Progressive Multifocal Leukoencephalopathy in a Young Male With Concurrent Neurosyphilis and HIV Infection: A Case Report

Abstract

Background

The co-infection of human immunodeficiency virus (HIV) and neurosyphilis presents a significant clinical challenge due to the increased risk of opportunistic infections, including progressive multifocal leukoencephalopathy (PML).

Case Presentation

A 23-year-old unmarried male with an unprotected sexual history presented with progressive right upper limb weakness and slurred speech for 10 days. He was diagnosed with HIV and neurosyphilis co-infection, and neuroimaging/cerebrospinal fluid studies confirmed PML.

Conclusions

This case highlights the importance of screening for HIV and neurosyphilis in young patients with neurological symptoms and the need for awareness of opportunistic infections such as PML in immunocompromised individuals.

Plain Language Summary Title

A Young Man With HIV and Neurosyphilis Develops a Rare Fatal Brain Disease

Plain Language Summary

This case study discusses a 23-year-old man who was diagnosed with both HIV and neurosyphilis and later developed a rare brain disease called progressive multifocal leukoencephalopathy (PML). Due to his weakened immune system from these infections, he experienced symptoms like arm weakness and slurred speech. The report emphasizes the importance of testing young people with neurological symptoms for conditions like HIV and neurosyphilis. It also highlights the need for healthcare providers to be aware of PML and other opportunistic infections in individuals with compromised immune systems. Early recognition and management of such cases are crucial for better patient outcomes.

Introduction

Human immunodeficiency virus (HIV) infection often leads to neurological complications, which can be primary (direct viral effects) or secondary (due to immunosuppression). Primary disorders include HIV-associated neurocognitive disorder, vacuolar myelopathy, and polyneuropathy, affecting all immune levels regardless of CD4⁺ T cell counts. Secondary disorders, such as progressive multifocal leukoencephalopathy (PML) and central nervous system (CNS) lymphoma, arise from severe immunosuppression. ¹ PML, caused by JC polyomavirus reactivation, is rare but severe, presenting with diverse neurological deficits and high mortality in immunodeficient patients, particularly those with immune deficiency syndrome (AIDS). ² It is characterized by progressive neurological deficits and often leads to significant mortality in immunodeficient patients, particularly those with AIDS. The clinical manifestations of PML are quite diverse, including weakness, motor and sensory deficits, hemianopsia, cognitive abnormalities, aphasia, and coordination and gait difficulties. ³ Syphilis, the most prevalent sexually transmitted infection in an HIV-infected cohort in China. ⁴ Evidence exists to suggest that syphilis manifests distinctively in individuals co-infected with HIV, especially among those experiencing severe immunosuppression. In this context, the progression to neurosyphilis is more prevalent. ⁵ Patients co-infected with syphilis and HIV are at high risk of PML. We present a case of a young male with concurrent syphilis, HIV infection, and PML, emphasizing the diagnostic challenges and the importance of early detection and management.

Case Presentation

A 23-year-old unmarried Chinese male from Datong City, Shanxi Province, presented with progressive weakness in the right upper limb for 1 month and slurred speech for 10 days, accompanied by memory impairment and slowed reactions. He had no fever, headache, nausea, or vomiting. On February 15, 2025, he visited our emergency department. Cranial computed tomography showed multiple low-density areas in the left cerebral hemisphere, and magnetic resonance imaging (MRI) revealed abnormal signals in the left frontal, parietal, temporal, and occipital lobes, as well as the periventricular region and basal ganglia (Figure 1), with no enhancement on contrast-enhanced imaging (Figure 2).

Figure 1.

Magnetic resonance image of the brain showing patchy areas of abnormal signal intensity in the left frontal, parietal, occipital, and temporal lobes, as well as in the periventricular regions and the basal ganglia. These areas demonstrated high signal intensity on T2-FLAIR imaging and slightly increased signal intensity on DWI and ADC maps.

Figure 2.

Enhanced cranial magnetic resonance imaging (MRI) shows no significant enhancement of the lesions in the left temporal and parietal lobes and periventricular regions.

