV DNA in CSF detected by PCR. Thirty-three herpes zoster patients and 40 healthy blood donors served as control groups. NFL levels in serum and CSF correlated strongly in the patients with VZV CNS infection. Encephalitis was associated with significantly higher levels of NFL in both serum and CSF compared with meningitis and Ramsay Hunt syndrome. Surprisingly, herpes zoster controls had very high serum NFL levels, comparable with those shown in encephalitis patients. We show that analysis of serum NFL can be used instead of CSF NFL for estimation of neuronal injury in patients with VZV CNS infection. However, high levels of serum NFL also in patients with herpes zoster, without signs of CNS involvement, may complicate the interpretation.

Clinical spectrum and prognosis of neurological complications of reactivated varicella-zoster infection: the role of immunosuppression.

Immunosuppressed patients are at higher risk for developing herpes zoster (HZ), and neurological complications are frequent in them. However, the influence of immunosuppression (IS) on the severity and prognosis of neurological complications of varicella-zoster virus (VZV) reactivation is unknown. We studied retrospectively patients with neurological complications due to VZV reactivation who attended our hospital between 2004 and 2019. We aimed to assess the clinical spectrum, potential prognostic factors, and the influence of the immune status on the severity of neurological symptoms. A total of 98 patients were included (40% had IS). Fifty-five patients (56%) had cranial neuropathies which included Ramsay-Hunt syndrome (36 patients) and cranial multineuritis (23 patients). Twenty-one patients developed encephalitis (21%). Other diagnosis included radiculopathies, meningitis, vasculitis, or myelitis (15, 10, 6, and 4 patients, respectively). Mortality was low (3%). At follow-up, 24% of patients had persistent symptoms although these were usually mild. IS was associated with severity (defined as a modified Rankin scale greater than 2) (odds ratio, 4.23; 95% confidence interval, 1.74-10.27), but not with prognosis. Shorter latency between HZ and neurologic symptoms was the only factor associated with an unfavorable course (death or sequelae) (odds ratio, 0.82; 95% confidence interval, 0.71-0.95). In conclusion, the clinical spectrum of neurological complications in VZV reactivation is wide. Mortality was low and sequelae were mild. The presence of IS may play a role on the severity of neurological symptoms, and a shorter time between HZ and the onset of neurological symptoms appears to be a negative prognostic factor.

Indolent varicella encephalitis with vasculopathy in an immunocompromised patient.

A 68-year-old female with B-cell non-Hodgkin's lymphoma presented to us with sequential blindness followed by hemiparesis. Four months earlier, the patient had developed chicken pox that was treated with intravenous acyclovir. An MRI brain showed multiple cerebral infarcts and beaded appearance of her intracranial vasculature. PET-CT showed hypermetabolism in the right frontal lobe and pons suggestive of encephalitis. Cerebral spinal fluid examination showed 15 cells and varicella zoster vasculopathy (VZVV) polymerase chain reaction was positive. A final diagnosis of indolent VZVV vasculopathy and encephalitis in an immunocompromised individual was made. This case highlights the slow and indolent progression of varicella central nervous system involvement.

Neuroinfecciones en tiempos de COVID-19 / Neurological infections during the COVID-19 epidemic

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[An autopsied case of severe varicella zoster virus-associated encephalomyelitis under immunosuppressant therapy].

The patient was a 40-year-old woman who was previously diagnosed with systemic lupus erythematosus and myasthenia gravis and had received prednisolone and tacrolimus for more than 7 years. In February 2017, she noticed pain in her lower back and weakness of the lower limbs, and was referred to our hospital on day 5. She had shingles in the right lower thoracic dermatomes and Brown-Séquard syndrome with right-sided dominant weakness in her lower limbs and left-sided superficial sensory disturbance below the L1 level. Varicella zoster virus (VZV)-associated myelopathy was suspected because of her symptoms and clinical findings. Despite the immediate administration of intravenous acyclovir after hospitalization, she lost consciousness and experienced a seizure related to cerebral hemorrhage in the left temporal lobe on the night of day 5. MRI showed enhanced lesions along the spinal cord and leptomeninges of the brainstem and temporal lobe. VZV-IgG and VZV-DNA were positive in the cerebrospinal fluid. Based on these clinical features and laboratory findings, she was diagnosed as VZV-associated vasculopathy and myelopathy. She subsequently had multiple cerebral infractions and hemorrhage, and developed sudden cardiopulmonary arrest on day 6, culminating in death on day 17. Autopsy showed that inflammatory mononuclear cells had infiltrated the vascular walls of the spinal cord. Immunohistochemistry revealed that some neurons and macrophages in the white matter of the spinal cord were positive for VZV. In addition, atrophic neurons, satellite cells surrounding these neurons, and infiltrating macrophages were immune-positive for VZV at the L2 dorsal root ganglia. These findings were consistent with VZV-associated vasculopathy and myelitis. Under immunosuppressive conditions, VZV can cause shingles and neuronal complications such as vasculopathy and myelitis, which are sometimes fatal despite the immediate administration of intravenous acyclovir. New treatment drugs or drugs to prevent VZV activation are desired.

Parálisis de sexto nervio craneal en adulto inmunocompetente con varicela / Sixth cranial nerve palsy in an immunocompetent adult patient with varicella

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