# A Complex Case of Neurological Symptoms in an Immunocompromised Patient: From Lymphoma to Tick-Borne Encephalitis

## Table of Contents

- Key Points
- Introduction: Why This Case Matters
- Patient History and Background
- Symptoms and Initial Presentation
- Diagnostic Testing and Results
- Differential Diagnosis: Considering All Possibilities
- Final Diagnosis and Confirmation
- Clinical Implications for Patients
- Limitations and Considerations
- Patient Recommendations
- Frequently Asked Questions
- Source Information

## Key Points

- A 69-year-old man with lymphoma history developed progressive ataxia and cranial nerve palsies.
- Initial concerns included cancer recurrence, but MRI and CSF tests were atypical for lymphoma.
- Powassan virus encephalitis was diagnosed via CSF PCR, a rare tick-borne flavivirus.
- Immunocompromised patients may have severe disease from infections that are mild in others.
- Specialized testing is needed for tick-borne illnesses not covered in standard panels.

## Introduction: Why This Case Matters

This detailed case study illustrates the diagnostic challenges that can arise when immunocompromised patients develop neurological symptoms. The patient had multiple complex medical factors including a history of lymphoma treatment, ongoing immunosuppression, and significant outdoor exposures that created a complicated diagnostic picture.

For patients with compromised immune systems, even rare infections can become serious concerns that require specialized testing and expertise to identify. This case highlights how tick-borne illnesses can manifest with severe neurological complications and how important thorough diagnostic evaluation is for patients with complex medical histories.

## Patient History and Background

The patient was a 69-year-old man with an extensive medical history that significantly influenced his current condition. He had been diagnosed with systemic diffuse large B-cell lymphoma (DLBCL) three years earlier, which had been treated with bendamustine and rituximab chemotherapy.

One year after his initial diagnosis, the patient experienced a relapse of his lymphoma that had spread to his central nervous system (CNS). This CNS lymphoma was positive for Epstein-Barr virus (EBV). His treatment included high-dose methotrexate followed by tisagenlecleucel (CAR T-cell therapy) and later ibrutinib.

His additional medical conditions included:

- Hypertension (high blood pressure)
- Dyslipidemia (abnormal cholesterol levels)
- Nonischemic dilated cardiomyopathy (heart muscle disease)
- Urinary retention
- Thrombosis of the superior mesenteric vein (blood clot in abdominal vein)
- Hypogammaglobulinemia (low antibody levels)
- Attention deficit-hyperactivity disorder
- Mood disorder

The patient took multiple medications including acyclovir prophylaxis, apixaban, atorvastatin, dextroamphetamine-amphetamine, empagliflozin, fluconazole, metoprolol succinate, sacubitril-valsartan, sulfamethoxazole-trimethoprim prophylaxis, tamsulosin, and venlafaxine. He also received periodic intravenous immune globulin infusions for infection prevention.

## Symptoms and Initial Presentation

The patient had been active and participating in water sports until two weeks before admission when he fell while sailing and struck his back. Following this accident, he developed pain in his midback and over his right lower ribs.

Over the next two weeks, he experienced progressively worsening symptoms:

- Progressive weakness and coordination difficulties with his hands
- Inability to feed himself due to coordination problems
- Headache similar to previous migraine headaches

On examination at the hospital, doctors found:

- Temperature: 36.3°C, blood pressure: 107/65 mm Hg, pulse: 86 beats per minute
- Slow and mildly hypophonic (quiet) speech
- End-gaze nystagmus (involuntary eye movements) in both eyes
- Fasciculations (muscle twitches) in the legs
- Increased muscle tone in the right arm and leg
- Weakness on finger abduction in both hands
- Ataxia (coordination problems) in both hands on finger-nose-finger testing
- Weakness and hyperreflexia in the right arm

During his hospital stay, his symptoms continued to worsen significantly. By the fourth day, his hypophonia (quiet speech) worsened and lethargy developed, with worsening hand ataxia and new truncal ataxia (torso coordination problems). By the fifth day, he developed sixth cranial nerve palsy in both eyes and difficulty swallowing solids.

## Diagnostic Testing and Results

Initial blood tests showed a white-cell count of 4860 per microliter (reference range: 4500 to 11,000), with a lymphocyte count of 260 per microliter (reference range: 1000 to 4800), indicating significant lymphopenia (low lymphocyte count) consistent with his immunocompromised state.

