Polyradiculopathy and myelitis

The clinical syndrome of CMV polyradiculopathy and myelitis usually has an insidious onset with low back pain radiating to the perianal area and progressive lower extremity weakness, hypo- or areflexia, and variable sensory deficit, usually with preserved proprioception and vibratory sensation. Most patients develop urinary retention and fecal incontinence due to bladder and/or anal sphincter dysfunction. The disease clinically resembles Guillain–Barré syndrome but may be differentiated by lack of sphincter involvement in the latter.

Diagnosis of CMV polyradiculopathy is based on the characteristic neurologic features described above. The cerebrospinal fluid (CSF) abnormalities are unusual for a viral infection: pleocytosis with predominant polymorphonuclear leukocytosis and hypoglycorrhachia. Culture of CSF is usually positive, but antigen or DNA assays are more sensitive methods of diagnosis. Magnetic resonance imaging (MRI) may reveal enhancement of leptomeninges and clumping of lumbosacral roots. Characteristic pathologic changes seen in CMV polyradiculopathy are demyelination and destruction of axons.

Acute CMV polyradiculopathy should be differentiated from idiopathic lumbosacral polyradiculopathy, in which CSF pleocytosis is predominantly mononuclear and clinical improvement is seen without CMV treatment. Lymphoma, tuberculosis, syphilis, and toxoplasmosis also cause similar clinical syndromes.

Encephalitis with dementia and ventriculoencephalitis

CMV encephalitis (CMVE) with dementia and ventriculoencephalitis are the two syndromes of CMVE described in AIDS patients. CMVE with dementia, the more common of the two syndromes, is well described neuropathologically [8] as a multifocal, scattered micronodular encephalitis that resembles HIV encephalitis, the cause of HIV-associated dementia (HIVD) [9]. CMV ventriculoencephalitis is a late and terminal event with acute onset of encephalitis often associated with cranial nerve involvement and nystagmus. The significance of differentiating CMVE and HIVD lies in the different drugs available for treatment.

CMVE is seen more commonly among men who have sex with men (MSM), which may reflect the increased CMV seroprevalence in that population [10]. CMVE always occurs in patients with CD4 counts of < 100 cells/mm³ and should be suspected in patients presenting with a subacute encephalopathy who have had AIDS for more than 1 year. Clinicians should suspect a diagnosis of CMVE in patients who have a history of systemic CMV infection, especially those with CMV retinitis who develop encephalopathic features and change in mental status.

Patients with dementia caused by CMVE usually have a more acute onset and rapid progression than patients with HIVD. The encephalopathic symptoms include delirium and confusion, lethargy and somnolence, apathy and withdrawal, personality changes, and focal neurologic signs with cranial nerve involvement. During the course of illness, recurrent fever episodes may occur that may be attributed to other opportunistic infections (e.g. Mycobacterium avium complex). Psychomotor slowing, primitive reflexes, and peripheral neuropathy may also be seen in CMVE. Distal sensory polyneuropathy usually antedates the onset of CMVE [11].

The course of encephalopathic illness in both CMVE and HIVD includes progressive worsening in mental status until death. The median survival of CMVE patients is significantly shorter (weeks) compared with that of HIVD patients (months). Autopsies reveal a range of neuropathology, including ependymal and subependymal necrosis, areas of demyelination, and microglial nodules that are more frequently encountered than typical nuclear and cytoplasmic CMV inclusions [12]. Neuropathologic evaluations of CMVE and HIV co-infection of single cells suggests that CMV and HIV increase each other’s replication in the brain [13].

It is difficult to make a definitive diagnosis of CMVE, and laboratory investigations are not helpful in distinguishing CMV from HIVD. Electrolyte abnormality, especially hyponatremia, is more commonly present in CMVE patients [14]. There are insufficient data to determine whether CMV antigen or DNA is regularly detected in CSF. Conversely, detection of CMV DNA may only reflect latent, but not active, CMV diseases. MRI scans showing meningeal enhancement consistent with ventriculitis and periventricular enhancement are helpful in differentiating CMVE from HIVD. However, periventricular enhancement may also be seen in lymphoma, toxoplasmosis, and pyogenic brain abscesses. Progressive ventriculomegaly, if seen in serial computed tomography scans, is highly suspicious for CMVE [15, 16].

Combination therapy with ganciclovir and foscarnet is commonly used, especially when disease progression is noted with single-agent therapy but trials of single versus combined therapy have not been performed.

