Cytomegalovirus Encephalitis in a Heart Transplant Recipient Presenting With Behavioral Changes and Functional Neurologic Deficits

Abstract

Background

Cytomegalovirus (CMV) encephalitis is a rare but serious complication in immunocompromised patients, particularly transplant recipients as they are heavily immunosuppressed.

Case Summary

We report the first documented case to our knowledge of CMV encephalitis in a 67-year-old male heart transplant recipient, confirmed by cerebrospinal fluid polymerase chain reaction. The patient presented with confusion and distinct behavioral changes, yet brain magnetic resonance imaging revealed no acute abnormalities.

Discussion

This case highlights the potential for CMV encephalitis to present with significant neurologic symptoms without any radiologic abnormalities, emphasizing the importance of molecular diagnostics in immunocompromised patients with unexplained neurologic deterioration.

Take-Home Messages

CMV encephalitis in transplant recipients can present with significant neurologic symptoms despite normal brain magnetic resonance imaging, necessitating cerebrospinal fluid analysis for timely diagnosis and management. Close monitoring of CMV viremia and neurologic status is critical, as clinical improvement may lag behind virologic clearance, necessitating individualized treatment strategies.

Graphical Abstract

History of Present Illness

A 67-year-old man with a history of nonischemic cardiomyopathy, which progressed to stage D heart failure necessitating orthotopic heart transplantation 6 months earlier (cytomegalovirus [CMV] serostatus: D+/R–), presented to the transplant clinic with a constellation of symptoms. He reported progressive malaise, low-grade fever, and generalized weakness over several weeks, culminating in confusion, forgetfulness, and impaired coordination of upper extremity movements over the 5 days preceding his visit. Additional symptoms included decreased appetite with unintentional weight loss, lightheadedness, and blurry vision.

Take-Home Messages

• •CMV encephalitis in transplant recipients can present with significant neurologic symptoms despite normal brain MRI findings, necessitating CSF analysis for timely diagnosis and management
• •Close monitoring of CMV viremia and neurologic status is critical, as clinical improvement may lag behind virologic clearance, necessitating individualized treatment strategies.

On physical examination, his vital signs were as follows: temperature, 98.3 °F; heart rate, 110 beats/min; blood pressure, 107/59 mm Hg; and respiratory rate, 25 breaths/min. Neurologically, he was alert but oriented only to person. The examination was notable for bilateral upper extremity tremors and mild lower extremity edema up to the ankles. Cardiovascular, pulmonary, and abdominal examinations were unremarkable.

Previous immunosuppression included count-based antithymocyte globulin for 3 days with methylprednisolone 1 mg/kg every 8 hours after transplant. He was converted to oral steroids on postoperative day 3 and weaned over 3 months according to our center's protocol. His current immunosuppressive regimen included tacrolimus and mycophenolate mofetil. He was also taking voriconazole and dapsone for routine post-transplant infectious prophylaxis. Notably, valganciclovir had been discontinued 1 month earlier per institutional protocol. He had been adherent to regular follow-up in the orthotopic heart transplant clinic, where serial transthoracic echocardiography and right heart catheterization with endomyocardial biopsies consistently demonstrated preserved graft function, with a left ventricular ejection fraction >50%, normal cardiopulmonary hemodynamics, and no evidence of acute rejection.

His past medical history includes chronic kidney disease stage (CKD) stage 3a, type 2 diabetes mellitus not requiring insulin, and anemia of chronic disease.

Differential Diagnosis

Given his presentation, the differential diagnosis included CMV infection, other opportunistic infections, metabolic derangements, cerebrovascular accident/transient ischemic stroke, and acute allograft rejection.

Investigations

On admission, laboratory evaluation revealed acute kidney injury on a background of CKD stage 3a, with a serum creatinine level of 2.92 mg/dL (reference [ref]: 0.70-1.30 mg/dL), blood urea nitrogen level of 47 mg/dL (ref: 7-25 mg/dL), and potassium level of 5.3 mmol/L (ref: 3.5-5.0 mmol/L). Electrocardiography and troponin levels were unremarkable without dynamic changes.

The initial white blood cell count was 7,470/mm³, but it declined to 4,110/mm³ after fluid resuscitation and remained in the perileukopenic range (4,000-5,000/mm³). Serial blood cultures were negative despite intermittent fevers.

A chest x-ray at presentation showed no evidence of pneumonia or other acute pathology. Subsequent computed tomography (CT) of the abdomen and pelvis did not reveal any signs of intra-abdominal infection or abscess formation. Endomyocardial biopsy showed no evidence of acute rejection, (International Society for Heart and Lung Transplantation grade 0), and transthoracic echocardiography demonstrated preserved graft function. Right heart catheterization demonstrated normal cardiopulmonary hemodynamics.

