ABSTRACT

Latar belakang: Manifestasi neurooftalmik pada infeksi Human Immunodeficiency Virus (HIV) melibatkan jaras penglihatan aferen dan eferen. Keterlibatan neurooftalmik disebabkan infeksi langsung maupun akibat infeksi oportunistik. Skrining kelainan neurooftalmik sebaiknya dilakukan walaupun tanpa keluhan penglihatan, sehingga dapat mengidentifikasi gejala dan tanda neurooftalmik serta merujuk pada ahli neurooftalmik

Tujuan : Untuk mengetahui hubungan antara kadar CD4 dengan manifestasi neurooftalmik pada penderita HIV positif.

Metode Penelitian: Penelitian ini bersifat crossectional dengan sumber data primer yang diambil secara konsekutif dari penderita HIV positif di RSUP Haji Adam Malik Medan. Subjek dilakukan pemeriksaan kadar CD4 dan pemeriksaan fisik neurologi dan neurooftalmik berupa pemeriksaan visus, lapangan pandang, pemeriksaan pupil dan funduskopi.

Hasil : Terdapat 45 subjek penelitian dengan karakteristik demografi mayoritas subjek adalah laki-laki (71,1%), kelompok usia 31-40 tahun (55,6%) dengan rerata usia 35,98+9,23 tahun, pekerjaan wiraswasta (46,7%), sudah menikah (60%) dan suku Batak (62,8%). Kadar CD4 < 200 sel/µL dijumpai pada 55,6% dengan nilai median 162 sel/µL (30-878). Mayoritas manifestasi klinis neurooftalmik dijumpai pada 52% subjek dengan kadar CD4 < 200 sel/µL dengan gejala pandangan kabur (22,2%) dengan tanda klinis kelainan pada funduskopi (20%). Terdapat hubungan yang signifikan antara kadar CD4 dengan manifestasi neurooftalmik pada penderita HIV (p < 0,005).

Kesimpulan: Terdapat hubungan yang signifikan antara kadar CD4 dengan manifestasi neurooftalmik pada penderita HIV (p < 0,005).

Kata Kunci: CD4, HIV, neurooftalmik, funduskopi, visual

ABSTRACT

Background : The neuroophthalmic manifestations of HIV infection involve afferent and efferent visual pathways. Neuroophthalmic involvement is caused by direct infection and opportunistic infections. Screening for neuroophthalmic manifestations should be done even without vision complaints to identify neuroophthalmic signs and symptoms and refer to a neuroophthalmologist soon.

Objectives : To determine the relationship between CD4 levels and neuroophthalmic manifestations in HIV positive patients .

Methods : It was a cross-sectional study with primary data sources taken consecutively from HIV positive patients at Haji Adam Malik General Hospital in Medan. Subjects were examined for CD4 levels and also performed the neuroophthalmic and neurological physical examination such as visual acuity examination, visual field, pupil examination and funduscopy.

Results : There were 45 subjects with demographic characteristics the most of subjects were male (71.1%), age group 31-40 years (55.6%) with an average age of 35.98 + 9.23 years, self-employed (46.7%), married (60% ) and Bataknese (62.8%). CD4 levels < 200 cells/µL were found at 55.6% with a median value of 162 cells/µL (30-878). The most of neuroophthalmic clinical manifestations were found in 52% of subjects with CD4 levels <200 cells/µL with symptoms of blurred vision (22.2%) and clinical signs of funduscopic abnormalities (20%). There was a significant relationship between CD4 levels and neuroophthalmic manifestations in HIV patients (p<0.005).

Conclusion : There was a significant relationship between CD4 levels and neuroophthalmic manifestations in HIV patients (p<0.005).

