HIV-1–Associated Progressive Polyradiculopathy

Etiology

The HIV virus is neuroinvasive, neurotropic, and neurovirulent for central and peripheral nervous cell cells. However, underlying etiologies for neuropathy depend on the immune status of HIV patients. Inflammatory neuropathies occur at a higher CD4 count, and opportunistic infections lead to neuropathies at a lower CD4 count.[5][6] Classically, progressive polyradiculopathy is associated with cytomegalovirus (CMV) infection in patients with HIV. Nevertheless, its association with other infectious etiologies has also been demonstrated, such as a varicella-zoster virus (VZV), mycobacterium tuberculosis (TB), treponema pallidum, Epstein-Barr virus (EBV), toxoplasma, cryptococcus, and herpes simplex virus.[5][7][8][9][10] Non-infectious etiologies such as primary spinal lymphoma, metastasis from systemic lymphoma, paraneoplastic polyradiculopathy, and lymphomatous meningitis have also been observed.[10][11][12] Lumbosacral radiculitis after reactivation of HSV-2 in patients with HIV has also been reported.[13] 

Infective and lymphoma-related etiologies are usually subacute and progressive. Chronic inflammatory demyelinating polyradiculopathy (CIDP) and diffuse infiltrative lymphocytosis (DIL) are less commonly seen. Rarely, 2 types of subacute lumbosacral polyradiculopathy syndromes are seen with HIV seroconversion, known as HIV-associated variant of Guillain Barre syndrome (GBS), a type of acute inflammatory demyelinating polyradiculopathy and another type with motor axonal GBS.[14] Idanivir-induced epidural lipomatosis has also been reported, which led to lumbar polyradiculopathy and resolved with the discontinuation of the drug.[15] A clinical course with milder features was also observed in a few studies, which were more benign and had lesser neurological deficits and CSF findings, unlike those seen in CMV infection, with either spontaneous recovery or quick recovery after surgical decompression. Thus, while investigating known HIV-positive patients, it is essential to exclude etiologies with a similar presentation in the general population, especially in patients with a well-controlled disease under highly active antiretroviral therapy (HAART).[12]

Epidemiology

Since the advent of ART, HIV has altered from a progressive and fatal disease to a chronic condition. Consequently, the prevalence of HIV-associated complications is also increasing. Even though the literature lacks precise data, in around 10 to 15% of HIV-infected patients, neurological symptoms are clinically prevalent; however, pathological evidence of neuropathy can be seen in almost all patients with advanced acquired immunodeficiency syndrome (AIDS).[16] HIV-associated neuropathies are seen frequently in the adult population, and not many cases have been noted in children—also, the odds of recovery decrease as age increases. Advancing age, obesity (high BMI), diabetes, and major depressive disorders are proposed to be other risk factors for the development of neuropathies in HIV patients.[17][3] Literature indicates that prompt treatment with antivirals is associated with a mortality reduction from 100% to 22%.[18]

Pathophysiology

Clinical studies have failed to demonstrate evidence of HIV infection causing direct injury in the spinal cord and nerves. It is hypothesized that this syndrome occurs in patients with HIV due to direct infection of cells by the virus or by indirect toxicity of viral gene products and host inflammatory response. The latter is considered more likely; however, data to prove this mechanism is also lacking, although mitochondrial DNA damage has been observed in affected neurons in patients with HIV.[3]

Superimposed CMV infection causes leakage of endothelial capillary tight junctions and loss of integrity of the blood-brain barrier, which also accounts for the presence of latently infected cells in CSF.[19] The symptoms are responsible for the necrosis and inflammation of the spinal cord and roots by direct subpial and subependymal infection of the CMV virus. CMV encodes its DNA polymerase but uses host RNA polymerase for replication, which happens in a specialized compartment in the host cell nucleus, evident as inclusion bodies.[20] It is proposed that infected ependymal cells detach and travel via CSF pathways to implant caudally.[21] It was found that the UL146 and UL147 genes of CMV encode proteins with a sequence similar to human chemokine CXC and thus have high-affinity binding with CXCR2 receptors present on polymorphonuclear neutrophils (human IL8 mimetic). By recruiting neutrophils, CMV efficiently disseminates throughout the body and gains lifelong latency in leucocyte progenitors.[22]

