Clinical Vignette

A 65-year-old man with a history of follicular lymphoma initially treated with conventional chemotherapy 4 years previously was given three courses of rituximab for maintenance therapy because of persistence of clonal changes in his bone marrow. He developed confusion, dysarthria, and aphasia after the third course. MRI revealed nonenhancing lesions in the posterior and frontal lobes and left centrum semiovale. Peripheral blood PCR was positive for JC virus, but CSF was negative.

Brain biopsy demonstrated changes characteristic of progressive multifocal leukoencephalopathy (PML). His peripheral blood demonstrated a CD4 count of 100. Treatment with cidofovir was ineffective as the patient’s clinical condition worsened with progressive aphasia and confusion, urinary and fecal incontinence, flaccid paralysis of the left arm, accompanied by radiologic progression with mass effect. He died 3 months after presentation.

Epidemiology

JC virus is a human polyomavirus (a small nonenveloped virus with a circular, double-stranded DNA genome). Infection is acquired during childhood and persists in the kidney. JC virus is the cause of PML, a rare demyelinating disease of immunosuppressed patients. PML causes rapidly progressive focal neurologic deficits without signs of increased intracranial pressure. PML is most often an AIDS-defining illness, although it occurs in other immunocompromised settings such as long-term corticosteroid or methotrexate (MTX) therapy. Although one may usually consider such in more chronic settings of the immunocompromised, we have seen one instance of an individual who developed and subsequently died of PML 9 months after commencing MTX therapy. Recently, several cases of PML are reported in patients treated with the monoclonal antibodies natalizumab for multiple sclerosis and Crohn disease as well as rituximab. This has significantly limited the utilization of natalizumab, a medication that initially was felt to be the most promising therapy ever developed for MS patients. The incidence of PML in HIV-infected patients has decreased after the introduction of highly active antiretroviral therapy (HAART) therapy; however, HAART may “uncover” PML, with it developing within 6 months of commencement of this therapy.

PML occurs most commonly in systemic lupus erythematosus among the various rheumatologic disorders.

Clinical Presentation

PML has a variable presentation depending on which part of the brain is initially infected. The temporal profile and clinical symptomatology are no different in HIV patients than in those with other immunodeficiencies, such as acute leukemias. Common neurologic scenarios include a progressive hemiparesis, visual field deficits, aphasia, and cognitive impairment. Occasional patients present with a pure cerebellar truncal and/or appendicular ataxia, or cranial nerve deficits. Late in the course of PML, affected patients develop severe neurologic deficits, including cortical blindness, quadriparesis, profound dementia, and coma.

Lesions may be primarily located in the cerebral white matter or sometimes in the cerebellum and brainstem (Fig. 51-1). Spinal cord involvement is rare but is reported. However, survival remains poor once PML is diagnosed. As there is no specific antiviral medication effective for PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

Figure 51-1 Progressive Multifocal Leukoencephalitis.

Diagnosis

MRI scans reveal hypodense, nonenhancing lesions of the cerebral white matter. The severity of clinical findings is often greater than is suggested by the extent of involvement on computed tomographic (CT) scan. The latter may even be normal. MRI typically helps to differentiate brain tumors, especially lymphoma, or abscesses in the immunocompromised. A spongiform encephalopathy caused by a prion, Creutzfeldt–Jakob disease, is a fatal infectious disease that sometimes presents with a progressive cerebellar syndrome or various focal cerebral lesions. However, this does not have a predilection for immunocompromised hosts.

PCR has been used to amplify JC virus DNA in CSF samples (sensitivities range from 60% to 100%). CSF cell count and chemistry results are usually normal. EEG may reveal focal slowing or may be normal early in the course of PML.

A definitive diagnosis of PML requires identification of the characteristic pathologic changes on brain biopsy: multiple asymmetric foci of demyelination at various stages of evolution in the cerebral white matter. The oligodendrocytes demonstrate characteristic cytopathic effects, including nuclear enlargement, loss of normal chromatin pattern, and intranuclear accumulation of deeply basophilic homogenous staining material. Electron microscopy reveals polyomavirus particles in enlarged oligodendrocyte nuclei (see Fig. 51-1).

