Diagnosis, Workup and Treatment
The differential diagnosis in this patient with variable blurry vision with no apparent ocular basis includes nonorganic visual loss and higher cortical visual loss. Given the patient’s unremarkable eye exam and inconsistent responses, he was thought to have nonorganic visual loss and was planned for discharge with outpatient follow-up. However, after examination of the left temporal lesion raised the possibility of malignancy, the treating physicians further discussed the patient’s care with his infectious disease doctor.
It was learned that the patient had poorly controlled HIV despite prescribed HAART therapy and was at high risk for opportunistic disease. As a result, an MRI of the brain was obtained which demonstrated extensive T2 flair lesions consistent with demyelination and in the clinical context were concerning for progressive multifocal leukoencephalopathy (PML) (See Figure 2). He was admitted to the Neurology Service for further evaluation.
Further testing revealed an elevated HIV viral load of 1,440 (normal range <48) and CD4 count of 15 (normal range >400). A lumbar puncture was performed, which revealed few WBCs, no malignant cells and an elevated JC polyomavirus titer of 2,505,426 copies/ml (normal range <500 copies/ml) consistent with the diagnosis of PML. An excisional biopsy of the left temporal lesion revealed invasive moderately differentiated squamous cell carcinoma, which is found at higher incidence in patients with HIV/AIDS and was a further clue to the patient’s immunosuppressed status.1
There are currently no effective treatments that target the JC Polyoma virus. Therefore, the treatment options for this patient were focused on controlling his HIV infection to reconstitute his immune system. The patient had been prescribed a multidrug combination of HIV therapy but had not been compliant with his medication regimen. Compliance with his medication regimen was stressed and close follow-up with his infectious disease doctor was arranged. Additional follow-up on this patient was not available after hospital discharge.
Discussion
Progressive multifocal leukoencephalopathy is a rare demyelinating disorder of the central nervous system that occurs secondary to the JC polyomavirus.2 PML is rarely observed in otherwise immunologically normal individuals and occurs almost exclusively in patients with abnormal T cell immunity, most commonly individuals with HIV. Approximately 80 to 90 percent of the population is infected with JC virus before adulthood, but it is not known if PML results from primary infection or reactivated latent infection. The leading hypothesis is that the latent JC virus can be reactivated in the immunosuppressed brain, leading to disease progression.2 The diagnosis of PML is made by the combination of neurological findings consistent with focal lesions of the CNS, white matter lesions with no mass effect or enhancement on MRI, and detection of JC virus DNA by polymerase chain reaction in the cerebrospinal fluid or histopathological evidence of PML on brain biopsy.3
The AIDS pandemic rapidly changed the incidence of PML, with a 20-fold increase in cases from the early 1980s to the early 1990s.2However, the development of HAART has dramatically decreased the incidence of PML since the mid 1990s.4 Even with combination antiretroviral therapy, 50 percent of patients die within six months of PML onset, although a more recent study indicated that five drug combination therapy may reduce mortality.3 Yet even with these new therapies only 38 percent of patients with PML recover to live independently.3 A low CD4 count and high number of JC virus DNA copies in the cerebrospinal fluid have been shown to be early risk factors for death.3 Although this patient had poorly controlled HIV, cases of PML in patients successfully treated on HAART with normal CD4 counts and undetectable viral loads have been reported and thus the treating ophthalmologist must always consider PML and other opportunistic diseases in any patient with HIV and vision loss.5
The most common symptoms associated with PML are weakness and cognitive disturbances, but they can also include speech abnormalities, headaches, gait disorders, visual impairment and sensory loss.2 In two case series of PML patients that developed ophthalmologic manifestations, the most common signs were progressive retrochiasmal visual field defects, supranuclear and nuclear cranial nerve palsies and nystagmus ataxia.6,7 Bilateral occipital lobe PML has been reported to cause cortical blindness.6-8
The diagnosis of cortical vision loss requires a detailed ophthalmologic examination but can be confused with nonorganic or functional vision loss in a patient with normal pupils and a normal fundoscopic exam.9 In this case, the patient’s variability of responses ranging from reading single letters with an acuity of 20/30 to not being able to count fingers at 12 inches raised the suspicion of nonorganic vision loss. However, patients with higher cortical vision loss often have increased acuity with single letters similar to that of patients with amblyopia, and concomitant cognitive deficits, as in this patient, may complicate the assessment of vision. This patient may also have had simultagnosia, which could account for his poor visualization of the Ishihara color plates. Ophthalmologists should maintain a high index of suspicion in patients with possible cortical vision loss and should proceed to neuroimaging, preferably with MRI, for definitive evaluation.