Tubercular polyradiculopathy may be an extension of TB meningitis or secondary to vertebral or other primary TB lesions. It causes extensive exudate formation, which may encase the spinal root and cause impingement.[8] Non-infectious polyradiculopathy occurs with infiltration of the leptomeninges, spinal cord, and spinal roots with lymphoma cells.[11] In inflammatory radiculopathies, rapid response to corticosteroid therapy suggests the host immune response is responsible for the pathology. HIV-associated GBS variant is produced by neurotropic strains or molecular mimicry and autoimmune reaction.[23]

Histopathology

Post-mortem examination discloses extensive inflammation and necrosis predominantly involving roots and cords in patients with HIV-associated polyradiculopathy. Focal congestion, edema, and polymorphonuclear cell infiltrates are seen in necrotic regions. Intracytoplasmic and intranuclear inclusion bodies are evident in the cells of necrotic lesions in the subarachnoid spaces and Schwann cells due to CMV infection in HIV-positive patients.[16] Subarachnoid space granulomas may be seen in TB polyradiculopathy.

History and Physical

HIV-associated progressive polyradiculopathy occurs due to various etiologies; however, the clinical picture is similar in most cases. There is a variation in time of onset according to the etiology of the syndrome, where infectious polyradiculopathy is seen in the late stages of HIV infection. Still, inflammatory polyradiculopathy may be seen in the mid to late stages of HIV infection. The AIDP/GBS variant of the disease is usually seen at seroconversion.[16] Asymmetric progressive paraparesis, diffuse areflexia, and sphincter disturbance are cardinal features of progressive lumbosacral polyradiculopathy (PP) with or without the involvement of more distal sites of the peripheral nervous system. Progressive radiculopathy in HIV patients often presents as cauda equina syndrome and cervical involvement is usually absent. The classical presentation of this syndrome includes a gradual progression of lower extremity weakness and numbness and often a prior diagnosis of cytomegalovirus disease.[2] Decreased sensation generally begins in distal limbs or the saddle region when involving the sacral nerve roots and can be asymmetric. A rapid progression can ensue, with flaccid paralysis or paraplegia, or a slowly progressing indolent course of evolving symptoms may be seen. 

The initial presentation involves lower back pain with acute or subacute motor weakness. This weakness is frequently accompanied by hyporeflexia or even areflexia, extensor plantar response, and loss of sphincter action. Sometimes, sensory symptoms may be seen as shock-like pain in dermatomal spread occurring spontaneously or elicited by movement. Rarely are sacral dysesthesias seen. The involvement of the upper limbs or cranial nerves in this syndrome is rare.[5] Additionally, sphincter action may be spared in inflammatory PP, whereas CIDP may show a relapsing-remitting course.[24] In the case of CMV-associated PP, concomitant non-neurologic CMV infection is common and may be subclinical. In syphilis, PP has been observed only in early infection before developing classical manifestations of secondary syphilis when the patient may be seronegative.[9]

A recent case series from South Africa identified a unique presentation of this syndrome, which presented as acute or subacute severe lower motor neuron weakness confined to the lower limbs in patients who were ultimately diagnosed with HIV infection.[25] These patients had normal sensory examinations and preserved sphincter function. In contrast to classical polyradiculopathy of HIV, these patients did not have any identifiable opportunistic infection, nor did they have an advanced degree of immunosuppression. The authors of this series identified this cohort as a further variant of GBS associated with HIV or a distinct clinical entity of this syndrome. 

Evaluation

In most cases, a diagnosis of polyradiculopathy can be made on purely clinical grounds; however, further testing should be conducted to exclude other neurologic conditions and identify the etiologic cause of the radiculopathy.