The patient had no prior history of infectious diseases. The patient had a history of a generalized erythematous rash in December 2024 that resolved spontaneously. He had a 4-year smoking history (10 cigarettes/day) and a history of unprotected sexual encounters, but denied alcohol consumption. His family history was unremarkable. Physical examination revealed widespread, old, brownish pigmented skin patches. Neurological examination showed clear consciousness, reduced memory and calculation abilities, slightly dysfluent speech, shallow right nasolabial fold, muscle strength of grade 3 in the right upper limb and grade 4 in the right lower limb, and a positive right-sided Babinski sign.

Laboratory tests revealed lymphocytopenia (absolute value 0.61 × 10⁹/L, 10.2%), neutrophilia (82.2%), elevated squamous cell carcinoma antigen (3.42 ng/mL), and elevated homocysteine (20.50 umol/L). HIV antibody test was positive (pending confirmation), and serum syphilis-specific antibodies were positive (treponema pallidum particle agglutination+ [TPPA+], rapid plasma reagin [RPR] 1:32+). Lumbar puncture showed an opening pressure of 210 mm H₂O and a closing pressure of 120 mm H₂O. Cerebrospinal fluid (CSF) analysis revealed no cells, normal glucose (2.91 mmol/L), slightly elevated protein (0.38 mmol/L), elevated IgG (52.70 mg/L), and IgA (7.32 mg/L). CSF TPPA was weakly positive (±), and CSF RPR was negative.

Metagenomic next-generation sequencing (mNGS) of CSF showed high relative abundance of human polyomavirus 2 (79.94%) and HIV type I (72.01%). Autoimmune encephalitis antibody panel showed serum anti-GABA_B receptor antibody at a titer of 1:10, while anti-GABA_B receptor in CSF was negative. Magnetic resonance spectroscopy (MRS) revealed elevated choline (Cho) peaks and reduced N-acetylaspartate (NAA) peaks, with a Cho/NAA ratio of 0.395 (Figure 3).

Figure 3.

MRS shows the findings in the lesion of the left centrum semiovale: A lactate peak was observed between 1.33 and 1.35 ppm. An NAA peak was detected at approximately 2.02 ppm, with a reduced amplitude. A Cr peak was present at around 3.05 ppm. A Cho peak was noted at approximately 3.20 ppm, with an elevated amplitude. The ratios of Cr to NAA (Cr/NAA) and NAA to Cho (NAA/Cho) were 0.755 and 0.395, respectively.

The patient was initially treated with ceftriaxone for syphilis and acyclovir for antiviral therapy, with slight improvement. On day 10 of hospitalization, he developed fever (up to 40 °C) and seizures, with an electroencephalogram (EEG) showing left frontal spike wave rhythm (Figure 4). Repeat blood tests showed no abnormalities, and we thought that the seizures could be related to a Herxheimer reaction due to treatment for syphilis. Following symptomatic management with dexamethasone, the patient's symptoms improved. On the 15th day of hospitalization, HIV antibody confirmatory testing via Western blot assay by the Taiyuan Center for Disease Control and Prevention showed HIV-1-positive antibodies with positive reactions in multiple bands (gP160, gP120, gP41, P66, PS1, P31, P24, and P17).

Figure 4.

Electroencephalogram (EEG) findings during wakefulness and ictal discharge. During wakefulness, frequent slow waves and sharp-slow waves are seen in the left temporal region. At seizure onset, low-amplitude slow activity and spike-wave rhythm from the left frontal region, with increasing amplitude and frequency. Abnormal activity spread to the ipsilateral central/anterior areas, then to adjacent/contralateral regions. As the seizure evolved, EEG frequency slowed, with slow waves interspersed and transitioning into slow activity with sharp waves. Background EEG activity normalized postictally.

Subsequently, the patient was transferred to a specialized hospital for HIV/AIDS treatment and was initiated on a regular antiretroviral therapy (ART) regimen consisting of bictegravir/emtricitabine/tenofovir alafenamide. However, after 2 months of treatment, there was still no significant improvement in the patient's condition. The patient's absolute CD4⁺ T-cell count was 14 cells/µL, and the absolute CD8⁺ T-cell count was 893 cells/µL. This significant discrepancy between CD4⁺ and CD8⁺ T-cell counts highlights the immunological challenges faced by patients with HIV infection.