Therapy

Unfortunately, there is no specific antiviral therapy effective for PML. Although there were some preliminary studies suggesting that cidofovir, a nucleoside analog active against polyomaviruses, might have therapeutic potential, recent results from a large multi-institutional trial are disappointing. We continue to have an overriding need for an effective PML therapy. Marked clinical and radiographic improvement in HIV-infected patients with PML has been seen after treatment with combination HAART regimens that include a protease inhibitor. Aggressive antiretroviral treatment of underlying HIV infection seems to be the most reasonable therapeutic approach to management in HIV-infected patients, as patients receiving HAART therapy have a lower incidence of PML. The opportunity for treatment may be better with the natalizumab-induced PML patient in that steroid pulse therapy led to clinically significant recovery in one patient. Unless the accompanying underlying immune deficit can be reversed as noted above, PML typically progresses to death fairly rapidly.

Epidemiology

This chronic, subacute, and, rarely, acute CNS infection is caused by Cryptococcus neoformans, a yeast-like fungus. Distributed worldwide in soil, fruits, and matter contaminated by pigeon excreta, this organism probably enters the body through the lungs and then disseminates to all organs (Fig. 51-2). Mild, self-limited infections are common.

Figure 51-2 Cryptococcosis and Listeriosis.

Clinical Presentation

Cryptococcal disease can develop in both healthy and immunocompromised patients. Chronic meningitis is the most common presentation. These patients are often afebrile and have no more than minimal nuchal rigidity. Clinically this disorder usually presents insidiously over a matter of months with symptoms of low-grade headache, nausea, irritability, somnolence, and clumsiness. Cranial nerve involvement occurs in 20% of patients characterized by diminished visual acuity sometimes with papilledema, diplopia, and facial numbness. Dementia may occur in some secondary to direct cerebral involvement.

Diagnosis

Examination of the CSF demonstrates an elevated opening pressure, a lymphocytic leukocytosis with a WBC count of 40–400/mm³, increased CSF protein concentration, and a decreased glucose level in 50% of patients. Although India ink preparations can define the organism, specific cultural isolation of C. neoformans is the best diagnostic test. Lacking such definitive confirmation, diagnosis is made by culturing or identifying the organism with periodic acid-Schiff or methenamine-silver stain in a CNS specimen. PCR is not yet available. Latex agglutination for detection of cryptococcal capsular antigen (in serum and CSF) is also available and is helpful in monitoring therapy response. Urine cultures are positive in approximately 33% of patients.

Therapy

Treatment is best carried out with at least a 2-week course of intravenous amphotericin B with or without flucytosine. Thereafter, oral fluconazole is administered for at least 6 weeks. Maintenance therapy is recommended for patients with either HIV or AIDS until immune reconstitution occurs with combination antiretroviral therapy.

Epidemiology

Listeria monocytogenes is a gram-positive rod that has pathologic connotations in neonates and immunocompromised adults. The bacterium is widespread and is isolated from soil, water, animal feed, and sewage.

Clinical Presentation

This organism must always be suspected in patients with either AIDS or those individuals receiving long-term prednisone or azathioprine therapy who develop acute meningitis. Neurologic presentation is similar to that of any acute bacterial meningitis. Headache, fever, meningismus, and, occasionally, seizures and focal symptomatology predominate.

Diagnosis

CSF identification of gram-positive rods in association with a polymorphonuclear leucocytosis and a concomitant low CSF glucose level (50% of serum glucose) are the cornerstones to recognition of this uncommon form of bacterial meningitis (see Fig. 51-2).

Therapy

Ampicillin and gentamicin are the treatments of choice.

Epidemiology

Nocardia are present in the soil and decaying vegetable matter. This bacterium is one of two usually benign microorganisms that can lead to a focal cerebritis especially when it occurs within an immunosuppressed clinical setting. The other is a parasite, toxoplasmosis; it is discussed in the last section of this chapter. When Nocardia asteroides leads to a brain abscess, it enters through the respiratory tract, even though the pulmonary focus may not be prominent. Because the initial pulmonary focus is suppurative and not well localized, this allows the infection to spread to the brain.