Keywords : CD4, HIV, neuroophthalmic, fundoscopy . visual

INTRODUCTION

Human Deficiency Virus (HIV), the etiology of Acquired Immunodeficiency Syndrome (AIDS ) has been endemic for a long time since 1981.¹ Every day more than 7000 people with AIDS are infected and every 20 seconds AIDS patients died and become the fifth leading cause of death in adults.² Based on data from the World Health Organization (WHO), approximately 17 million HIV patients received antiretroviral therapy in 2015.³

Clinical manifestations of HIV/AIDS vary according to the stages of the disease.⁴ Neuroophthalmic manifestations are often found both in HIV and AIDS patients.⁵ Previous study found that blindness due to complications of HIV infection was the cause of the highest morbidity rate with a prevalence of 6.9%-23%. This study found that as CD4 level decreased, the prevalence of ocular manifestations due to HIV infection would increased. Bekele et al in 2013 found that CD4 levels < 200 cells/ µL had a significant association for the risk factor of ocular manifestations in patients with HIV, therefore low CD4 levels were ocular disease predictor in HIV patients.⁶

There is no consensus recently stated that routine screening of HIV patients should perform evaluation ophthalmic disease by ophthalmoscope examination. Therefore, routine ophthalmologic screening is recommended in HIV-1 patients with CD4 levels were < 200 cells/ µL due to the high prevalence of ocular disease in this CD4 category both in subjects with neurophthalmic symptoms and asymptomatic subjects.⁷ Clinicians should screen for ophthalmic and neurophthalmologic abnormalities even in the absence of visual complaints, to help them determine the neuroophthalmic signs and symptoms and then refer to a neurophthalmologist.⁸

METHODS

It was analytic observational study with cross-sectional design using primary data source on hospitalized patients or Policlinic patints at H.Adam Malik General Hospital Medan in April 2022-October 2022. This study got agreement from Committee Local Health Ethics and Research. Criteria inclusion subject is positive HIV patients based on history, physical examination and serological test, 18 years old, conscious and willing to participate in study by informed consent. Exclusion criteria were patients who were could not be assessed in while performing examinations such as patients with aphasia, dementia, patients who were unable to sit and patients with systemic disease diabetes mellitus and hypertension which caused neuroophthalmic manifestations. Sampling was carried out by consecutive sampling method on 45 HIV positive subjects.

This study was an observational analytic study with a crossectional design using primary data sources on patients who were treated or outpatients at H.Adam Malik Hospital Medan in April 2022-October 2022. This study has received approval from the local Ethics and Health Research Committee. The inclusion criteria of the subjects were HIV positive patients clinically based on anamnesis, physical examination and supporting by serology tests, aged 18 years, conscious and willing to participate in the study by signing informed consent. The exclusion criteria were subjects who could not be assessed in performing examination such as aphasia, dementia, subjects who were unable to sit and patients with systemic diseases of diabetes mellitus and hypertension that cause neurophthalmic manifestations. Sampling was taken by concecutive sampling method on 45 HIV positive patients.

The patient was performed blood sampling for CD4 level examination in the laboratory. They also underwent history taking, neurological physical and neuroopthalmic examination. The histories were neuroophthalmic symptoms like blurry vision, diplopia and visual hallucinations. Neuroophthalmic examination such as visual acuity test using the Rosenbaum visual acuity card, visual field examination using confrontation technique, light reflex examination to assess pupil reaction, eye movement, presence of nystagmus, ptosis and also fundoscopy examination using Elch Allyn D-eye digital funduscopy . CD4 levels divided into 2 categories : namely < 200 cells /L and > 200 cells /L, the neuroophthalmic symptoms and signs were divided into presence or absent symptoms and signs. Data study were analyzed by using SPSS software and will be presented in form frequency tables. The relationship between CD4 levels with manifestation neuroophthalmic in HIV positive patients was assessed by using Chi-square test or Fisher's exact test.

RESULT

There were 45 eligible HIV positive subjects met the criteria inclusion. Most of the subjects were 31-30 years category (55.6%), male (71.1%), Batak ethnicity (46.7%). The majority (46.7%) of subjects were self-employed and had a high school education level (53.3%). The mean duration of subjects being diagnosed with HIV was 32.6 ± 35.4 months. The mean duration of the subjects receiving ARVs was 28.8 ± 32.2 months. (Table 1)

Characteristics of CD4 level in HIV subjects were showed in table 2. The mean CD 4 level was 259.5 ± 221.4 cells/ µL , divided into CD4 levels ≤ 200 cells/µL (55.6%) and CD4 levels ≥ 200 cells/µL (44.4%) .