Mononeuritis multiplex

This is the least common of all the neurologic syndromes attributed to CMV. Clinical characteristics of CMV mononeuritis are more varied than polyradiculopathy/myelitis. Patients may present with multifocal, patchy and/or asymmetrical sensory and motor deficits. Cranial nerve palsies caused by CMV, especially in the recurrent laryngeal nerve, have been reported in the setting of severe immunosuppression [17]. This symptom may occur with other manifestations of CMV (e.g. polyradiculopathy, encephalitis, or retinitis). Pathologic findings in peripheral nerve biopsies have shown endoneurial necrosis with cellular infiltrates and Schwann cells showing CMV inclusions.

Painful distal neuropathy

A syndrome of painful distal symmetrical neuropathy of subacute onset limited to the feet and associated with some numbness and weakness has been reported with CMV infection [18].

Ganciclovir/valganciclovir

Pharmacology and dosage

Ganciclovir is available for clinical use in intravenous formulations, as well as a sustained release intraocular implant. The oral form of ganciclovir has been replaced by valganciclovir. Intravenous ganciclovir is used for initial induction therapy, followed by either intravenous ganciclovir or oral valganciclovir for maintenance therapy.

Initial intravenous induction treatment for CMV disease consists of 5 mg/kg twice daily for 14–21 days or until there is an adequate clinical response. The standard intravenous dosage for maintenance therapy is approximately one-half the induction dose (i.e. 5 mg/kg per day, 7 days/week) or, if oral valganciclovir, 900 mg daily, with food.

When administered by intravenous infusion over 1 h in the usual dosage of 5 mg/kg, peak ganciclovir blood levels are approximately 8–9 μg/mL, and the serum half-life is 3.5 h. The absolute bioavailability of oral valganciclovir capsules is approximately 60%. When administered orally as 900 mg with food, peak serum levels approach those achieved by intravenous administration of 5 mg/kg. Oral valganciclovir may be used for induction treatment and is the drug of choice for maintenance therapy [25]. Because ganciclovir is excreted unchanged through the kidneys, dosage for intravenous ganciclovir must be reduced in patients with renal impairment. Dosage adjustments should also be considered for oral valganciclovir. The appropriate dose reductions are presented in Table 34.2. Initial response in retinitis (improvement or stabilization in vision or ophthalmoscopic appearance) occurs in approximately 75% of treated patients [6]. By comparison, the disease is relentlessly progressive in 90% of patients if left untreated. Visual-field defects present at the onset of therapy do not reverse, but a decrease in visual acuity caused by edema of the macula may improve with treatment. Retinal detachment may occur in later stages as the necrotic retina scars and thins.

Table 34.2 Ganciclovir dosage adjustment in patients with impaired renal function

Prior to the availability of HAART, maintenance therapy throughout the life of the patient was critical for CMV retinitis because the virus is only suppressed by ganciclovir and is not eliminated. Even with continued maintenance therapy, CMV retinitis eventually progressed. Why this occurred is not clearly understood, but it is likely related to suboptimal drug delivery to the retina. This hypothesis is supported by the longer times to progression achieved with the ganciclovir intraocular implant, which delivers greater concentrations of ganciclovir to the vitreous [26]. Viral resistance does not appear to be involved in most progressions of CMV retinitis [27].

With successful ART, it is possible for selected patients with CMV retinitis to discontinue maintenance therapy but not until CD4 count has exceeded 100 cells/mm³ for 3–6 months and the retinitis is inactive [28].

Intravitreal injection of ganciclovir has been used in certain special situations, such as in patients in whom neutropenia limited the systemic use of the drug, and in one series [29] appeared effective and relatively safe. Sustained intravitreal release of ganciclovir has been accomplished using a surgical implantable device [14, 30, 31]. This implant, which is designed to deliver ganciclovir into the vitreous over several months, has been shown to be highly efficacious for local control of retinitis. When the implant is used, oral valganciclovir should also be given at least until CD4 function is restored by ART. This is needed to treat or prevent contralateral eye or systemic disease. The implant delivers approximately five times as much ganciclovir compared with intravenous therapy and may be useful in treating low-level GCV-resistant CMV retinitis.

Foscarnet

Foscarnet is a pyrophosphate that inhibits the DNA polymerase of CMV. Specifically, the drug blocks the pyrophosphate-binding site of the viral DNA polymerase, preventing cleavage of pyrophosphate from deoxyadenosine triphosphate [38]. This action is relatively selective in that CMV DNA polymerase is inhibited at concentrations < 1% of that required to inhibit cellular DNA polymerase. Unlike such nucleosides as acyclovir and ganciclovir, foscarnet does not require phosphorylation intracellularly to be an active inhibitor of viral DNA polymerases. This biochemical fact becomes especially important with regard to viral resistance, because the principal mode of viral resistance to nucleoside analogs is a mutation that eliminates phosphorylation of the drug in virus-infected cells. Foscarnet can be used to treat patients with ganciclovir-resistant CMV; cross-resistance to foscarnet is rare. However, patients treated with foscarnet may develop foscarnet resistance due to mutations in the viral polymerase UL54 [36].

