Rapid onset of neurological symptoms in an HIV-positive patient with progressive multifocal leukoencephalopathy: a case report

Abstract

Introduction and importance:

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by substantial damage to oligodendrocytes. It clinically presents as movement impairment, cognitive disability, language aphasia, dysarthria, and visual impairments. It was first identified in 1958. It is commonly associated with either Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Case presentation:

A 40-year-old male Asian farmer presented with altered behavior, fever, and weakness on the right side of his body after suffering a widespread tonic-clonic seizure. His medical background included a tonsillectomy, treatment for pulmonary tuberculosis, and hepatitis C (negative polymerase chain reaction). On admission, he had asymmetric plantar responses, pallor, brisk deep tendon reflexes, an oral thrush, and decreased strength and tone in the muscles on his right side. The findings of the laboratory tests revealed elevated pH, red blood cells, lymphocytes, and protein in the cerebrospinal fluid, as well as an elevated erythrocyte sedimentation rate, abnormal liver function tests, and no bacterial growth. Magnetic resonance imaging (MRI) showed bilateral parietal, temporal, and frontal lobe high signal lesions (T2W, FLAIR sequences), with more severe lesions in the left lobe and no contrast enhancement, consistent with the imaging features of PML. According to the spinal tap, the patient was JC virus-positive. HIV testing indicated a significant viral load, and electroencephalogram recorded seizures.

Clinical discussion:

JC virus reactivation causes PML, a serious brain condition in patients with weak immune systems. HIV and immunosuppressive drugs are thought to be the potential risk factors behind the reactivation of the JC virus and the appearance of PML. Symptoms like seizures and fever are not usually associated with PML, but the presence of these symptoms hints toward the complexity of the diagnosis of this case. Doctors should focus on treating the root cause of the weakened immune system to help patients. PML was identified by combining the results of an MRI scan with the patient’s HIV status and the results of a spinal tap. The patient’s health deteriorated even after receiving corticosteroids, acyclovir, nutritional supplements, and palliative therapy. As time passed, he developed neurological complications, respiratory failure, and ultimately death.

Conclusion:

This case highlights the more aggressive and unique course of PML in HIV patients, it underscores the importance of assessment of the neurological symptoms in high-risk individuals. As PML carries high mortality risk it necessitates prompt diagnosis and treatment with antiretroviral drugs to slow the disease progression.

Introduction

Progressive multifocal leukoencephalopathy (PML) is an infrequent and often fatal demyelinating ailment that typically manifests as movement impairments, cognitive decline, trouble with speech and language, and visual abnormalities^[1^]. This condition was first noted in 1958 and is mainly observed in patients with Hodgkin’s lymphoma and chronic lymphocytic leukemia^[2^].

Highlights.

• Progressive multifocal leukoencephalopathy (PML) arises from JC virus reactivation.

• PML presents with rapid neurological decline and atypical symptoms like seizures.

• When diagnosing PML in immunocompromised patients, magnetic resonance imaging and cerebrospinal fluid analysis are essential.

• HIV-positive people with high viral loads are at greater risk of developing PML.

• In HIV patients, antiviral treatment and a balanced CD4+ count may decrease the progression of PML.

Reactivation of the JC virus in immunocompromised individuals results in rapid loss of oligodendrocyte and multifocal demyelination of the brain tissue giving rise to a clinical picture of PML. This rapidly spreading localized condition results in substantial neurological impairments^[3^]. It progresses from early mild neurological symptoms to intermediate significant impairments and, ultimately, to advanced severe deficits, frequently leading to severe disability or even death^[4^].

“In this study, we report the case of a forty-year-old farmer who presented to the outpatient department (OPD) complaining of right-sided weakness, fever, and altered behavior. The farmer was conscious and lying in a resting, perplexed state, with a normal pulse, blood pressure, and heart rate (18/min). His X-ray revealed right basal tiny atelectatic bands, and he tested positive for HIV and was anti-HCV reactive.” This work has been reported according to the Case Report (CARE) 2013 guidelines^[5^].