Lumbar Puncture

Cytomegalovirus is the third most common cause of all neurologic complications associated with HIV but the most common cause of polyradiculopathy.[26] A lumbar puncture is frequently performed in patients who present with neurologic symptoms in association with an HIV infection. Cerebrospinal fluid (CSF) studies usually reveal several findings.[27][28] These include:

• Pleocytosis with polymorphonuclear leucocyte predominance (usually > 60% of normal CSF count)
• Hypoglycorrhachia with CSF glucose < 40 mg/dl or CSF to serum glucose ratio of less than or equal to 0.5
• Increased protein levels
• Absent neoplastic cells

CSF testing for CMV is positive in 50% of the cases, and quantitative PCR assay is the preferred method for viral detection.[29] CMV DNA amplification in CSF can be done by polymerase chain reaction (PCR) assay and branched DNA signal amplification assay. Quantitative intrathecal synthesis of immunoglobulins specific for recombinant phosphoprotein (pp150) of CMV or CMV-specific IgM is also available for diagnosis. The immune response is associated with recovery or treatment. PCR has higher diagnostic specificity than immune response and improves with treatment. It is useful for monitoring disease progression and evaluating treatment regimens or drug failure. In immunocompromised patients, viral levels could be undetectable and thus unreliable.[30][31][32] CMV-pp67 antigenemia assay is useful for diagnosing and monitoring CMV infection in HIV-positive patients. CMV pp67 mRNA in CSF detects active infection only, whereas DNA PCR may also detect latent disease viruses. CSF culture is insensitive.[19]

Electrodiagnostic Testing

Electromyography (EMG) and nerve conduction studies are the most useful tests for these patients. A needle EMG can detect physiologic abnormalities consistent with radiculopathy and determine the severity of the injury in these patients. It can help exclude other neurologic complications of HIV and may be able to determine the duration of the disease.[33] Electrodiagnostic studies usually reveal axonal polyradiculopathy, with absent or low amplitude responses in nerve conduction studies and denervation of lower extremity muscles.[5] However, the needle EMG has limited sensitivity in patients with predominant dorsal root involvement. EMG may reveal multifocality, asymmetry, radicular involvement, chronicity, neuromuscular junction, and muscle disease.[34][35] Electrodiagnostic studies in CMV-PP show axonal loss of spinal roots leading to denervation potentials in concerned myotomes. In contrast, inflammatory-PP shows axonal loss with superimposed delayed latencies and conduction blocks, suggesting predominant demyelinating pathology.[16][34]

Magnetic Resonance Imaging (MRI) and CT Myelography

MRI readily detects structural pathology responsible for polyradiculopathy. Abnormal contrast enhancement of the nerve roots is frequently seen.[12] MRI is the imaging modality of choice and the first investigation done for radiculopathy to rule out focal compressive pathologies. MRI reveals intense nodular leptomeningeal enhancement along the affected nerve roots. If the MRI is negative or shows equivocal findings in a patient with high clinical suspicion, if the MRI is contraindicated, or if the patient has surgical spinal hardware, CT myelography with intrathecal contrast is used. Spinal T1-weighted MRI with gadolinium-DTPA shows enhancement of the pial lining of the affected nerve roots.[34][36]

Other Testing 

Depending on the patient history and local endemicity, CSF testing for Z-N staining/ADA activity/CSF culture for mycobacteria, CSF VDRL, HIV RNA in CSF, visualization of Cryptococcus in CSF or IgG in blood for Toxoplasma or BM biopsy for lymphoma could be done to rule out other etiologies.[37] HIV-associated TB radiculopathy shows raised CSF cell count and reduced CSF glucose with raised or depleted protein in CSF. Unlike GBS in HIV-negative patients, CSF in HIV-positive patients shows WBC pleocytosis, but no albumin-cytological dissociation is seen.[16][23] Serum syphilis serology should also be considered in patients who present with radiculopathy and concomitant HIV infection because patients with early syphilis may present with polyradiculopathy before any other sign of secondary syphilis.[9] It is important to note, however, that syphilis serology can be falsely negative in patients with severe immunosuppression.[9] This warrants repeat syphilis testing if no other etiologic agent for PP is found on initial testing.[9] 

Treatment / Management

The general approach to treatment should focus on treating potential etiologic causes and controlling HIV. In patients with suspected HIV-associated progressive polyradiculopathy, empirical therapy for CMV must be considered.[37] Considering the frequency of CMV-PP, prophylaxis should be targeted at a CD4 count below 0.1 x 10⁹/L.[38] The HAART regimen should be started speedily to suppress viral load and raise CD4 count, accompanied by appropriate therapy for the underlying etiology.[39] However, in ART-naive patients, HAART should be withheld for the initial 14 days to prevent immune reconstitution inflammatory syndrome (IRIS), which may cause more damage.[40](B2)