Imaging studies revealed important findings:

- CT head showed postsurgical changes from previous left frontal craniotomy and a 6mm calcified lesion in the left centrum semiovale
- CT angiography revealed acute fractures of the posterior right 11th and 12th ribs
- MRI head showed faint increased signal intensity within the left cerebellar hemisphere
- Follow-up MRI on hospital day 9 showed signal hyperintensity in both cerebellar hemispheres, cerebellar folia, and brainstem

Lumbar puncture (spinal tap) performed on the sixth hospital day showed:

- Opening pressure: 15 cm of water (normal)
- 21 nucleated cells per microliter (reference range: 0 to 5)
- Cell composition: 77% lymphocytes, 14% monocytes, 9% unclassified cells
- CSF glucose: 51 mg/dL (2.8 mmol/L; reference range: 50-75 mg/dL)
- CSF total protein: 74 mg/dL (reference range: 5-55 mg/dL)
- No bacteria on Gram's staining
- Numerous lymphocytes with rare atypical forms on cytology
- No evidence of monoclonal B-cell population on flow cytometry

Electromyography and nerve conduction studies showed evidence of a subacute neurogenic process involving multiple nerve roots at cranial and cervical levels.

## Differential Diagnosis: Considering All Possibilities

The medical team considered multiple possible causes for the patient's neurological deterioration, focusing on three main categories: immune-mediated conditions, cancer recurrence, and infections.

**Immune-Mediated Conditions:** Autoimmune disorders account for approximately 6% of sporadic cerebellar ataxia in adults. The team considered various antibody-mediated conditions but noted these were unlikely given the patient's impaired humoral and cell-mediated immunity.

**Cancer Recurrence:** The patient's history of CNS lymphoma made recurrence a strong consideration. However, the MRI didn't show typical enhancing lesions, and flow cytometry didn't reveal monoclonal B cells. The symmetric cerebellar involvement was also unusual for lymphoma.

**Infectious Causes:** Multiple infections were considered:

- Fungal infections (unlikely due to ongoing fluconazole treatment)
- Bacterial infections including Lyme disease (testing negative) and Listeria (unlikely without abscesses on MRI)
- Viral infections including JC virus, West Nile virus, and herpes viruses
- Tick-borne infections including Powassan virus

The combination of tick exposures, rapid neurological deterioration, cerebellar symptoms, and CSF findings made Powassan virus encephalitis the most likely diagnosis.

## Final Diagnosis and Confirmation

The diagnostic team determined that Powassan virus encephalitis was the most likely diagnosis based on several key factors:

Powassan virus is an arthropod-borne flavivirus closely related to tickborne encephalitis virus. It's transmitted by Ixodes scapularis (deer ticks) and has been increasingly reported in the upper Midwest and New England regions.

The clinical features that supported this diagnosis included:

- Recent tick bites reported by the patient
- Rapid progressive neurological deterioration over weeks
- Cerebellar involvement with ataxia and coordination problems
- Cranial nerve palsies (sixth nerve involvement)
- CSF showing lymphocytic pleocytosis (21 cells/μL with 77% lymphocytes)
- MRI showing symmetric cerebellar and brainstem abnormalities without mass effect
- Lack of response to multiple antimicrobial treatments

Confirmatory testing was performed using CSF polymerase chain reaction (PCR) testing for Powassan virus, which is the test of choice for immunocompromised patients with suspected infection.

## Clinical Implications for Patients

This case has several important implications for patients, particularly those with compromised immune systems:

Immunocompromised patients face increased risks from infections that might cause minimal symptoms in healthy individuals. Powassan virus, while rare, can cause severe disease in patients with impaired immune function.

The diagnosis required specialized testing not typically included in standard infectious disease panels. This highlights the importance of discussing potential tick exposures with healthcare providers and considering rare tick-borne illnesses in appropriate clinical scenarios.

For patients with lymphoma history and neurological symptoms, the diagnostic process must carefully balance concerns about cancer recurrence with evaluation for infectious causes, particularly when immunosuppression is present.

## Limitations and Considerations

Several limitations should be considered when interpreting this case:

The diagnosis relied on specialized testing that may not be readily available at all medical centers. This could delay diagnosis and treatment in areas where Powassan virus is emerging.

In immunocompetent hosts, Powassan virus RNA is often transient and may be undetectable by the time patients seek care, making diagnosis more challenging.

The patient's complex medical history and multiple medications created potential confounding factors that complicated the diagnostic process.

Tick-borne illness testing can be less reliable in profoundly immunocompromised patients who may not mount typical antibody responses.

