TAG: The OI Report - CMV-associated neurological disorders

THE OI REPORT:
A Critical Review of the Treatment & Prophylaxis of
AIDS-Related Opportunistic Infections (OIs)

CYTOMEGALOVIRUS-ASSOCIATED NEUROLOGICAL DISORDERS
by Theo Smart

INTRODUCTION
Cytomegalovirus (CMV) can cause a number of distinct neurological syndromes (in addition to end-organ disease in the eyes, gut, lungs and elsewhere) such as mononeuropathy multiplex (inflammation or disease involving individual nerves in unrelated portions of the body), myelitis/polyradiculopathy (acute inflammation of a large number of the spinal nerves accompanied with pain, muscle wasting and paralysis), and two forms of encephalitis (brain disease): diffuse micronodular encephalitis (DME, scattered nodular lesions in the brain), ventriculoencephalitis (VE, inflammation of the brain's ventricles) (Morgello 1987; Vinters 1989; Said 1991; Cinque 1992; Fuller 1992; Kim 1993).

The actual rate of CMV infection of the central nervous system (CNS) is unclear. One two year study reported that CMV encephalitis is found in only 1% of patients with advanced AIDS (Gallant 1992). The figure may accurately reflect the rate of clinical diagnosis, but not the true incidence rate. In neurological autopsy studies, CMV infection of the CNS is found in between 20 and 28% of the brains studied (Morgello 1987; Cinque 1995).

Other figures have been produced by the AIDS Ocular Research Unit, University of California, San Diego, which calculated that CMV encephalitis occurs in around 42% of autopsied patients with CMV retinitis. The rate was almost 75% in more advanced cases of retinitis. In contrast, it was very uncommon in people without CMV retinitis (Bylsma 1995).

While there is no proof that all of the cases of CMV neurological disease detected upon autopsy were rapidly progressive or caused the patients' death, there is substantial evidence suggesting that patients are adversely affected by these undiagnosed infections. One study notes that even less advanced CMV infections may affect neurocognitive function. A team from the HIV Neurobehavioral Research Center at the University of California, San Diego, compared 16 patients with newly diagnosed CMV retinitis, but without clinical dementia to 32 matched controls with similar CD4 counts, age and education. They found neuropsychological impairment (most commonly attention and verbal deficits) in two-thirds of the patients with newly diagnosed CMV retinitis, and in about one-third of these cases the impairment was caused by CMV rather than HIV. Evidence of physical damage to the central nervous system detectable by magnetic resonance imaging (MRI) brain scans was approximately twice as frequent in the patients with retinitis than in the matched controls (McCutchan 1995).

While these findings are challenging, they do not prove a direct mechanism for CMV in neurological performance, since indirect mechanisms such as cytokine toxicity associated with CMV infection or visual interference in testing may explain the differences observed (David Clifford, personal communication). Researchers from San Diego's Neurobehavioral Center reported that the risk of cognitive impairment associated with CMV encephalopathy was seven-fold higher than of HIV encephalopathy (Ellis 1995). The authors concluded that "unrecognized CMV encephalitis may be an important cause of both mild and severe neurocognitive impairment in patients with advanced HIV infection."

CLINICAL MANIFESTATIONS AND NEUROPATHOLOGY
Mononeuropathy multiplex occurs when CMV infects the cranial and peripheral nerves resulting in face, wrist and foot palsies (Lipkin 1985). Mild forms that resolve spontaneously often strike patients fairly early in the course of HIV disease (So 1994).

Polyradiculopathy is strictly a late-stage AIDS event, caused by CMV infection of the nerve roots and spinal cord leading to axonal necrosis (Behar 1987). The condition may accompany or possibly lead to VE (McCutchan 1995). One case review of 23 patients reported that over a period of roughly two weeks, the condition began with weakness, leg and back pain, and sensory loss in the legs in association with loss of bladder control (usually leading to urinary retention) or loss of anal-sphincter control. This is followed by an ascending paralysis of the lower extremities (So 1994).

The two CMV-encephalitic syndromes are distinguished primarily by their neuropathologies. DME is characterized by widely scattered small microglial nodules and inclusion-bearing cytomegalic cells primarily concentrated in the gray matter of the brain (McCutchan 1995). VE appears to be the result of an invasion by CMV via the CSF, beginning in the ependymal cells lining the ventricles and moving progressively layer by layer through the subependymal layers into the periventicular brain (Wiley 1986). This infection leads to necrosis of the cranial nerves and paraventricular parenchyma (Kalayjian 1993).