The author would like to thank Mark L. Moster, MD, Wills Eye Institute Neuro-Ophthalmology Service.
1. Purgina B, Pantanowitz L, Seethala RR. A Review of Carcinomas Arising in the Head and Neck Region in HIV-Positive Patients. Patholog Res Int;2011:469150.
2. Berger JR. Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep 2007;7:461-9.
3. Gasnault J, Costagliola D, Hendel-Chavez H, et al. Improved Survival of HIV-1-Infected Patients with Progressive Multifocal Leukoencephalopathy Receiving Early 5-Drug Combination Antiretroviral Therapy. PLoS One 2011;6:e20967.
4. Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis 2009;48:1459-66.
5. Mascarello M, Lanzafame M, Lattuada E, Concia E, Ferrari S. Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART. J Neurovirol 2011;17:196-9.
6. Ormerod LD, Rhodes RH, Gross SA, Crane LR, Houchin KW. Ophthalmologic manifestations of acquired immune deficiency syndrome-associated progressive multifocal leukoencephalopathy. Ophthalmology 1996;103:899-906.
7. Wein F, Francis GS, Gans MS, Connolly WE, Burnier MN, Jr. Neuro-ophthalmic findings in progressive multifocal leukoencephalopathy. Can J Ophthalmol 1998;33:270-5.
8. Smith DD, Robinson MR, Scheibel SF, Valenti WM, Eskin TA. Progressive multifocal leukoencephalopathy (PML) in two cases of cortical blindness. AIDS Patient Care 1994;8:110-3.
9. Flanagan C, Kline L, Cure J. Cerebral blindness. Int Ophthalmol Clin 2009;49:15-25.
The differential diagnosis in this patient with variable blurry vision with no apparent ocular basis includes nonorganic visual loss and higher cortical visual loss. Given the patient’s unremarkable eye exam and inconsistent responses, he was thought to have nonorganic visual loss and was planned for discharge with outpatient follow-up. However, after examination of the left temporal lesion raised the possibility of malignancy, the treating physicians further discussed the patient’s care with his infectious disease doctor.
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Further testing revealed an elevated HIV viral load of 1,440 (normal range <48) and CD4 count of 15 (normal range >400). A lumbar puncture was performed, which revealed few WBCs, no malignant cells and an elevated JC polyomavirus titer of 2,505,426 copies/ml (normal range <500 copies/ml) consistent with the diagnosis of PML. An excisional biopsy of the left temporal lesion revealed invasive moderately differentiated squamous cell carcinoma, which is found at higher incidence in patients with HIV/AIDS and was a further clue to the patient’s immunosuppressed status.1
There are currently no effective treatments that target the JC Polyoma virus. Therefore, the treatment options for this patient were focused on controlling his HIV infection to reconstitute his immune system. The patient had been prescribed a multidrug combination of HIV therapy but had not been compliant with his medication regimen. Compliance with his medication regimen was stressed and close follow-up with his infectious disease doctor was arranged. Additional follow-up on this patient was not available after hospital discharge.
