A 48-year-old man owns a large corporate travel company and frequently travels throughout Europe, Asia, Africa, and South America. He is left-handed. On one of his many business trips, he notices the onset of right hand clumsiness, unsteady gait, forgetfulness, and a mild headache. These symptoms persist and occasionally interfere with the man's ability to carry out his professional activities. He is a little worried about this, but his business is at a very critical stage, so he adapts to the symptoms the best he can and continues to travel for another three weeks. By the time the man returns to the U.S. and seeks medical treatment from his regular physician, he has developed decreased vision and a mild pain his right eye, and he is finding it increasingly difficult to express himself verbally. His condition continues to deteriorate as his physician awaits the results of routine tests. Over the next 10 days, he becomes unable to sign his own checks and develops a distinct tremor in his right hand. Because of the alarmingly progressive nature of the man's disease, his physician then refers him to a clinic that specializes in neurological disorders.

The man's vital signs are normal. On neurologic examination, he is alert, attentive, and oriented to name, place, and time. He follows one-step commands well but has difficulty with multi-step commands. His speech is telegraphic, but comprehension seems intact. Object naming and writing of full sentences are severely impaired. Muscle tone is increased in the right arm and leg, and the man has a right-sided hyperreflexia. He has bilateral ankle clonus and a right extensor plantar response. He also has a right homonymous hemianopsia and right-sided weakness in an upper motor neuron distribution. The man exhibits a wide-based, right circumductive gait, with the right upper extremity flexed at the elbow and held across his chest. He also has nonpurposeful and nonrhythmic movements of the right arm superimposed on a low amplitude rhythmic postural and kinetic tremor.

The man has no history of any prior medical illness and did not experience any prodromal or viral-like illness prior to the onset of his symptoms. He consumes about 2-3 ounces of alcohol daily, and he stopped smoking 12 years ago.

Question 6.1: What is your preliminary diagnosis?

The multiplicity of neurological symptoms argues against diseases that are related to a single, focal infection (e.g., brain abscess or subdural empyema) and diseases that typically present with a more limited or defined range of symptoms (e.g., bacterial meningitis or viral encephalitis). The apparent multifocal nature of this disease; its progressive aspect; and the combination of altered mental state, visual deficits, and upper motor neuron weakness, though not definitive, are all suggestive of progressive multifocal leukoencephalopathy (PML).

Question 6.2: How can you confirm the diagnosis?

Many routine lab tests (including leukocyte and platelet counts; hemoglobin and blood glucose; kidney, liver, and thyroid function; urinalysis; etc.) are normal in patients with PML. Imaging is the most useful tool, and MRI is somewhat more sensitive than CT. A lumbar puncture is worth doing because, even though the CSF is often normal, protein is sometimes elevated and it may be possible to detect DNA of the causative agent, the JC virus, in the CSF using a PCR-based test.

It should be noted that PML occurs almost exclusively in patients who develop an illness characterized by immune deficiency (e.g., Hodgkin's disease or HIV infection) or who become immunodeficient as a result of anticancer therapy. At the present time, the vast majority of PML cases are associated with victims of AIDS, and 1 10% of AIDS victims may eventually develop PML. Although the patient in this case has not previously been diagnosed with AIDS or HIV infection, he has traveled extensively in areas where AIDS is prevalent among prostitutes. Therefore, it is probably worth testing him for HIV infection while conducting the tests for PML. Should he test negative for HIV infection, some other cause of possible immunodeficiency should be sought.

Test Results:

The MRI revealed multifocal asymmetric, coalescing white matter lesions situated periventricularly, in the centrum semiovale, in the parietal-occipital region, and in the cerebellum. These lesions have increased T2 and decreased T1 signal. In FLAIR mode, there is enhancement. They do not show any peripheral enhancement and are not associated with edema or mass effect.

The CSF cell count is 7 cells/mm3 and CSF protein is 98 mg/dL. The PCR test for JC virus DNA is positive. HIV tests (ELISA and Western blot assay) are also positive. The man's CD4+ lymphocyte count is 184 cells/mm3 and his CD4+/CD8+ cell ratio is 0.16. The level of HIV-1 RNA copies was 32,200/mL. These results indicate that the patient not only has PML, but is also in a reasonably advance stage of AIDS.

Question 6.3: How did the disease come about?

The JC virus, a polyoma virus, is most often acquired during childhood, when it usually causes a mild, self-limited disease and then assumes a latent phase within the CNS. Although as many as 80% of adults are infected, JC virus-induced disease is rare and, as noted earlier, develops almost exclusively in immunocompromised individuals. Replication of the reactivated virus leads to the formation of multifocal areas of demyelination of varying size throughout the CNS. (Apparently the virus destroys myelin producing oligodendroyctes in the CNS.) In addition to demyelination, there are characteristic cytologic alternations in both astrocytes and oligodendrocytes. The astrocytes are tremendously enlarged and contain hyperchromatic, deformed, and bizarre nuclei, with frequent mitotic figures. Oligodendrocytes have densely staining nuclei that contain viral inclusions formed by crystalline arrays of JC virus particles.

Question 6.4: What is the man's prognosis?

At the present time, no effective therapy is available specifically for PML. However, some patients with HIV-associated PML have shown dramatic clinical improvement associated with improvement of their immune status following institution of AIDS therapy. The patient in this case was started on highly active antiretroviral therapy (HAART) consisting of Combvir (zidovudine and lamivudine) 1 tablet twice daily and nelfinavir 250 mg 5 tablets daily. Vaccines against several viral disease and prophylaxis to prevent Pneumocystis carinii (jirovecii) pneumonia were also initiated. After 4 months, several of the patient's neurological symptoms had improved noticeably and his HIV viral load had decreased to 574 copies/mL. His therapy was continued and follow up evaluations every 3-4 months were planned.