In both syndromes, dementia, delirium, confusion, apathy, and lethargy are common (Kalayjian 1993; Holland 1994). Some of the symptoms of DME depend upon the location of the nodular lesions, (as is often the case in toxoplasmosis, CNS lymphoma or PML) (Holland 1994). Patients with VE, meanwhile, often experience cranial nerve palsies and nystagmus (rhythmic, involuntary eye movement). Both conditions are rapidly fatal. In one study of patients with VE, the median survival was only 5 weeks (Kalayjian 1993), while those diagnosed with DME had a slightly longer median survival of 8.5 weeks in another study (Holland 1994). The full spectrum of DME has not been investigated, and milder forms with less rapid progression may exist.

DIAGNOSIS
In aggressive cases of CMV CNS disease, the onset of symptoms is so abrupt, and the progression so rapid, that the infection may dramatically progress within the time it takes clinicians to distinguish it from other AIDS-related neurological conditions. There are some distinctive features of CMV neurological disease, however. For example, CMV encephalitis occurs very late in the course of HIV disease, while signs of the most common alternate diagnosis, HIV encephalopathy, appear earlier and more gradually. Dementia was more commonly observed than cognitive or motor disturbances in one early autopsy study of patients with DME (Navia 1986). Holland and colleagues reported much higher levels of delirium, confusion, apathy, withdrawal and focal deficits among patients with CMV encephalopathy than in patients with HIV encephalopathy.

Other hallmarks of CMV CNS infection, such as electrolyte abnormalities, pleocytosis (cell infiltrates in the CSF) and enhancement of the brain ventricles on MRI brain scans suggest CMV infection, particularly in the presence of CMV retinitis (Holland 1994; McCutchan 1995). In cases of polyradiculopathy, an MRI shows a characteristic enlargement of the conus medullaris, and clumping of lumbosacral rootlets, or with gadolinium, contrast enhancement of the lower spinal cord leptomeninges (So 1994). The conditions are sometimes associated with CMV adrenalitis (infection of the adrenal glands, evidenced by reported electrolye abnormalities consistent with adrenal insufficiency (high levels of potassium, low levels of sodium) (Holland 1994; McCutchan 1995). These markers allow for a presumptive, but not a definitive diagnosis, since they also may occur in other neurological conditions as well.

Until recently, finding proof of active CMV infection in the CNS has been difficult without conducting a brain biopsy. Even though the CSF is believed to be the primary route through which CMV enters the CNS (particularly with VE and polyradiculopathy), the virus is rarely cultured from the CSF (So 1994).

Tests for CMV DNA by polymerase chain reaction (PCR) of the CSF may be diagnostic in the appropriate clinical setting. Some studies report that such assays are dramatically more sensitive than culturing and that the virus is usually only detected in cases of active CNS CMV infection (Cinque 1995). One study by Achim and colleagues (Achim 1994) found that the test was not as specific, since CMV DNA was detected by PCR in the CSF of 58% of the patients without CMV-associated neurological conditions. Limited experience using the new tests or use of post-mortem CSF samples may explain some of these contrasting results. Also, this was a study of autopsy specimens, and McCutchan points out that the virus could have entered the CSF post-mortem (McCutchan 1995).

It stands to reason that even if CMV DNA can be found in the CSF of people who do not have clinical CNS CMV disease, quantitative assays may provide a better indication of who is at risk for disease. A German study suggests that CMV DNA loads in the CNS were 10- to 1000-fold higher in patients with CMV neurological disease than in those without (Kuhn 1995). Researchers from Roche Molecular Systems and UC San Francisco reported in 1996 that CMV DNA was detected in 24 of 26 patients with polyradiculopathy and that levels were consistently above 1000 CMV DNA copies per milliliter (mL), except in one case of a patient on therapy (Long 1996). CMV DNA levels were generally under 100 per mL of CSF in patients with other CMV neurological conditions. Another group of researchers recently published data correlating the presence of CMV DNA in the CSF of all but one of 13 patients with CMV CNS disease, while no CMV DNA was found in control subjects. High levels of CMV DNA (1000 copies per mL) were associated with severe disease, VE in particular, and uniformly shorter survival (Arribas 1995).

