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.
Akashi: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.
Asterisk with author names denotes non-ASH members.