Clinical Presentation

Various focal clinical signs occur apropos to the site of organism sequestration in the brain. In the absence of a contiguous abscess, meningitis is infrequent.

Diagnosis

Brain biopsy is the most reliable diagnostic technique if the diagnosis cannot be made by evaluation of pulmonary or skin lesions (Fig. 51-3). Nocardia are weakly acid-fast and can be stained with the modified Ziehl–Neelsen method. They may be isolated on Sabouraud’s medium or brain–heart infusion agar, but growth may not be visible for 2–4 weeks.

Figure 51-3 Nocardiosis.

Therapy

Sulfonamides are the drugs of choice for nocardiosis. Therapy should continue for at least 3 months or several weeks after clinical resolution of the lesion.

Clinical Vignette

A 41-year-old woman with a history of HIV disease diagnosed 14 years previously and who had Pneumocystis jirovecii pneumonia 6 years previously, was clinically stable on a regimen of zidovudine, lamivudine, and nelfinavir. She presented with a 6-week history of intermittent garbled speech, an inability to form or find words, some short-term memory loss recently as well as left frontal headache. Two nights before admission, she developed acute but transient right-sided weakness. The next evening, she experienced a generalized tonic-clonic seizure. On exam, she had some word-finding difficulty with slurred speech and slightly diminished sensation in her right arm. Her temperature was 37.8° C (100.1° F).

Brain CT and later an MRI scan revealed a 3- by 5-cm left parietal lesion. Total CD4 count was 4/mm³ and HIV viral load was 79,000 copies/mL; toxoplasma IgG was 1627 IU/mL. Treatment was initiated with pyrimethamine and sulfadiazine accompanied by phenytoin. Three weeks later, brain MRI demonstrated marked improvement in the lesion with resolution of enhancement and midline shift. HIV genotyping revealed a viral strain with resistance to all three classes of antiretroviral agents.

Epidemiology

Toxoplasma gondii is a parasite that infects most mammalian species (Fig. 51-4). Humans may acquire T. gondii infections by ingestion, transplacental transmission, blood transfusion, or organ transplantation. Oral route infection results from ingestion of T. gondii cysts in undercooked food (pork, lamb) or T. gondii oocysts found in the feces of 1% of cats. Human intestinal tract enzymes liberate T. gondii trophozoites, which cause clinical toxoplasmosis. Serologic evidence of Toxoplasma infection is present in 50% of the U.S. population. In most instances, T. gondii is a subclinical infection primarily manifested by cervical lymphadenopathy.

Figure 51-4 Toxoplasmosis.

Clinical Presentation

Four major T. gondii clinical syndromes occur: congenital, ocular, lymphadenopathic, and severe neurologic or disseminated disease occurring in 50% of immunocompromised patients. Diffuse encephalitis, meningoencephalitis, or cerebral mass lesions are the predominant neurologic abnormalities in advanced AIDS or HIV patients having toxoplasmosis.

Focal masses are sometimes multiple in number, leading to multifocal potential symptoms depending on the clinical site of involvement.

Diagnosis

Brain MRI with gadolinium is the most sensitive diagnostic technique for HIV or AIDS patients. HIV patients with multiple toxoplasma mass lesions usually show dramatic improvement after 2 weeks of therapy.

Invariably, the CD4-helper lymphocyte count in patients with AIDS is less than 100/mm³ (normal is 800/mm³). The CSF has a mild lymphocytic pleocytosis, and increased protein; the glucose level remains normal. An indirect fluorescent antibody test measuring IgG antibodies is the most widely used diagnostic procedure. Results become positive 1 to 3 weeks after infection; positive titers persist for many years. Definitive diagnosis requires a fourfold increase in IgG titer or a single high IgM titer. A CSF examination is not required.

Therapy

Pyrimethamine and sulfadiazine are the most effective chemotherapeutic agents. Treatment is continued for 4–6 weeks. In patients with AIDS, maintenance therapy is often needed until immune reconstitution occurs with combination antiretroviral therapy.