Human Herpesvirus 6 DNA In Cerebrospinal Fluid Research Articles

Incidence and Differential Diagnosis of Human Herpes Virus-6 Associated Encephalitis/Myelitis in Allogeneic Stem Cell Transplantation That Mimics Calcineurin Inhibitor-Induced Pain Syndrome

Background: Human herpes virus-6 (HHV6)-associated limbic encephalitis/myelitis is rare but life-threatening nervous system complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When the allo-HSCT recipients present encephalitis-associated manifestations such as short-term memory dysfunction, disorientation, consciousness disturbance and seizures, it is essential to immediately perform polymerase chain reaction (PCR) analysis for detection of HHV6 viral DNA in the cerebrospinal fluid (CSF) for the definite diagnosis. However, if reactivation of HHV6 is confined to the spinal cord but not cerebrum, these patients lack encephalitis-like symptoms but manifest only sensory nerves-related symptoms such as severe unexplained pain, dysesthesia and prutitus, leading to the delayed examination of HHV6 DNA detection in CSF. As a result, the patients with HHV6-associated myelitis can be sometimes misdiagnosed as having calcineurin inhibitor (CI)-induced pain syndrome (CIPS), since such manifestations are commonly observed in these two syndromes. In this study, we evaluate incidence and clinical features of HHV6 encephalitis/myelitis and CIPS after allo-HSCT.Method: We retrospectively reviewed the medical records of 435 patients who underwent allo-HSCT between 2002 and 2014 in our facility. HHV6-associated encephalitis/myelitis was directly proved when HHV6 DNA was detected by PCR in CSF. For those patients who were unable to undergo lumbar puncture because of severe thrombocytopenia or a deteriorated general condition, we diagnosed HHV6-associated encephalitis/myelitis if they satisfied more than 2 of the following 3 criteria: (1) typical clinical manifestations as described above; (2) detection of HHV6 DNA in peripheral blood; or (3) limbic encephalopathy based on the selective involvement of the medial temporal lobe on magnetic resonance imaging (MRI). CIPS was diagnosed using three factors: (a) typical clinical manifestations including unexplained severe pain and cutaneous pruritus without skin rash; and (b) not detection of HHV6 DNA in CSF; or (c) abnormal findings at X-ray, MRI, or bone scintigraphy at joint of knee and foot.Results: Twenty-five patients were diagnosed as having HHV-6 encephalitis/myelitis with a cumulative incidence of 5.7%. Median onset was on day 19 after transplantation. HHV-6 encephalitis/myelitis was documented in 15 of 99 cord blood transplant (CBT) recipients (15.2%) and 10 of 336 recipients (3.0%) transplanted with bone marrow or peripheral blood stem cells. This result suggests that a higher incidence of HHV-6 encephalitis/myelitis occurring in CBT recipients. Four patients manifested typical symptoms at the onset of HHV6-associated encephalitis. However, 11 patients presented with dysesthesia and pruritus, described as typical manifestations of patients with CIPS, and the remaining 10 showed both symptoms. Six of 11 patients with CIPS-like symptom also exhibited dysautonomia (bladder and rectal disturbance and sinus tachycardia) and/or abdominal pain. Positive results for brain MRI scans (limbic encephalitis) were observed in 9 of 14 patients (64.3%) who developed encephalitis-type symptoms, which were not found in the 11 patients who had CIPS-like symptoms; none presenting with CIPS-like symptoms had positive results for spinal MRI as well. On the other hand, 8 patients (1.8%) were diagnosed as having CIPS on the 5 to 91 days (madian 22 days) posttransplant. For graft-versus-host disease (GVHD) prophylaxis, 2 patients received cyclosporine, and 6 received tacrolimus. CI concentrations in these patients were maintained within the target ranges at onset of the pain. Abnormal findings at X-ray and MRI were not observed in all patients, but only one patient showed abnormal findings at joint of hand, finger and ankle in bone scintigraphy. For the treatment of CIPS, in 7 patients dosage of CI was reduced, whereas in one CI was switched into another one. Clinical symptoms in all of these patients were improved and exacerbation of GVHD was not seen.Conclusion: Detection of HHV6 DNA in CSF is crucial to make a differential diagnosis of HHV6 myelitis and CIPS. Transplantation physicians should be aware that CIPS-like dysesthesia and pruritus might be early manifestations to suggest the reactivation of HHV6, especially for patients who develop myelitis. DisclosuresAkashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

