# Posttransplant acute limbic encephalitis
**Posttransplant acute limbic encephalitis** (PALE) is a rare, acquired, non-paraneoplastic limbic encephalitis that develops in the setting of treatment-related immunosuppression, typically after allogeneic (Transplanted from a genetically different donor) hematopoietic stem cell transplantation, with onset of confusion, headache, anterograde amnesia, seizures, and/or loss of consciousness 2 to 6 weeks following transplantation[1](https://www.orpha.net/en/disease/detail/163921). The syndrome was characterized in a 2007 [Neurology](https://www.edgepedia.org/neurology) study from [Brigham and Women's Hospital](https://www.edgepedia.org/brigham-and-womens-hospital) and Harvard Medical School, where the acronym PALE was coined for the combination of amnesia and limbic MRI abnormalities associated with human herpesvirus-6 (HHV-6)[2](https://pubmed.ncbi.nlm.nih.gov/17620548/) • [3](https://ndl.ethernet.edu.et/bitstream/123456789/12833/1/Michael%20J.%20Aminoff.pdf).
| Key fact | Detail |
|---|---|
| Definition | Rare, non-paraneoplastic limbic encephalitis arising under treatment-related immunosuppression, typically after allogeneic hematopoietic stem cell transplantation (HSCT)[1](https://www.orpha.net/en/disease/detail/163921) |
| Timing | Onset of confusion, headache, anterograde amnesia, seizures, and/or loss of consciousness 2 to 6 weeks after transplantation[1](https://www.orpha.net/en/disease/detail/163921) |
| Imaging | Bilateral, non-enhancing T2 hyperintensities in limbic structures on MRI[1](https://www.orpha.net/en/disease/detail/163921) |
| Main infectious association | CSF PCR for HHV-6 positive in 6 of 9 patients in the defining series[2](https://pubmed.ncbi.nlm.nih.gov/17620548/) |
| Supportive findings | Mild CSF pleocytosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)[1](https://www.orpha.net/en/disease/detail/163921) • [2](https://pubmed.ncbi.nlm.nih.gov/17620548/) |
| Frequency | 14 PALE cases among 485 consecutive adults undergoing allogeneic hematopoietic cell transplantation at one center between 2005 and 2017[4](https://www.sciencedirect.com/science/article/abs/pii/S0150986109001527) |
| Classification | Orphanet ORPHA:163921; ICD-10 G04.8; prevalence unknown[1](https://www.orpha.net/en/disease/detail/163921) |
## Clinical features
In the case series that defined the condition, nine allogeneic HSCT recipients developed acute limbic encephalitis and shared a recognizable, uniform set of features: loss of the ability to form new memories, SIADH, a slight rise in white cells in the cerebrospinal fluid, and EEG changes over the temporal regions that frequently indicated seizures, whether overt or silent.[2](https://pubmed.ncbi.nlm.nih.gov/17620548/) On T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted sequences, MRI revealed areas of increased signal in the uncus, amygdala, entorhinal cortex, and hippocampus.[2](https://pubmed.ncbi.nlm.nih.gov/17620548/) Orphanet summarizes the imaging signature as bilateral, non-enhancing T2 hyperintensities in limbic structures[1](https://www.orpha.net/en/disease/detail/163921).
The one brain autopsy in the series showed limbic gliosis and profound neuronal loss in the amygdala and hippocampus[2](https://pubmed.ncbi.nlm.nih.gov/17620548/).
## Relationship to HHV-6
Acute limbic encephalitis had been reported in the setting of treatment-related immunosuppression and attributed to HHV-6 before the syndrome was formally characterized[2](https://pubmed.ncbi.nlm.nih.gov/17620548/). In the nine-patient series, CSF PCR assays for HHV-6 were positive in six of nine patients on initial lumbar puncture[2](https://pubmed.ncbi.nlm.nih.gov/17620548/). To test the association, the investigators reviewed CSF HHV-6 PCR results from all HSCT patients at their center from March 17, 2003, through March 31, 2005: among 27 HSCT patients whose CSF was tested over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis[2](https://pubmed.ncbi.nlm.nih.gov/17620548/). The authors concluded that PALE can be associated with the CSF presence of HHV-6 but that the pathogenic role of the virus requires further exploration[2](https://pubmed.ncbi.nlm.nih.gov/17620548/).
HHV-6 is described as the major cause of PALE in immunosuppressed patients following hematopoietic stem cell transplant[5](https://openalex.org/W1899142186). Other viruses have been implicated occasionally: a 2010 case report described a PALE syndrome possibly related to Epstein-Barr virus, with confusion and anterograde amnesia six weeks after transplantation and bi-hippocampal and amygdala signal abnormalities on MRI, the first described case of PALE possibly related to EBV[4](https://www.sciencedirect.com/science/article/abs/pii/S0150986109001527).