Given the concern for viral reactivation, a quantitative polymerase chain reaction (PCR) assay for CMV was performed in the blood, revealing a markedly elevated viral load of 17,185,648 copies/mL (ref: <34.5 copies/mL) on admission (Figure 1).

Figure 1.

WBC and CMV PCR Trend From Initial Presentation

Line graph representation of plasma cytomegalovirus polymerase chain reaction (CMV PCR) and white blood cell (WBC) trends starting from the date of admission (day 0).

While hospitalized, the patient's neurologic status deteriorated significantly. He became increasingly drowsy and somnolent, with worsening confusion. Neurologic examination revealed diffusely hyperreflexic (3+) deep tendon reflexes, marked disorientation, and the emergence of stereotyped movements upon waking. These consisted of sequentially examining each hand and arm with full supination and pronation, followed by a similar movement of the opposite arm.

Notably, there was no evidence of nuchal rigidity, and the patient was able to flex his neck without discomfort. Brain magnetic resonance imaging (MRI) was obtained and showed no areas of cortical or subcortical signal abnormality suggestive of encephalitis (Figure 2).

Figure 2.

MRI Brain in Setting of PCR Confirmed CMV Encephalitis

Brian magnetic resonance imaging showing no evidence of edema, mass lesion, hemorrhage, or acute infarct. There was no abnormal enhancement.

Cerebrospinal fluid (CSF) analysis was obtained on hospital day 10 by interventional radiology under CT guidance after 2 failed bedside attempts and confirmed CMV-related central nervous system infection, with the following findings:

• •Glucose: 59 mg/dL (ref: 40-70 mg/dL)
• •Protein: 52 mg/dL (ref: 15-45 mg/dL)
• •CMV PCR: positive

Management and Hospital Course

Given the high clinical suspicion for CMV infection at presentation, intravenous ganciclovir was initiated before serologic confirmation of CMV viremia. The extremely high CMV viral load (>17 million copies/mL) indicated severe systemic infection, necessitating careful management of both antiviral therapy and immunosuppression.

Owing to the patient's perileukopenic state and the absence of acute transplant rejection, mycophenolate mofetil was withheld to reduce the immunosuppressive burden. Additionally, target tacrolimus trough levels were lowered from 10 to 12 ng/mL to 6 to 8 ng/mL to allow for an adequate immune response while minimizing the risk of rejection. The patient received intravenous fluid support, which led to an improvement in renal function back to baseline.

Serial CMV PCRs showed a progressive decline, confirming response to therapy. Combination therapy with foscarnet was considered, though held because of decline in viral load and CKD with recent kidney injury. Despite the reduction in CMV levels, the patient did not exhibit significant neurologic improvement until the viral load fell below 16,000 copies/mL around hospital day 20. This improvement began with a progressive decrease in tremors from generalized to intermittent from days 15 to 19. By hospital day 21, the patient was more alert and talkative without tremors or neurologic findings on examination (Table 1).

Table 1.

Plasma CMV PCR and WBC Trends Since Hospitalization

Days Since Hospitalization	Plasma CMV PCR (IU/mL)	WBC (K/uL)
Day 0	1,718,568	4.41
Day 7	4,949,855	5.39
Day 14	487,192	9.66
Day 20	15,728	8.95
Day 27	14,489	7.15
Day 33	4,328	4.74
Day 54	708	7.66
Day 62	925	7.91
Day 70	532	8.43
Day 77	384	10.33
Day 84	448	8.43

Day 0 indicates the date of admission.

CMV = cytomegalovirus; PCR = polymerase chain reaction; WBC = white blood cell.

Given persistent odynophagia and poor oral intake, gastroenterology and otolaryngology were consulted to evaluate for possible concurrent CMV colitis or esophagitis, respectively. CT of the abdomen and pelvis showed no evidence of colonic wall thickening, and therefore suspicion for CMV colitis was quite low. A bedside nasopharyngoscopy did not reveal any significant abnormalities. Despite this, the patient required a nasogastric tube for nutrition.

By hospital day 21, the patient showed significant symptomatic improvement and increased oral intake. Enteral nutrition was weaned over the next several days, and by hospital day 29 the patient was consuming adequate oral nutrition, leading to removal of the nasogastric tube. At discharge, he was placed on an adjusted immunosuppressive regimen with continued CMV monitoring and scheduled follow-up in the transplant clinic.