Successful ganciclovir therapy in a patient with human herpesvirus-6 encephalitis after unrelated cord blood transplantation: usefulness of longitudinal measurements of viral load in cerebrospinal fluid

There have been no reports of human herpesvirus-6 (HHV-6) encephalitis treatment based on both HHV-6 DNA load and the antiviral agent's concentration in the cerebrospinal fluid (CSF). A 20-year-old male with a hematological malignancy developed HHV-6 encephalitis 15 days after unrelated cord blood transplantation (UCBT). He had fever, chest pain, memory impairment, and insomnia. His CSF showed no increased cell counts, but the amount of HHV-6 DNA was elevated to 2.0 × 10(6) copies/ìgDNA. Magnetic resonance imaging (MRI) of the head revealed abnormal high-intensity signals in the left limbic system on T2-weighted and diffusion-weighted images. Intravenous administration of ganciclovir (GCV) was initiated at 5 mg/kg every 12 h on day 18, and was continued until day 137. The amount of HHV-6 DNA in the plasma became undetectable on day 25. The HHV-6 load in the CSF decreased to 1.5 × 10(3) copies/ìgDNA on day 32, and reached undetectable levels on day 53. The mean concentration of GCV 1 h after an infusion of 5 mg/kg was 4.12 mg/mL in plasma and 0.7 mg/mL in CSF. The chest pain and insomnia disappeared on days 35 and 47, respectively. Memory defects recovered up to day 85. Serial quantification of HHV-6 DNA in CSF may be useful for successful treatment with GCV in post-transplant HHV-6 encephalitis.

Cord-Blood Hematopoietic Stem Cell Transplant Confers an Increased Risk for Human Herpesvirus-6-Associated Acute Limbic Encephalitis: A Cohort Analysis

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease.

Infections aiguës à herpèsvirus humain 6 (HHV-6) : quand et comment traiter ?

The pathogenicity of human herpesvirus 6 (HHV-6) still raises numerous questions. Acute HHV-6 infections correspond to primary infections, reactivations or exogenous reinfections. The expression of related clinical symptoms is highly variable but may be extremely severe, particularly among immunocompromised patients. The prototypic severe disease associated with these infections is limbic encephalitis occurring in stem cell transplant recipients. The diagnosis of acute HHV-6 infections relies on the quantitation of viral load in whole blood by means of quantitative PCR. The demonstration of HHV-6 causative role in the genesis of clinical symptoms requires additional investigations such as the search for HHV-6 DNA in cerebrospinal fluid in case of encephalitis. The chromosomal integration of HHV-6 DNA is a rare event among HHV-6-infected subjects but may alter the interpretation of virological results. Therapy with ganciclovir, foscarnet or cidofovir has not yet clear indications but, at the current stage of knowledge, only concerns the treatment of highly symptomatic infections. The usefulness of prophylactic or pre-emptive antiviral chemotherapy has not yet been convincingly demonstrated. Treatment efficacy must be checked through a clinical and virological follow up, based in part on quantitative PCR approaches. Controlled studies are urgently needed with the goal of evaluating the cost-effectiveness of HHV-6 follow up and therapy in different clinical situations.

Search for Herpesviruses in cerebrospinal fluid of facial palsy patients by PCR

Conclusions: Herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) DNA were not detected in the cerebrospinal fluid (CSF) of patients with acute idiopathic peripheral facial palsy (Bell's palsy). Our results indicate either the absence of these viruses or the presence of technical shortcomings. The role of human herpesvirus 6 (HHV-6) in this disorder and the significance of a positive HHV-6 DNA finding in the central nervous system need further investigation. Objective: Our goal was to determine whether DNA of HSV-1, VZV, or HHV-6 can be found by polymerase chain reaction (PCR) in the CSF of peripheral facial palsy patients. Materials and methods: We used PCR to detect the presence of HSV-1, VZV, and HHV-6 DNA in CSF. This was a retrospective case control study with 33 peripheral facial palsy patients (34 CSF samples) in the study group (26 with Bell's palsy, 5 with simultaneously diagnosed herpesvirus infection, 1 with puerperal facial palsy, 1 with Melkersson-Rosenthal syndrome). The control group included 36 patients, most with diagnosed or suspected Borreliosis and facial palsy or sudden deafness. Results: One patient with Bell's palsy had HHV-6 DNA in CSF. Neither HSV-1 nor VZV DNA was detected in patients or controls.