## Risk factors and frequency
A retrospective study of 485 consecutive adults who underwent allogeneic hematopoietic cell transplantation between January 2005 and November 2017 identified 14 PALE cases and 11 cases of calcineurin inhibitor-induced encephalopathy. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor, graft-versus-host disease prophylaxis with a calcineurin inhibitor and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE, possibly in part through HLA-mismatch-derived alloimmune responses[4](https://www.sciencedirect.com/science/article/abs/pii/S0150986109001527).
## Treatment and outcomes
All patients in the defining series were treated with foscarnet or ganciclovir, and the authors recommended that treatment considerations include aggressive seizure control and, possibly, antiviral therapy; cognitive recovery varied among long-term survivors[2](https://pubmed.ncbi.nlm.nih.gov/17620548/).
Neurological sequelae can be substantial, particularly in children. Three children with HHV-6-associated PALE 20 to 23 days after cord blood transplantation for leukemias developed symptomatic generalized epilepsy, with generalized seizures including tonic seizures emerging 11 to 18 months after PALE; seizures were frequent and resistant to multiple antiepileptic drugs, and the two younger patients regressed in their general abilities while the older patient developed a severe amnestic syndrome that halted intellectual development[5](https://openalex.org/W1899142186). A later case report and review described epileptic encephalopathy after HHV-6-related PALE in children, with diverse and intractable seizures, significant EEG abnormalities, hippocampal changes, and cognitive decline, and suggested that autoimmune mechanisms may also be involved in disease onset[6](https://rheumatology.cureus.com/articles/356208-epileptic-encephalopathy-after-human-herpes-virus-6-related-post-transplant-acute-limbic-encephalitis-in-children-a-case-report-and-review-of-the-literature?score_article=true).
## Differential diagnosis
PALE sits within the broader differential diagnosis of acute encephalopathy after transplantation. Limbic encephalitis in general requires exclusion of infectious causes, especially [herpes simplex virus encephalitis](https://www.edgepedia.org/herpes-simplex-virus-encephalitis), as well as toxic-metabolic causes, neurodegenerative disorders, neoplasms such as lymphoma, and neurological complications of chemotherapy[7](https://www.ncbi.nlm.nih.gov/books/NBK519523/). In transplant recipients, drug-related encephalopathies such as calcineurin inhibitor-induced encephalopathy occur alongside PALE; the same retrospective study that quantified PALE risk also identified 11 cases of calcineurin inhibitor-induced encephalopathy among 485 patients[4](https://www.sciencedirect.com/science/article/abs/pii/S0150986109001527). The American Society for Transplantation and Cellular Therapy has proposed the TAME (transplant-associated altered mentation and encephalopathy) framework, which classifies acute encephalopathy after hematopoietic cell transplantation into early and late forms based on posttransplant timing[8](https://www.sciencedirect.com/science/article/pii/S2666636724003488). A recent Practical Neurology review lists anterograde amnesia and seizures several weeks after hematopoietic stem cell transplant as the presentation pointing to post-transplant acute limbic encephalitis from HHV-6[9](https://pn.bmj.com/content/practneurol/early/2026/04/29/pn-2024-004299.full.pdf).
## References
1. [Posttransplant acute limbic encephalitis, Orphanet (ORPHA:163921)](https://www.orpha.net/en/disease/detail/163921)
2. [Seeley WW, Marty FM, Holmes TM, et al. (2007). Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 69:156-165.](https://pubmed.ncbi.nlm.nih.gov/17620548/)
3. [Aminoff MJ. Transplantation neurology chapter (PALE acronym), Aminoff's Neurology and General Medicine text](https://ndl.ethernet.edu.et/bitstream/123456789/12833/1/Michael%20J.%20Aminoff.pdf)
4. [EBV limbic encephalitis after allogenic hematopoietic stem cell transplantation, Journal of Neuroradiology 37:189-191 (2010), with PALE risk-factor study abstract](https://www.sciencedirect.com/science/article/abs/pii/S0150986109001527)
5. [Symptomatic generalized epilepsy after HHV6 posttransplant acute limbic encephalitis in children (Freeman & Harvey)](https://openalex.org/W1899142186)
6. [Epileptic encephalopathy after HHV-6-related PALE in children: a case report and review, Cureus](https://rheumatology.cureus.com/articles/356208-epileptic-encephalopathy-after-human-herpes-virus-6-related-post-transplant-acute-limbic-encephalitis-in-children-a-case-report-and-review-of-the-literature?score_article=true)
7. [Paraneoplastic Limbic Encephalitis, StatPearls, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK519523/)
8. [Transplantation-Associated Altered Mentation and Encephalopathy (TAME): A New Classification, ASTCT Committee on Practice Guidelines](https://www.sciencedirect.com/science/article/pii/S2666636724003488)
9. [Suspected encephalitis in adults, Practical Neurology](https://pn.bmj.com/content/practneurol/early/2026/04/29/pn-2024-004299.full.pdf)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Nervous and sensory conditions › Infections and inflammatory encephalitides of the nervous system*
*Initially written Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license