Risk of HHV6-Associated Post-Transplant Acute Limbic Encephalitis (PALE) after Umbilical Cord Blood Stem Cell Transplantation: A Cohort Analysis.
Authors: Marty Francisco M. , Ho Vincent T. , Seeley William W. , Cutler Corey S. , Koreth John , Alyea Edwin P. , Soiffer Robert J. , Antin Joseph H. , Baden Lindsey R. 
Published: October 2019

Background: PALE is an infrequent but distinct syndrome following HSCT, usually associated with HHV6 reactivation. We sought to establish the epidemiologic risk factors for PALE and its clinical characteristics at DFCI/BWH.

Methods: The allogeneic HSCT cohort transplanted from 10/1/01 to 9/30/05 was analyzed. Follow up concluded on 12/31/05. PALE was diagnosed by the acute development of amnesia, confusion, abnormal behavior or other limbic phenomena; the presence of abnormal MRI signals involving the hippocampus and mesial temporal lobes, and/or detection of HHV6 DNA in CSF. Baseline and HSCT covariates included age, sex, malignancy being treated, treatment protocol (conditioning regimen, GVHD prophylaxis), stem cell source, HLA matching, and incident acute GVHD and its severity. Clinical, MRI, CSF, and EEG characteristics of PALE patients were obtained. Univariate and logistic regression analysis were performed.

Results: 672 patients received an initial HSCT during the period. PALE was diagnosed in 13/672 for a cumulative incidence of 1.93%. All but one were male, median age was 48 years (22–61). Underlying hematologic malignancy was CLL in 3, MDS in 2, AML in 2, CML in 2, NHL and myelofibrosis in 1 each. Median symptom onset was on day +31 (range, 14–61). Initial symptoms included confusion in 12, amnesia in 11, abnormal behavior in 10 and seizures in 2. Epileptiform activity on EEG was detected in 8/11 patients. MRI demonstrated hyppocampal and mesial temporal lobe T2/FLAIR hyperintensities in 10/11. Initial CSF analysis demonstrated a median WBC of 4 (1–25), with lymphocytic or monocytic predominance; median CSF protein was 53mg/dl (29–106); median glucose: 72mg/dl (56–181); HHV6 type B was found in 8/8 specimens where typing of virus was performed. Once the diagnosis was suspected or confirmed, foscarnet or ganciclovir was administered for 21–28 days. 11/13 patients received antiepileptic drugs; levetiracetam was most commonly used. 3 patients died by week 6 after HSCT. Progressive encephalitis contributed to death in 2 of them, both cord blood recipients. Another 4 patients died before day 180 as result of refractory GVHD and/or hepatic VOD. 6 patients were alive as of 12/31/05. 9/10 survivors demonstrated mild to severe deficits in episodic memory that impaired activities of daily living. Follow-up MR imaging often showed volume loss within the medial temporal lobes.

Cord-blood transplantation was the most significant risk factor for the development of PALE followed by male gender. Both remained significant after adjustment for each other (c=0.80). Acute GVHD occurred in 11/13 patients: it preceded PALE in 5 patients and followed PALE in 6. No other significant associations were noted.

Conclusions: Male cord-blood HSCT recipients are at increased risk of HHV6-associated PALE. Prompt recognition and treatment of the syndrome is essential. Strategies for monitoring and preemptive treatment in this high-risk group should be evaluated.

HHV6-associated PALE Risk after HSCT Covariate Cases Cohort % Univariate OR (95% CI) Multivariate OR (95% CI) Cord SC 5 29 17.2 16.5 (5.03–54.3 17.2 (5.05–58.4) Adult SC 8 643 1.24 - - Male 12 397 3.02 8.54 (1.10–65.9) 8.88 (1.12–70.2) Female 1 275 0.36 - - Unrelated 7 349 2.01 6.00 (0.73–49.0) - Related 1 294 0.34 - -