Discussion
Progressive multifocal leukoencephalopathy is a rare demyelinating disorder of the central nervous system that occurs secondary to the JC polyomavirus.2 PML is rarely observed in otherwise immunologically normal individuals and occurs almost exclusively in patients with abnormal T cell immunity, most commonly individuals with HIV. Approximately 80 to 90 percent of the population is infected with JC virus before adulthood, but it is not known if PML results from primary infection or reactivated latent infection. The leading hypothesis is that the latent JC virus can be reactivated in the immunosuppressed brain, leading to disease progression.2 The diagnosis of PML is made by the combination of neurological findings consistent with focal lesions of the CNS, white matter lesions with no mass effect or enhancement on MRI, and detection of JC virus DNA by polymerase chain reaction in the cerebrospinal fluid or histopathological evidence of PML on brain biopsy.3
The AIDS pandemic rapidly changed the incidence of PML, with a 20-fold increase in cases from the early 1980s to the early 1990s.2However, the development of HAART has dramatically decreased the incidence of PML since the mid 1990s.4 Even with combination antiretroviral therapy, 50 percent of patients die within six months of PML onset, although a more recent study indicated that five drug combination therapy may reduce mortality.3 Yet even with these new therapies only 38 percent of patients with PML recover to live independently.3 A low CD4 count and high number of JC virus DNA copies in the cerebrospinal fluid have been shown to be early risk factors for death.3 Although this patient had poorly controlled HIV, cases of PML in patients successfully treated on HAART with normal CD4 counts and undetectable viral loads have been reported and thus the treating ophthalmologist must always consider PML and other opportunistic diseases in any patient with HIV and vision loss.5
The most common symptoms associated with PML are weakness and cognitive disturbances, but they can also include speech abnormalities, headaches, gait disorders, visual impairment and sensory loss.2 In two case series of PML patients that developed ophthalmologic manifestations, the most common signs were progressive retrochiasmal visual field defects, supranuclear and nuclear cranial nerve palsies and nystagmus ataxia.6,7 Bilateral occipital lobe PML has been reported to cause cortical blindness.6-8
The diagnosis of cortical vision loss requires a detailed ophthalmologic examination but can be confused with nonorganic or functional vision loss in a patient with normal pupils and a normal fundoscopic exam.9 In this case, the patient’s variability of responses ranging from reading single letters with an acuity of 20/30 to not being able to count fingers at 12 inches raised the suspicion of nonorganic vision loss. However, patients with higher cortical vision loss often have increased acuity with single letters similar to that of patients with amblyopia, and concomitant cognitive deficits, as in this patient, may complicate the assessment of vision. This patient may also have had simultagnosia, which could account for his poor visualization of the Ishihara color plates. Ophthalmologists should maintain a high index of suspicion in patients with possible cortical vision loss and should proceed to neuroimaging, preferably with MRI, for definitive evaluation.
The author would like to thank Mark L. Moster, MD, Wills Eye Institute Neuro-Ophthalmology Service.
1. Purgina B, Pantanowitz L, Seethala RR. A Review of Carcinomas Arising in the Head and Neck Region in HIV-Positive Patients. Patholog Res Int;2011:469150.
2. Berger JR. Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep 2007;7:461-9.
3. Gasnault J, Costagliola D, Hendel-Chavez H, et al. Improved Survival of HIV-1-Infected Patients with Progressive Multifocal Leukoencephalopathy Receiving Early 5-Drug Combination Antiretroviral Therapy. PLoS One 2011;6:e20967.
4. Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis 2009;48:1459-66.
5. Mascarello M, Lanzafame M, Lattuada E, Concia E, Ferrari S. Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART. J Neurovirol 2011;17:196-9.
6. Ormerod LD, Rhodes RH, Gross SA, Crane LR, Houchin KW. Ophthalmologic manifestations of acquired immune deficiency syndrome-associated progressive multifocal leukoencephalopathy. Ophthalmology 1996;103:899-906.
7. Wein F, Francis GS, Gans MS, Connolly WE, Burnier MN, Jr. Neuro-ophthalmic findings in progressive multifocal leukoencephalopathy. Can J Ophthalmol 1998;33:270-5.
8. Smith DD, Robinson MR, Scheibel SF, Valenti WM, Eskin TA. Progressive multifocal leukoencephalopathy (PML) in two cases of cortical blindness. AIDS Patient Care 1994;8:110-3.
9. Flanagan C, Kline L, Cure J. Cerebral blindness. Int Ophthalmol Clin 2009;49:15-25.