Discussion

In orthotopic heart transplant recipients, CMV remains a significant cause of morbidity and mortality, occurring in approximately 20% to 30% transplant recipients within the first year.¹ Prophylactic antiviral therapy and routine viral load monitoring are standard strategies, particularly in patients with a donor-positive/recipient-negative (D+/R–) serostatus, as they tend to portray the highest risk of reactivation. Despite preventive measures, CMV infections still occur, with symptoms ranging from mild fever and malaise to severe complications such as pneumonitis, gastroenteritis, and, rarely, encephalitis.^2,3

CMV encephalitis is an uncommon but severe complication of CMV viremia, most frequently reported in patients with HIV/AIDS, which may mimic HIV-associated neurocognitive disorders.⁴ Though rare, CMV encephalitis has been reported in stem cell and solid organ transplants (<1%).⁵ To our knowledge, this is the first reported case in the literature of CMV viremia in a patient after orthotopic heart transplant. The clinical presentation of CMV encephalitis primarily involves altered mentation, which can make differentiation from HIV-associated cognitive impairment difficult. However, CMV encephalitis is more commonly characterized by delirium, confusion, and focal neurologic deficits, whereas HIV-associated neurocognitive disorders tend to present with a more insidious cognitive decline. In contrast, CMV ventriculoencephalitis often has a more acute onset, manifesting as lethargy, confusion, and cranial nerve involvement.⁵

In this case, the patient's progressive neurologic symptoms, including disorientation, stereotyped repetitive movements, and diffuse hyperreflexia, were suggestive of CMV ventriculoencephalitis. This condition is typically associated with periventricular enhancement on brain imaging, raising suspicion for possible frontal lobe involvement. However, despite the patient's profound neurologic deterioration, brain MRI did not reveal any acute abnormalities. A similar finding has been previously reported in CMV encephalitis but not in solid organ transplant recipients.⁶ This case highlights the critical importance of CSF analysis in immunocompromised patients with unexplained neurologic symptoms, even with normal neuroimaging.⁷

The management of CMV encephalitis depends on the severity of neurologic impairment and the patient's ability to tolerate antiviral therapy. Current treatment recommendations are primarily based on data from patients with HIV/AIDS-related CMV encephalitis. In severe cases, such as patients presenting with obtundation and confirmed CMV encephalitis, dual therapy with intravenous ganciclovir and foscarnet is recommended. Combination therapy has been associated with improved outcomes, though it carries a significant risk of nephrotoxicity and therefore necessitates close monitoring of renal function monitoring and dose adjustments.

Currently, there are no formal guidelines for the treatment of CMV encephalitis in solid organ transplant recipients.^8,9 However, in transplant recipients with CMV detected in CSF, existing recommendations from HIV/AIDS literature may serve as a reasonable framework for treatment.¹⁰ In this patient, the neurologic symptoms were unique, featuring distinct repetitive movements, cognitive dysfunction, and personality changes. Combination therapy was considered in our patient, though deferred owing to concurrent renal injury. While CMV PCR levels declined with treatment, significant neurologic recovery was delayed, underscoring the complexity of managing CMV-related central nervous system infections in immunocompromised transplant recipients.

Conclusions

CMV encephalitis is an exceedingly rare yet severe complication in patients after orthotopic heart transplant. Our patient's presentation, marked by progressive cognitive decline and distinct repetitive movements, highlights the first reported case of CMV encephalitis in an orthotopic heart transplant recipient. While antiviral therapy led to viral clearance, neurologic improvement did not follow perfectly in suit. This case underscores the need for further research into the optimal management of CMV encephalitis in the non-AIDS population. Consideration for combination antiviral therapy must be made, especially once this diagnosis is confirmed in patients with marked neurologic decline.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Visual Summary.

Timeline of Events

Timeline	Events
Day 1	A 67-year-old male heart transplant recipient presented to transplant clinic with progressive malaise, low-grade fever, weight loss, confusion, forgetfulness, and impaired coordination.
Days 1-2	Initial laboratory tests showed acute kidney injury, mild leukopenia, and significantly elevated CMV viral load (17,185,648 copies/mL). Brain MRI showed no acute abnormalities.
Day 2	Initiated intravenous ganciclovir owing to high suspicion of CMV-related central nervous system infection. Immunosuppression adjusted (mycophenolate mofetil withheld, tacrolimus trough target lowered).
Days 2-14	Neurologic status deteriorated, with worsening confusion, hyperreflexia, and repetitive stereotyped movements. MRI obtained, with no acute abnormalities. CSF analysis confirmed CMV encephalitis (CMV PCR positive).
Days 14-20	Continued CMV viremia monitoring; viral load progressively declined. Neurologic improvement correlated with viral load reduction <16,000 copies/mL (around hospital day 20).
Day 21	Marked neurologic and clinical improvement. Increased oral intake led to gradual weaning off enteral nutrition.
Day 29	Discharged with ongoing CMV monitoring and adjusted immunosuppressive regimen. Scheduled follow-up in transplant clinic.

CMV = cytomegalovirus; CSF = cerebrospinal fluid; MRI = magnetic resonance imaging; PCR = polymerase chain reaction.