Discussion and Conclusions

Neurosyphilis and HIV Co-Infection

HIV infection is associated with a wide spectrum of neurological complications, categorized into primary infections, secondary infections, neoplasms, and HIV-associated stroke. ¹ CNS disorders occur in 10% to 20% of people living with HIV, with neurotoxoplasmosis, neurocryptococcosis, PML, and neurosyphilis being the most common. ⁶ Neurosyphilis, caused by Treponema pallidum, can occur at any stage of syphilis and is accelerated in HIV co-infection. Diagnosis is complicated by potential false-negative serological tests. ⁷ HIV and syphilis synergistically worsen clinical outcomes, with syphilis increasing the risk of HIV acquisition and exacerbating HIV parameters, including higher viral loads and lower CD4 counts. ⁸ In co-infected patients, serologic tests for syphilis may be modified or non-reactive. ⁹ HIV infection can alter the natural progression of syphilis, leading to more aggressive forms and increased prevalence of neurosyphilis, which may present with atypical features. ¹⁰ Neurosyphilis should be considered in the differential diagnosis of neurological conditions in HIV-positive patients. ⁸ In this case, the patient presented with neurological symptoms consistent with both HIV and syphilis infections. The diagnosis was supported by a positive serum HIV antibody test, a positive CSF HIV RNA sequence, positive serum TPPA and RPR tests, and a weakly positive CSF TPPA test. We believe that he can be diagnosed with a co-infection of neurosyphilis and HIV. GABA_B receptor antibodies were negative in the CSF, with a positive serum titer of 1:10, indicating insufficient evidence for anti-GABA_B receptor antibody-associated encephalitis.

Neurosyphilis, AIDS, and PML

PML is classically associated with HIV but also occurs in multiple sclerosis, hematological malignancies, organ transplant recipients, and autoimmune deficiency states. ¹¹ Co-infection with HIV and neurosyphilis increases the risk of opportunistic infections, including PML. HIV impairs the immune system, and in advanced cases with low CD4 counts, JC virus reactivation often precedes PML, a rare but frequently fatal demyelinating disease of the CNs. The American Academy of Neurology published diagnostic criteria for PML in 2013, categorizing cases as definite, probable, or possible based on clinical presentation, brain MRI findings, and JC virus detection. ³ Recently published cases of HIV-associated PML highlight an aggressive disease form with rapid progression and mortality within months in 2 severely immunocompromised patients with very low CD4 counts who were similarly newly diagnosed with HIV and commenced on ART. ¹² PML is most common in individuals with AIDS, emphasizing the need for careful monitoring of neurological symptoms in HIV-positive patients. MRI typically shows multiple, asymmetric white matter lesions without enhancement, often in the frontal and parieto-occipital lobes, and less commonly in the basal ganglia and posterior fossa. ¹³ MRS reveals a decrease in NAA and creatine and increased choline products, myo-inositol, and lactate in the lesions of PML. ³ The MRS findings in our case are consistent with these characteristic features. However, MRI findings in our case revealed lesions in the basal ganglia, which are less commonly seen in PML. This finding is noteworthy as it contrasts with the more typical MRI manifestations of PML, which usually involve the white matter of the brain. The involvement of the basal ganglia in our case underscores the variability in MRI presentations of PML and highlights the importance of considering this diagnosis even in atypical locations. Meningovascular syphilis is characterized by endarteritis in the blood vessels throughout the CNS, stemming from chronic inflammation of the leptomeninges. This condition can lead to thrombosis and subsequent infarcts. Immunocompetent patients can also develop meningovascular syphilis. The middle cerebral artery is the most commonly affected vessel, with enhancement on gadolinium-enhanced imaging. The lesions in the basal ganglia of this patient did not show enhancement, so we think it is more likely to be PML. ¹⁴ Differences between neurosyphilis and PML are shown in Table 1.^1,14,15 Definitive diagnosis of PML requires clinical and imaging findings consistent with the disease, not better explained by other disorders, and detection of JC virus in CSF by polymerase chain reaction (PCR). ³ We utilized mNGS of the CSF to identify the underlying pathogen in this case. The mNGS revealed the presence of the JC virus, confirming the diagnosis of PML. This approach was chosen because mNGS can detect a broader range of pathogens compared to traditional PCR, especially in cases where the etiology is unclear. The sensitivity of mNGS is also higher, providing a more comprehensive diagnostic tool.^16,17 The case highlights the diagnostic challenges and treatment complexities associated with PML, particularly in the context of concurrent neurosyphilis and HIV infection. Despite the confirmation of JC virus infection through mNGS of CSF and subsequent initiation of a standard antiretroviral regimen, the patient's clinical course remained poor, emphasizing the need for more effective therapeutic strategies and ongoing patient monitoring.