Case presentation

A 40-year-old Asian male farmer presented to the OPD in a private hospital with symptoms of right-sided weakness (paresis), fever, and behavioral changes. His family members informed us that he was asymptomatic 1 month ago then he suddenly developed a general tonic-clonic type of seizure, 5 minutes in duration with frothing from the mouth, a tongue bite, and a poor urinary stream; subsequently, he developed weakness in the right side, which was not progressive and slurred speech. In addition, he manifested left-sided deviation of the mouth, abnormal behavior such as aggression, and rambling or irrelevant speech. He reported a low-grade, intermittent fever that resolved with antipyretic agents. He underwent tonsillectomy 5 years prior. Hepatitis C was diagnosed 3 years prior and treated with oral antivirals, and the polymerase chain reaction (PCR) results are currently negative. He had pulmonary tuberculosis 2 years prior and was treated with anti-tuberculosis therapy for 9 months. The T-spot TB test was negative. The patient’s initial vital signs were 76 beats per minute for the heart, 130/80 mmHg for blood pressure, 98°F for temperature, 18 breaths per minute for breathing, and 119 mg/dL for glucose. During his thorough physical examination, the physician noted that the patient had oral thrush and was pallor; nevertheless, no signs of cyanosis, clubbing, lymphadenopathy, or edema were observed. The rest of the results of the systemic examination were unremarkable. On neurological evaluation, the GCS score was 13/15, with average bulk and a decrease in the tone of the right lower limb. Muscle strength was graded 2/5 on the right and 5/5 on the left using the Medical Research Council scale. Hyporeflexia (except for upgoing plantar reflexes bilaterally) was noted throughout the body during the examination, with the deep reflexes being brisk. There was no meningeal irritation to be observed, although sensory and cerebellar exams could not be performed on this patient, as he was uncooperative. Laboratory work-up showed that the patient had an elevated erythrocyte sedimentation rate of 90 mm/h and a low hemoglobin level of 11.8 gm/dL. A liver function test revealed increased levels of protein (9.7 gm/dL), AST (47 U/I), and GGT (145 U/I). Serum electrolytes, renal function test results, and coagulation profiles were also in the normal reference range. For the viral markers, the anti-HCV test results were consistent with the undetected hepatitis C PCR results. Abdominal ultrasound was unremarkable, and a chest X-ray revealed right small basal atelectatic bands. According to the spinal tap, the patient was JC virus-positive. The electroencephalogram (EEG) report reveals a background rhythm characterized by a mixture of beta frequency over the occipital region and theta waves. Notably, sharp transients are observed in the left frontopolar lead, becoming especially prominent during photic stimulation. EEG also showed epileptiform discharges which are suggestive of seizure activity. The magnetic resonance imaging (MRI) report highlights extensive signal abnormalities detected in the bilateral parietal-temporal and frontal lobes, notably more pronounced on the left side with involvement of the corpus callosum. No postcontrast enhancement was observed. These changes could be easily detected via T1W and T2W axial views (Fig. 1) and FLAIR-weighted (Fig. 2) MRI of the brain.

Figure 1.

T1W and T2W axial views of an MRI of the brain.

Figure 2.

FLAIR-weighted MRI of brain.

A reactive ELISA and positive PCR were obtained from HIV testing. Moreover, the results of the PCR were confirmed with a viral load of 523 500 copies/ml. However, other tests, including MTB DNA PCR, HSV DNA PCR, and India ink preparation for Cryptococcus spp., were negative. No growth was identified by cerebrospinal fluid examination. The cerebrospinal fluid results revealed an elevated pH of 8.0, an increase in protein levels of 61 mg/dL, an elevated RBC count of 35/mm³, a lymphocytic count of 100%, and increased adenosine deaminase levels of 3 U/L. Other parameters from the CSF examination were normal. The differential diagnoses were herpes simplex encephalitis, tuberculous meningitis, HIV-associated neurocognitive disorder, and cerebrovascular accidents. Owing to the status of the HIV infection and other findings described above, the patient suffered from a neurological disease known as progressive PML. Furthermore, the clinical picture of progressive neurological deficits is consistent with the progression of PML in immunocompromised patients. The patient was given supportive management, including antiviral therapy (intravenous acyclovir 700 mg three times daily) with IV methylprednisolone 1 g once daily for HIV infection along with symptomatic management. Despite aggressive treatment, the patient developed respiratory failure due to brainstem involvement and subsequently died.

