Progressive Polyradiculopathy in HIV

Updated: Nov 05, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Overview

Overview

While distal symmetric polyneuropathy (DSP) is the most common peripheral nerve disorder seen in patients with HIV, other neuropathic conditions such as polyradiculopathy, acute and chronic inflammatory demyelinating polyneuropathies (IDP), mononeuropathies, mononeuropathy multiplex, and autonomic neuropathy also occur. [1]

Progressive polyradiculopathy typically occurs late in the course of HIV infection, unlike inflammatory demyelinating polyradiculoneuropathies in HIV, which usually occur earlier in the course of disease. [2, 3, 4]  While progressive polyradiculopathy in HIV is uncommon, it is more prevalent in patients with advanced immunosuppression when the CD4 T-cell count is below 50/µL, [5] although it rarely is seen with lesser degrees of immunosuppression. [6]  Given its rare occurrence, incidence rate is unknown. The lumbrosacral region is most often the affected site.

Polyradiculopathy typically results from cytomegalovirus (CMV) infection. In addition to causing mononeuropathy multiplex, in the patient with advanced AIDS, CMV can infect the cauda equina leading to inflammation and destruction of the lumbosacral nerve roots. [7] The most common manifestation of neurological CMV disease in HIV infection is retinitis followed by encephalitis, myelitis, multifocal polyneuropathy, and polyradiculopathy. [8, 9] CMV co-infection of the retina and other sites is common. An idiopathic form of polyradiculopathy exists, which has a better prognosis than the CMV-related form.

Histologically, polyradiculopathy typically features necrosis of nerve roots and endoneurial and epineurial blood vessels, along with marked inflammation. In CMV-associated cases, cytoplasmic and nuclear CMV inclusions may be apparent in Schwann cells and fibroblasts. 

CMV polyradiculopathy is rapidly fatal without treatment. Treatment with foscarnet or ganciclovir may improve or stabilize the condition. Clinical stabilization often occurs after initial worsening during the first 2 weeks of treatment. [3]  Even with treatment, mortality is 22%. In idiopathic polyradiculopathy, spontaneous improvement without treatment is common. [10]

Less common causes of polyradiculopathy in HIV infection include spinal lymphomas, diffuse infiltrative lymphocytosis syndrome, and CNS (central nervous system) opportunistic infections such as tuberculosis meningitis, syphilis, cryptococcosis, herpes simplex virus type 2, varicella-zoster virus, and toxoplasmosis. [6]  

Reactivation of HSV-2 after genital herpes with HIV infection can cause lumbosacral radiculitis. [11] Lumbosacral radiculopathy caused by tuberculous meningitis is due to infection of spinal leptomeninges characterized by granulomatous inflammation. This can compress nerve roots or the cord resulting in radiculopathy. [12] A single case of syphilitic lumbosacral radiculopathy has also been reported. [13]

Idanivir-induced epidural lipomatosis in the lumbar canal causing polyradiculopathy has been described; it resolved with discontinuation of the drug. [14]

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Clinical Presentation

Progressive polyradiculopathy presents as a cauda equina syndrome. CMV-related polyradiculopathy is characterized by rapidly progressive ascending numbness, pain, bowel dysfunction, and asymmetric weakness affecting the legs and later occasionally also the arms. [15] These symptoms can develop acutely over days or more subacutely in 1 to 6 weeks. Possibly co-existing CMV-related conditions include retinitis, colitis, and encephalitis. With idiopathic polyradiculopathy, symptoms are more benign and the clinical progression is slower. [16]

Physical examination

The following may be noted in CMV-related polyradiculopathy:

  • Rapidly progressive, ascending course

  • Paresthesias

  • Sensory loss, invariable

  • Rarely, sensory level suggestive of spinal cord involvement

  • Flaccid paraparesis

  • Areflexia

  • Urinary retention, constipation, or incontinence

  • Rarely, cranial neuropathies

  • Severe pain

  • Often asymmetrical, especially in the early stage of disease

  • Late involvement of the upper extremities

Herpes zoster is characterized by pain and itching followed by rash. Trigeminal and thoracic dermatomes are most commonly affected. [17]

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Diagnosis

The presence of CMV polyradiculopathy should be suspected in patients who have progressive lower extremity weakness and decreased or absent reflexes on neurologic examination. (See Clinical Presentation.)

An MRI or contrast CT scan of the spinal cord (or myelogram) should be performed to exclude mass lesions. Nerve root thickening supports the diagnosis of CMV polyradiculopathy.

A lumbar puncture should be done for CSF analysis. A CSF polymorphonuclear pleocytosis with a negative CSF bacterial culture strongly suggests CMV polyradiculopathy in a patient with AIDS who has a CD4 cell count < 50 cells/microL. A positive test for CMV DNA in the CSF supports this diagnosis. [18]

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CSF Analysis

Cerebrospinal fluid (CSF) analysis may be useful for differentiation between the various etiologies: the infectious forms (eg, CMV, cryptococcosis, tuberculosis, toxoplasmosis), the idiopathic form, and the neoplastic form (ie, lymphoma). In addition to routine studies, analysis of the CSF for cytology, CMV, Venereal Disease Research Laboratory test (VDRL), and cryptococcal antigen may be performed. The most sensitive techniques, including polymerase chain reaction (PCR), are required to rule out specific treatable infections.