Table 1.

Comparison of Neurosyphilis and PML.

Feature	Neurosyphilis	PML
Pathogen	Treponema pallidum	JC virus
Clinical presentation
Common symptoms	Cognitive decline, cranial nerve palsies, and meningitis	Cognitive decline, hemiparesis, aphasia, and visual disturbances
Onset	Gradual or subacute	Subacute to chronic
Diagnostic criteria
Serology	Positive TPPA and RPR	Negative TPPA and RPR
CSF analysis	Elevated white cell count and positive VDRL	Normal or mildly elevated white cell count, and JC virus detection
Imaging	MRI shows multiple enhancing lesions	MRI shows nonenhancing white matter
Treatment
Antibiotics	Penicillin-based therapy	Antiretroviral therapy
Immunomodulation	None	Considered in some cases
Prognosis	Variable, dependent on treatment and adherence	Poor, often progressive despite antiretroviral therapy

Abbreviations: PML, progressive multifocal leukoencephalopathy; CSF, cerebrospinal fluid; RPR, rapid plasma reagin; TPPA, treponema pallidum particle agglutination; VDRL, Venereal Disease Research Laboratory; MRI, magnetic resonance imaging.

To our knowledge, few studies have addressed the co-infection of syphilis, AIDS, and PML. One notable case involved a young man presenting with atypical CNS demyelination, initially suspected as neuromyelitis optica spectrum disorder due to a large tumefactive lesion and extensive transverse myelitis. However, negative anti-aquaporin-4 antibodies and positive HIV serology led to consideration of tuberculosis myelitis and neurosyphilis. Despite ART and steroids, the patient did not improve, and a brain biopsy suggested PML, though JC virus PCR was negative, indicating nonspecific chronic inflammation. ¹⁸ Another case reported by Alvarez-Mulet et al ¹⁹ involved a patient with newly diagnosed AIDS presenting with progressive dysarthria and gait instability. Neuroimaging and CSF studies confirmed PML. Despite reduced HIV viral load with ART, the patient's condition worsened, with expanding CNS lesions. ¹⁹ These cases highlight that individuals with HIV and sexually transmitted diseases such as syphilis are at high risk for severe PML. The interplay between these infections necessitates comprehensive management and adapted diagnostic practices, considering overlapping neuropsychiatric symptoms that complicate timely diagnosis and treatment.

This case report has some limitations. First, in the early stage of treatment, we lacked the CD4/CD8T-cell count, a key marker for diagnosing HIV-related neurological damage. However, during the follow-up period, we obtained the patient's ART regimen and CD4/CD8 counts after 2 months, which are instrumental in evaluating the treatment efficacy. Second, the 2-month follow-up was done via phone, so we didn't get detailed medical records from a specialist hospital. Third, we did not perform a brain biopsy, although it is not essential for PML diagnosis.

The case highlights diagnostic challenges in a young male with concurrent neurosyphilis, HIV, and PML. It underscores the importance of screening for HIV and neurosyphilis in patients with neurological symptoms and vigilance for opportunistic infections such as PML in immunocompromised individuals. Early detection and management are crucial for improving outcomes. Clinicians should maintain awareness of PML risk, advocate for regular neurological assessments, and utilize appropriate imaging to facilitate early intervention.