Ganciclovir and foscarnet

The results of a Studies of Ocular Complications of AIDS (SOCA) trial of combination therapy versus monotherapy for relapsed CMV retinitis were published in early 1996 [40]. Combination therapy (5 mg/kg per day ganciclovir and 90 mg/kg per day foscarnet) was significantly superior in delaying progression than either ganciclovir alone (10 mg per day) or foscarnet alone (120 mg/kg per day). This study also found no advantage in switching monotherapy. That is, patients in whom monotherapy failed with ganciclovir who then switched to high-dose foscarnet did not do better than patients who continued ganciclovir at the higher dose. The median times to progression were: foscarnet group, 1.3 months; ganciclovir group, 2.0 months; and combination group, 4.3 months (p < 0.001). Side effects were not statistically significantly different in any group, but the quality of life was poorest in the combination group as a result of the prolonged daily infusion time of 3.1 hours.

Cidofovir

Cidofovir represents a departure from previous nucleoside analogs because it appears to the cell as a nucleotide. It has a phosphonate moiety attached to a cytosine analog and does not require phosphorylation by viral-encoded enzyme. It is therefore active against the majority of ganciclovir-resistant CMV strains that only have resistance mutations in UL97, the phosphorylating gene. When polymerase, UL54, mutations occur in ganciclovir UL54 treated patients, cross-resistance to cidofovir is frequent. These UL54-resistance mutations also occur in patients treated with cidofovir de novo [36]. The drug also has an extremely long half-life, permitting intravenous administration as infrequently as every 2 weeks during maintenance treatment [41].

Cidofovir is nephrotoxic, especially to the proximal renal tubule, but toxicity can be diminished with prehydration and concomitant probenecid therapy. Renal function and toxicity must be monitored carefully, and proteinuria or a rising creatinine level are reasons for dosage reduction, interruption, or discontinuation. Concurrent administration of other nephrotoxic drugs must be avoided and there must be at least a 7-day period of “washout” of these drugs if their use precedes administration of cidofovir.

Orolabial infection

Orolabial infection in adults with AIDS is usually due to recurrent disease from previously latent infection. Primary infection of the mouth or nose may occur, however, in a seronegative individual who acquires infection at this site for the first time. Primary infection is more likely to occur in children with AIDS than in adults, because HIV infection in children (especially those infected prenatally) is more likely to precede initial exposure to HSV.

The incubation period of primary HSV infection ranges between 2 and 12 days. In the normal host, primary orolabial infection may be asymptomatic or result in clinically apparent gingivostomatitis [45–48, 55]. Immunocompromised patients are at greater risk than normal hosts of developing a severe clinical illness during primary HSV-1 infection, with a painful vesicular eruption occurring along the lips, tongue, pharynx, or buccal mucosa. The vesicles rapidly coalesce and rupture to form large ulcers covered by a whitish yellow necrotic film [55, 56]. Fever, pharyngitis, and cervical lymphadenopathy are often present in adults, whereas infants may display poor feeding and persistent drooling.

Following initial or primary infection, all infected patients remain at risk for virus reactivation and recurrent disease. Recurrent HSV gingivostomatitis (“fever blisters”) may occur spontaneously or as a result of external stimuli, such as a febrile illness, excessive wind or ultraviolet light exposure to the lips, surgical manipulation of the trigeminal nerve, or stress. Prodromal symptoms, consisting of tingling or numbness at the site of the impending recurrence, may be present from 12 to 24 hours before the onset of an HSV recurrence. Instituting antiviral therapy during the prodrome may shorten the duration of illness or may abort the development of visible cutaneous lesions (see Treatment of HSV Infection, below). Recurrences may increase in frequency and severity as immunosuppression worsens, although many AIDS patients will have only infrequent, mild, self-limiting recurrences throughout the course of their disease [51, 55].

In the normal host, orolabial herpes lesions usually heal in 7–10 days. By comparison, AIDS patients often have a prolonged illness with markedly delayed healing of mucocutaneous lesions. If left untreated, chronic ulcerative lesions with persistent viral shedding may last for several weeks [56].