Neuroophthalmic Signs and Symptoms Characteristics

The most common neuroophthalmic symptom in this study was blurred vision (24.4%) followed by double vision (8%). Visual hallucinations symptoms in this study were not found. (Table 3)

The neuroophthalmic clinical sign characteristics were in table 4. The majority of the neuroophthalmic clinical signs in this study were funduscopic abnormalities (17.8%), decreased vision (11.1%), N III, IV, VI paralysis (8.9%), pupil abnormality (4.4%), visual field abnormality (2.2%) and ptosis (2.2%) . Decreased vision was found in 5 subjects of this study with visual acuity were no light perception (2.2%), 1/300 (2.2%) and 20/25 – 20/800 (4,4%).

Association of CD4 levels and Manifestation Neuroophthalmic

Manifestations of neuroophthalmic signs and symptoms were in table 5. Symptoms of blurred vision were more common in 9 subjects (36%) with CD4 levels < 200 cells/µL, whereas in subjects with CD4 levels ≥ 200 cells/µL blurred vision was found in 2 subjects (10%), but there was no significant association between CD4 levels and blurred vision based on the Fisher's exact test (p = 0.495). Manifestations of double vision symptoms were found in subjects with CD4 levels < 200 cells/µL in 2 subjects (8%), whereas in subjects with CD4 levels ≥ 200 cells/µL there were no double vision symptoms, and based on the Fisher's exact statistical test it was not significant (p = 0.495). Neuroophthalmic symptoms such as visual hallucinations were not found in this study.

The most common neuroophthalmic clinical signs in this study were funduscopic abnormalities which were most common in subjects with CD4 levels < 200 cells/µL in 8 subjects (32%), whereas in subjects with CD4 levels ≥ 200 cells/µL none were found funduscopic abnormalities. Based on the fisher's exact statistical test, a significant association with CD4 levels and fundoscopic abnormalities (p = 0.006). The other clinical signs were found in groups subject with CD4 level < 200 cells/µL with visual acuity abnormalities (20%), N III, IV,VI parese (16%), pupil abnormalities (8%), ptosis (4%) and visual field abnormalities (4%), however there was no significant association based on fisher's exact statistical test between CD4 levels with clinical visual acuity abnormalities (p = 0.056), N III,IV,VI parese (p = 0.117), pupil abnormalities (p=0.495), ptosis (p = 1.000) and visual field abnormalities (p = 1.000).

Overall, neurophthalmic manifestations were most common found in HIV subjects with CD4 levels < 200 cells/µL as many as 9 subjects (36%), while in subjects with CD4 levels ≥ 200 cells/µL, there were not neuroophthalmic manifestations found in this study (table 6). Based on fisher's exact statistical test, a significant association was found between CD4 levels and neuroophthalmic manifestations in HIV positive patients (p = 0.002).

*Fisher's exact test

*Fisher's exact test

DISCUSSION

Characteristics Subject Study

Based on demographic data in this study, the majority of subjects aged 31-40 years were 25 subjects (55.6%). These results were relevant to Sharew et al study in 2015 which reported that the most age in HIV positive patients was over 37 years as many as 98 people (26.5%).⁹ Based on data from the Ministry of Health of Republic of Indonesia in 2019, the highest number of HIV infections in 2010-2019 was the age category of 25-49 years or productive age, which is the category age of the most HIV patients each year, where the possibility of transmission occurs at a young age.¹⁰

The majority sex in this study were male (71.1%). These results were relevant to a study by Luo et al in 2013 which reported that the sex male was the most common in HIV positive patients (76.1%). ¹¹ Based on data from the Ministry of Health of the Republic of Indonesia in 2019 that both HIV and AIDS, the proportion in the male group is about two times higher (65%) than in the female group (35%).¹⁰

The most subjects were married (60%). These results were close to Sharew and Azage's study in 2015, which the majority of subjects were HIV positive married (50.5%).⁹ Married indicates that a person is sexually active and if there is a feeling of dissatisfaction with their partner, it will trigger the person to look for another man or woman who can be a risk factor for HIV/AIDS transmission.¹²