TREATMENT
There have been no prospectively controlled studies of the treatment of CNS CMV disease, and the case reports are scant. Thus, there are no clear data on what is the best drug or dose to use, or what the duration of treatment should be. There are case reports of clinical responses to ganciclovir or foscarnet, but there is reason to believe that standard treatments of CMV retinitis may be inadequate as therapy for CMV infections in the brain. McCutchan and colleagues compared case studies of patients with polyradiculopathy who were treated to those of untreated patients and found that half of the treated patients survived for a median of 11 weeks while 7 untreated patients all died within four weeks (McCutchan 1995). It is hard to construe less than two months additional survival as a great success.

Furthermore, CMV encephalopathy often develops in patients receiving maintenance therapy for CMV retinitis (Mastroianni 1994, Paterson 1995, Berman 1994). Some treatment failures may be due to drug resistance. In two cases, CMV polyradiculopathy was associated by ganciclovir-resistant strains (Jokela 1994, Smith 1996). The degree of penetration by either ganciclovir and foscarnet into the CNS is unclear. The level of ganciclovir, in particular, in the CSF is substantially lower than in the plasma (Shepp 1985). On the other hand, Larry Drew of UCSF presented data in 1995 demonstrating that ganciclovir, with or without foscarnet can lower CMV load in the CSF (Drew 1995). Using the CMV bDNA assay, his team reported that treatment had antiviral activity in the CSF of 7 out of 8 patients with CMV neurological disease (Drew 1995). The lack of clinical response in these patients suggests that some of the nerve damage may be irreversible.

More promising data were presented by French researchers in 1996, reporting rapid clinical improvement (within 10-13 days) in four of four patients with CMV neurological disorders (three cases of encephalopathy and one myeloradiculitis) on a combination regimen of ganciclovir at 5 mg/kg every 12 hours, and foscarnet 60 mg/kg every 8 hours as induction therapy, followed by ganciclovir at 5 mg/kg, and foscarnet 90 mg/kg every day for maintenance. CMV DNA became undetectable in two out of two patients tested. No one stopped treatment due to toxicity, although one case of anemia and one case of leukopenia were observed (Couderc 1996).

These results support the rationale for ACTG 305, a six-month multicenter study of high-dose, aggressive combination foscarnet/ganciclovir therapy in at least 30 patients with recently diagnosed CMV encephalopathy or radiculomyelitis. Participants will be treated with 28 days of foscarnet 90 mg/kg and ganciclovir 5 mg/kg both twice daily followed by maintenance therapy with the same doses, but on a once-a-day basis. If they can tolerate it, those with prior experience on ganciclovir will receive higher ganciclovir doses (7.5 mg/kg twice a day for induction therapy and 10 mg/kg once a day for maintenance therapy). Up to ten patients who can not tolerate either agent will be treated with the alternate drug as a monotherapy. If patients fail on maintenance therapy, higher induction therapy doses will be reinitiated.

ACTG 305 seeks to answer many of the nagging questions surrounding CNS CMV disease. The study will evaluate both quantitative CMV DNA PCR and CMV bDNA as surrogate markers for disease severity, progression and response to therapy. The study also will investigate the role of drug resistance in the evolution of CNS CMV disease, and in treatment failure. Finally, researchers will try to perform as many brain autopsies as possible on those patients who die during the study to determine the level of drug that actually penetrates the brain.

EXPERIMENTAL TREATMENTS
It is hard to predict what effect recent improvement in the treatment of CMV retinitis will have upon the development of CMV-related neurological syndromes. The addition of cidofovir to the approved anti-CMV armamentarium increases the number of treatment options, and lobucavir, adefovir, and other new compounds from Gilead Sciences and Glaxo Wellcome are waiting in the wings. It is unclear whether the use of oral ganciclovir will decrease the rate of extraocular disease or merely engender resistance by supplying suboptimal levels of drug. Finally, the growing use of localized therapies for CMV retinitis such as ganciclovir implants or intravitreal cidofovir injections may increase the rate of extraocular CMV disease, which was prevented before by the use of systemic anti-CMV therapy.

Even if the use of localized therapy does increase the incidence of CMV encephalopathy or polyradiculopathy, with viral load monitoring of the CSF and an increased awareness of the conditions, the prospects for the treatment of CNS CMV disease are improving. Increased diagnosis creates an opportunity to conduct prospectively controlled clinical trials that will eventually improve treatment. Furthermore, early detection may enable treatment to prevent permanent damage to the nervous system.
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