In CMV-related polyradiculopathy, typical CSF findings are as follows:

  • Decreased glucose level

  • Markedly elevated protein level, but can be normal

  • Polymorphonuclear neutrophil (PMN)–predominant pleocytosis. One case report showed lymphocytic predominance.

  • Positive PCR for CMV

  • Absence of malignant cells

Pleocytosis usually comprises more than 60% PMNs, but the percentage is sometimes lower. In one study, only 50% of patients had PMN-preponderant pleocytosis. Positive CMV-PCR and elevated protein were the most common CSF findings. [19]

PCR of CSF has a 92% sensitivity and a 94% specificity in CMV-associated progressive polyradiculopathy. CMV culture is positive in only 50% of cases.

CSF findings are different in non-CMV-related progressive polyradiculopathy.

in lymphoma, CSF findings include lymphocytic pleocytosis.

In TB-related cases, CSF findings usually include (but not always) elevated protein, decreased protein and glucose, as well as PMN's often mixed with lymphocytes. Mycobacterial cultures as well as lymph node biopsies may also assist in diagnosis.

In idiopathic cases, CSF findings include:

  • Moderate mononuclear pleocytosis

  • Mildly elevated protein

  • Absence of identifiable infectious agents or malignant cells

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Other Tests

A complete blood count (CBC) may indicate very low CD4 lymphocyte counts. Blood and urine cultures may indicate CMV and other possible etiologic agents.

MRI with contrast or myelography is useful to exclude cauda equina or spinal cord compressive lesions resulting from lymphoma, syphilis, or toxoplasmosis. Possible findings include the following:

  • Meningeal enhancement consistent with arachnoiditis

  • Thickened nerve roots or root enhancement in cauda equina can be seen. This finding is nonspecific and inconsistently seen in CMV- associated polyradiculopathy.

Electromyography and nerve conduction studies may indicate the following:

  • Differentiation from other rapidly progressive neuropathies such as Guillain-Barré syndrome

  • Widespread denervation

  • Prolonged or absent F-waves

  • Low-amplitude or unobtainable tibial or peroneal compound muscle action potentials and sural nerve action potentials

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Treatment and Management

Treatment strategies depend on the etiology.

In idiopathic polyradiculopathy, spontaneous improvement without treatment is common. [10]

For cytomegalovirus (CMV)-associated polyradiculopathy, and other neurologic diseases, prompt initiation of therapy is critical. CMV polyradiculopathy can be fatal within 2 months, making early treatment extremely important.

The initial or induction phase of treatment for patients with CMV neurologic disease depends upon the degree of neurologic impairment as well as the patient’s ability to tolerate the anti-CMV regimen.

For individuals with mild CMV neurologic disease (eg, a patient with CMV polyradiculopathy or mononeuritis multiplex who has mild motor deficits), monotherapy is suggested rather than dual therapy. For patients  capable of taking oral medications, oral valganciclovir 900 mg twice daily is started. For individuals incabable of taking oral medications, intravenous ganciclovir (5 mg /kg every 12 hours) or foscarnet (90 mg/kg every 12 hours) can be used.

Cidofovir is an alternative therapy for the treatment of CMV disease in patients who cannot tolerate any of the other options (ie, ganciclovir, valganciclovir, or foscarnet). Although no controlled trials have evaluated cidofovir for the treatment of CMV neurologic disease, it has been used to treat CMV retinitis. However, the use of cidofovir is limited by its serious, irreversible nephrotoxicity that occurs via dose-dependent proximal tubular cell injury. Because of this toxicity, ganciclovir or foscarnet monotherapy with twice-daily dosing is preferable to using cidofovir.

Because of the risk of fulminant CMV infection in the setting of immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy (ART), a delay of 14 days before ART initiation can be considered.

After the induction anti-CMV treatment regimen has been completed, patients should be transitioned to a maintenance regimen until the CD4 count has increased to ≥ 100 cells/microL for at least six months. Valganciclovir is the typical agent for maintenance therapy. [18]

Induction therapy with ganciclovir and/or foscarnet should be continued until there is significant improvement in the patient’s neurologic symptoms, which typically occurs after several weeks of treatment. [20]

After the patient has improved and ART has been initiated, anti-CMV treatment can be simplified to a maintenance regimen such as valganciclovir monotherapy 900 mg/day. It is suggested to continue valganciclovir until the patient’s viral load is suppressed and the CD4 count has increased to ≥ 100 cells/microL for at least six months. This approach is based upon observational studies regarding the duration of maintenance therapy for patients with CMV retinitis. [21, 22, 23, 24]

Acyclovir inhibits activity of both HSV-1 and HSV-2.

In cases of subacute lumbosacral radiculopathy in immunocompetent individuals, symptoms can resolve spontaneously over weeks. Others have responded to corticosteroids. [25]

Symptomatic treatment for neuropathic pain include agents such as gabapentin, pregabalin, nortriptyline, amitriptyline, lamotrigine, venlafaxine, and duloxetine. Physical therapy is also recommended.

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