Characteristics of CD4 Levels

There was 55.6% of subjects had CD4 levels < 200 cells/µL and 44.4% of subjects had CD4 levels ≥ 200 cells/µL. The results were relevant to Narasimhaiah et al study in 2018 which was in India, that found HIV-positive subjects with the highest CD4 levels were in the group with CD4 levels of 51-199 cells/µL (39.2%) followed by the group with CD4 levels of 200- 499 cells/µL (26.7%). The main target of HIV virus infection is CD4 T lymphocytes so that HIV infection will cause a progressive decrease in CD4 T lymphocytes cell levels due to CD4 cell damage and decreased production which was caused by direct infection or through immune activation.^9,14 The main cause of morbidity and mortality among patients with advanced stages of HIV infection are opportunistic infections. Opportunistic infections usually do not occur in HIV-infected persons until the CD4 count has decreased from a normal level of about 1000 cells/µL to less than 200 cells/µL.¹⁵

Characteristics Neuroophthalmic Symptoms and Signs

About 50-80% of people with HIV require treatment for ocular disorders. Ocular manifestations in HIV can involve all structures of the eye, from the adnexa to the anterior and posterior segments of the eye.^8,16 Based on this study, neuroophthalmic manifestations were found in 20% of subjects with the most common symptoms were blurred vision (24.4%) and double vision (4.4%), while neuroophthalmic clinical signs in this study were fundoscopic abnormalities (17.8%), visual acuity impairment (11,1%), ocular eye movement paresis (8.9%), pupil abnormalities (4.4%) and ptosis (2.2%). Makunyane and Mathebula's study in 2018 on HIV positive patients also found that there were 31.6% of subjects with manifestations of the posterior eye segment and 16.9% of subjects with neuroophthalmic manifestations, mostly 27% funduscopic abnormalities (9% papilledema and 6.2% optic atrophy) and 1.6% oculomotor nerve parese.¹⁷ The neuroophthalmic manifestations in this study were relevant to the study of Acharya et al in 2012 that found the most common manifestation in 9.94% of subjects were papilledema followed by pupil abnormalities, optic neuritis, papil athropy, oculomotor nerve paresis, ptosis and primary papil athropy.¹⁸ Meanwhile, Sudharsan et al in 2013 in India reported 61 subjects with neurophthalmic lesions with manifestations of 49.45% being optic atrophy, 21.97% papilledema, 14.28% optic neuritis and 9.89% cranial nerve paresis.¹⁹

The neuroophthalmic manifestations of HIV infection can involve afferent and efferent visual pathways even in asymptomatic patients or without visual complaints.²⁰ Neuroophthalmic involvement can caused by direct viral effects on nerves or indirectly through opportunistic infections, vascular abnormalities and malignancies due to immunodeficiency.^8,16 However, only a few studies have specifically assessed the association of neuroophthalmic manifestation prevalence in HIV. Optic neuropathy in HIV/AIDS is caused by inflammation, ischemia, infection, compression, infiltration and increased intracranial pressure.¹⁶ Optic neuropathy in HIV is most often secondary to opportunistic infections such as CMV, syphilis, varicella zoster, cryptococcus, toxoplasmosis and tuberculosis.^8,16 In addition to optic neuropathy, HIV infection results in microvascular abnormalities that affect the retina, optic disc and cornea.¹⁶ On funduscopic examination, optic nerve abnormalities will be found disc edema in papillitis, disc edema accompanied by macular exudate in neuroretinitis and the presence of papilledema due to increased intracranial pressure from CNS infection (cryptococcal meningitis, toxoplasma encephalitis, tuberculous meningitis, CMV, neurosyphilis, and tuberculoma).^8,16 The study by Sharma et al in 2018 in India found opportunistic infections in the posterior segment of the eye found most were CMV retinitis (6.7%), and the other 6% were choroiditis; papilledema and optic atrophy.²¹

Association between CD4 levels and Neuroophthalmic Manifestation

There was a significant relationship between CD4 levels and neuroophthalmic manifestations in this study (p = 0.002). These results were relevant to sMakunyane and Mathebula study in 2018 found that neuroophthalmic manifestations were found in 17% subjects and about 80% of them had CD4 levels < 200 cells/µL and 20% of other subjects had CD4 levels ≥ 200 cells/µL and there were significant association between CD4 levels and neuroophthalmic manifestations (p < 0.05).¹⁷ In this study it was also found that the majority of subjects had CD4 levels < 200 cells/µL. HIV infection that attacks CD4 T lymphocytes will result in a decrease in CD4 levels which cause in an increased risk of opportunistic infections. In addition to CD4 levels, HIV viral load is a predictor of immune status in HIV positive patients.^14,22 Low CD4 levels in this study may increase the risk of opportunistic infections.¹³ Antiretroviral can improve life expectancy in people with HIV/AIDS. Neuroophthalmic manifestations can affect the quality of life in people with HIV/AIDS. ²³