Discussion

Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain caused by irreversible destruction of oligodendrocytes caused by reactivation of the JC virus (human polyomavirus 2), which principally occurs in individuals who have an incompetent immune system, either through any illness that typically impairs cell-mediated immunity or in patients who have a history of prolonged corticosteroid therapy or any history of graft transplantation^[6^]. The molecular background of JCV involves the presence of binding proteins in hosts that show an affinity for the NCCR (noncoding control region) of the JC virus; viral DNA transcription and translation must involve the synthesis of viral structural and functional proteins. Pathogenic serotypes are derived from nonpathogenic serotypes through the process of deletion and replication^[7^]. Many studies have reported that patients undergoing treatment for relapsing episodes of multiple sclerosis with natalizumab have shown signs and symptoms of reactivation of the JC virus^[7^]. In this case, the patient presented with typical symptoms of PML, and it is noteworthy that these symptoms manifested quickly in this case as opposed to other cases where symptoms appeared gradually and progressively^[8^]. In addition, what distinguishes our patient from other patients is the earliest manifestation of seizures, which are of generalized tonic-clonic representation with a duration of 5 minutes. While seizures are not ordinary symptoms of PML, their occurrence hints toward a late stage of the disease, which may have been present in our patient either at the cause of a more aggressive strain of the JC virus or due to severely weakened immunity, which can be evident by the high viral load of HIV (523 500 copies/mL) in our patient’s laboratory reports^[9^]. Although PML is a viral infection, fever is another rare clinical feature among patients with progressive multifocal leukoencephalopathy; however, it is an acute phase response and a marker of significant inflammation and infection. The patient’s complex past medical history of treated pulmonary tuberculosis and hepatitis C along with tonsillectomy due to tonsillitis also appreciated our attention in this case. Although there is no direct association between these diseases and PML, they are still suggestive of the weakened immunity of the patient, which, in this case, is due to HIV. Numerous studies have shown that HIV is the most prevalent factor behind the reactivation of the JC virus, particularly in those with advanced stages of HIV/AIDS^[10^]. Although there is no specific therapy that can reverse damage caused by the JC virus, the progression of the disease can be slowed down by antiretroviral drugs, which are particularly useful in the treatment of human immunodeficiency virus, which works by decreasing the viral load and restoring the CD4+ count within the normal range^[11^]. The diagnostic criteria for PML include a spinal tap, MRI, and CT scan. The spinal tap, including the JC virus gene amplification test, accounts for high percentiles of sensitivity and specificity, that is, 80% and 100%, respectively, and MRI highlights the demyelinating lesion within the brain tissue, which indicates progression and explains the clinical course of PML^[12^]. Under microscopy, brain biopsy reveals a triad of damaged and enlarged oligodendrocytes and unusual-looking astrocytes linked with the presence of the JC virus^[13^].

The patient’s spinal tap revealed a positive result for JC virus presence, and his neuroimaging reports indicated a widespread lesion involving both hemispheres’ parietal-temporal and frontal lobes, with predominant involvement of the left lobes without sparing the corpus callosum. These MRI findings provide a clear explanation for the patient’s right-sided weakness and left-sided mouth deviation. The altered mental status and behavior of this patient can also be explained by the involvement of the frontal lobe. This diagnostic approach was necessary for our patient to differentiate it from other space-occupying lesions of the brain and encephalitis, tuberculous meningitis, etc. A research paper written by Pavlovic et al^[14^] reported a high mortality rate of 30% within a year of the diagnosis of PML and 50%–60% 2 years after the initiation of antiretroviral therapy (ART). Additionally, advanced technology like AlphaFold, an artificial intelligence (AI) model can be used to learn the details of the structural protein of the JC virus, which in the future can be helpful to understanding the complex pathogenesis of PML and can lead to the development of new potential antiviral therapy directed against that particular set of protein^[15–18^]. This underscores the need for early diagnosis with an appropriate approach and timely intervention, which reduces the associated morbidity rate, decreases the economic burden, reduces the need for intensive health care and treatment, and has also been proven to improve the survival of patients. General practitioners should also perform tests for the JC virus when the patients come with symptoms of neurological deterioration^[19^].

Conclusion

This case illustrates the aggressive course and unusual presentation of PML in an HIV-positive patient, and the importance of clinicians having a high level of suspicion in the assessment of neurological symptoms in the immunocompromised patient. Since PML carries an extremely high mortality rate, prompt diagnosis and institution of ART continue to be important factors in the slowing of the disease process. Additionally, the development of AI, including AlphaFold AI modeling, offers new opportunities to crack the code of JC virus structure and pathogenesis in PML and possibly direct future research and therapeutic intervention.

Ethical approval

Ethics approval was not required for this case report.

Consent

Written informed consent was obtained from the patient for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

The authors did not receive any financial support for this work. No funding has been received for the conduct of this study.

Author contributions

S.W., L.K., and A.S. wrote the draft; Q.U.A. conceptualized the manuscript; M.-U.-R.A.B. identified the case; and U.I. and I.I.O. supervised, critically reviewed, and edited the manuscript.

Conflicts of interest disclosure

The authors declare that there is no conflict of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Inibehe Ime Okon.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Not applicable.