## Patient Recommendations

Based on this case, patients with compromised immune systems should consider the following recommendations:

1.
**Tick Prevention:** Use appropriate insect repellent, wear protective clothing, and perform thorough tick checks after outdoor activities in endemic areas
1.
**Exposure Reporting:** Report any tick bites or outdoor exposures to healthcare providers, especially when neurological symptoms develop
1.
**Early Evaluation:** Seek prompt medical attention for neurological symptoms including headache, coordination problems, or weakness
1.
**Comprehensive History:** Provide complete medical history including all medications, treatments, and immune status to healthcare providers
1.
**Specialized Testing Awareness:** Understand that some infections require specialized testing not included in standard panels

For patients with similar medical histories, this case emphasizes the importance of maintaining ongoing communication with oncology and infectious disease specialists about any new symptoms or exposures.

## Frequently Asked Questions

### Why do neurological symptoms in immunocompromised patients require extensive testing?

Immunocompromised patients have multiple potential causes for neurological symptoms, including cancer recurrence, infections, and immune-mediated conditions. In this case, the patient's history of CNS lymphoma made recurrence a strong possibility, but MRI and CSF flow cytometry did not support it. Infections like Powassan virus require specialized PCR testing not included in standard panels, and the patient's impaired immune response can make antibody tests unreliable. Therefore, a thorough evaluation is necessary to identify rare but serious causes.

### What is Powassan virus and how does it affect the brain?

Powassan virus is a tick-borne flavivirus transmitted by Ixodes scapularis ticks, increasingly reported in the upper Midwest and New England. It can cause severe encephalitis with rapid neurological deterioration, including ataxia, cranial nerve palsies, and altered mental status. In this case, the patient developed progressive cerebellar and brainstem symptoms, with CSF showing lymphocytic pleocytosis and MRI revealing symmetric cerebellar hyperintensities. Diagnosis is confirmed by PCR testing of CSF, especially in immunocompromised patients who may not mount antibody responses.

### Why does Powassan virus encephalitis come back after treatment?

The article does not describe recurrence of Powassan virus encephalitis after treatment. Instead, it emphasizes that the infection can cause rapid, progressive neurological decline in immunocompromised patients. There is no specific antiviral therapy for Powassan virus; management is supportive. The case highlights the diagnostic challenge rather than treatment outcomes. Patients with similar histories should seek prompt evaluation for new neurological symptoms, as early diagnosis may improve management.

### What should immunocompromised patients do to prevent tick-borne infections like Powassan virus?

Immunocompromised patients should use insect repellent, wear protective clothing, and perform thorough tick checks after outdoor activities in endemic areas. They should also report any tick bites or outdoor exposures to their healthcare providers, especially if neurological symptoms develop. Prompt medical attention for headache, coordination problems, or weakness is important.

### How is Powassan virus encephalitis diagnosed in immunocompromised patients?

In immunocompromised patients, the test of choice for diagnosing Powassan virus is PCR testing on cerebrospinal fluid (CSF). This is because antibody responses may be unreliable in these patients. The diagnosis is also supported by clinical features like rapid neurological deterioration, cerebellar symptoms, and CSF findings showing lymphocytic pleocytosis.

### What are the early symptoms of Powassan virus encephalitis?

Early symptoms include progressive weakness and coordination difficulties with the hands, inability to feed oneself, headache, and later, quiet speech, involuntary eye movements, muscle twitches, increased muscle tone, and ataxia. Symptoms worsen over days, leading to lethargy, difficulty swallowing, and cranial nerve palsies.

### Why is Powassan virus testing not always reliable in immunocompromised patients?

In immunocompromised patients, antibody responses may be blunted, making serologic tests unreliable. PCR testing on cerebrospinal fluid is preferred, but even this may be transient and undetectable by the time patients seek care. This can delay diagnosis, especially in areas where Powassan virus is emerging.

## Source Information

**Original Article Title:** Case 19-2025: A 69-Year-Old Man with Headache and Ataxia

**Authors:** Arun Venkatesan, M.D., Ph.D., Javier M. Romero, M.D., G. Kyle Harrold, M.D., and Erik H. Klontz, M.D., Ph.D.

**Publication:** The New England Journal of Medicine, 2025;393:176-84

**DOI:** 10.1056/NEJMcpc2412528

*This patient-friendly article is based on peer-reviewed research from the Case Records of the Massachusetts General Hospital.*


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