In contrast, Amsalu et al study in 2018 found a lower prevalence of ocular manifestations in 14.2% subjects ⁴⁶ compared to Bekele et al study in 2009 (25.3%)¹⁵ and Sharew et al study in 2013 (25,7%).⁵⁹ The lower prevalence of ocular manifestations in the study by Amsalu et al in 2018 was probably due to the longer duration of ARV consumption (> 5 years) in the majority of subjects, which has a positive impact on clinically affected HIV subjects with immune responses and CD4 levels.²⁴ In this study, the duration of ARV consumption subjects had a median of 12 months (0-120 months), which was less than 5 years.

Lestari et al study in 2013 reported HIV positive patients found that ocular disease in subjects was in 63.67% of subjects with around 80% of subjects having clinical stage 3 and 4 HIV based on WHO criteria. There was a significant association between WHO clinical stage and ocular disease (p = 0.009). Subjects who had co-infection associated with ophthalmic abnormalities and had 2.67 greater risk of developing ophthalmic abnormalities. CD4 levels < 50 cells/µL are significantly associated with the occurrence of ocular disease (p = 0.003) and had 2 times greater risk of developing ophthalmic disorders than subjects with CD4 levels ≥ 200 cells/µL. Ocular abnormalities are more common in subjects with clinical stages 3 of HIV and 4 who have poor clinical condition and immunity. Poor immunity will increase the risk of coinfection. Coinfection is a cause of morbidity that reduces the immune status of people with HIV/AIDS. Study on HIV/AIDS subjects with tuberculosis and hepatitis C coinfection and without coinfection showed that coinfection would result in poor clinical status, longer treatment time, low CD4 levels and slow immune response.²³

In this study, the most common neuroophthalmic manifestations were funduscopic abnormalities such as papilledema and followed by visual acuity impairment and paresis of cranial nerves III, IV, VI. The results of this study were relevant to Makunyane and Mathebula in 2018, Lamichhane et al in 2010 and Acharya et al in 2012 that the most common neuroophthalmic manifestations are funduscopic abnormalities in the form of papilledema and papil athrophy followed by cranial nerve paresis III and VI. ^17,18,25 Paresis of the eye movement in HIV is most often cranial nerves III and VI caused by opportunistic infections such as toxoplasma encephalitis, cryptococcus and syphilis.^8,16

This study also found that the mean duration of subjects diagnosed with HIV was 32.6 months and the mean duration of subjects taking ARVs was 32.6 months. Based on study by Amsalu et al in 2018 and Makunyane and Mathebula in 2018, subjects who consumed ARVs for less than 5 years tended to experience neuroophthalmic manifestations compared to duration of ARV consumption more than 5 years. The length period of the ARV consumption possibly will decrease plasma levels of RNA virus and the viral load permanently and will increase CD4 levels and will also improve immune status and decrease the infection opportunistic.^17,18

Limitations

The limitation of this study such as there are other factors that can affect neuroophthalmic manifestations such as duration of infection, other systemic diseases and duration of ARV therapy that has been given. In this study, it was not assessed whether neuroophthalmic abnormalities occurred before or after ARV administration, so it could not be assessed whether neuroophthalmic manifestations were affected by ARV administration. In addition, this study did not assess co-infection in HIV positive patients. Co-infection with HIV such as tuberculosis, hepatitis C can reduce CD4 levels and reduce the immune response therefore it can have an impact on opportunistic infections that can cause neuroophthalmic manifestations.

Conclusion

The most common neuroophthalmic manifestations found in subjects with CD4 levels less than 200 cells/µ L with the common manifestations were blurred vision and funduscopy abnormalities. There was a significant relationship between CD4 levels and neuroophthalmic manifestations in HIV positive patients (p < 0.05). Neuroophthalmic examination screening should be performed in people with HIV/AIDS, especially in patients with CD4 levels < 200 cells/µL to reduce visual impairment and blindness.

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