In HIV patients with CMV-PP, intravenous ganciclovir administration for 2 to 3 weeks is the first-line treatment for severe disease, while oral valganciclovir could be given for mild disease. Maintainance therapy with oral valganciclovir is advised for 6 months or until the CD4 count is above 0.1 x 10⁹/L.[40] If the patient gives a history of previous monotherapy for similar or different CMV manifestations or if the serial CSF reading shows persistent pleocytosis and hypoglycorrhachia after induction of ganciclovir therapy, the likelihood of treatment failure is high, and treatment with alternative drug or ganciclovir-foscarnet combination should be considered. In ganciclovir resistance, foscarnet infusion can be given alone or in combination with cidofovir.(B3)

With prompt therapy, the progression of neurological symptoms is controlled within 2 weeks, and virological tests become negative in a 3-week course. However, residual neurological deficits are still commonly seen after treatment completion. The antivirals prevent further virus replication; however, they do not cure the latent infection; thus, relapses are frequently seen. Hence, many studies suggest an indefinite course of ganciclovir in these patients.[18][28][41] Foscarnet is a valuable alternative drug for acyclovir-resistant herpes virus infection.[10] (B3)

For other infectious causes, a relevant antibiotic course should be given, accompanied by corticosteroids if necessary, to prevent the worsening of symptoms. In the case of neoplastic or paraneoplastic etiology, remission is seen with chemo/radiotherapy.[11] Plasmapheresis and IVIG have been used to treat GBS and other inflammatory pathologies in HIV patients.[23] In non-infectious etiologies and refractory cases, surgical decompression and spinal fusion are advised. However, considering the complications related to the procedure itself as well as that of anesthesia, surgery is reserved for failure of non-surgical methods and acutely deteriorating neurological symptoms.[42](B3)

In radiculopathy patients, supportive measures are advised to relieve pain, improve function, and better cope with the disease physically and psychologically. Some interventions like epidural corticosteroid injections and percutaneous spinal decompression are performed.[43][44][45] Acetaminophen, NSAIDs, opiates, physical therapy, and tractions for improving neurological deficits may be prescribed; however, the data supporting the use of such modalities is equivocal.[46][47][48][49](A1)

Differential Diagnosis

For the presentation of progressive sensorimotor polyradiculopathy, the following differentials are to be considered:

• Transverse myelitis: Acute and rapidly progressing course of paresis with CSF cell count and glucose within the normal range. Electrodiagnostic studies show predominantly demyelinating inflammatory pathology. MRI shows edematous changes at the affected spinal level.[50]
• Miller Fischer syndrome: GBS variant associated with ophthalmoplegia and ataxia, with a history of preceding viral infection.[50]
• Neurosyphilis: late sequelae of syphilis in immunocompetent patients, confirmed with serology[51]
• Toxic polyradiculopathy: Anti-PD1 agent like pembrolizumab in metastatic melanoma, late sequelae of ethylene glycol intoxication, a late adverse reaction of chemo-radiotherapy, post intrathecal injection of methotrexate[52][53][54]
• Inflammatory polyradiculopathy: associated with systemic lupus erythematosus[50]; Sjogren syndrome; or paraproteinemias[55]
• Leptomeningeal carcinomatosis should be considered in a lumbosacral polyradiculopathy picture with no structural lesions on imaging and the presence of malignant cells in CSF.[56]
• Vertebral artery dissection may present as cervical radiculopathy with prominent upper limb involvement[57]
• Lyme disease: Mimics GBS with similar CSF picture, diagnosis confirmed with positive serology for Lyme disease[58]
• Neurosarcoidosis: It is an important differential with the presentation of swelling and contrast MRI enhancement of spinal roots with raised CSF proteins and cells, and it responds well to prednisolone[59]
• Neurobrucellosis: caused by gram-negative bacilli of Brucella genus in endemic areas and presents as subacute motor polyradiculopathy with sensory nerve spared and muscle biopsy showing neurogenic changes with the secondary myopathic picture and CSF titer or culture showing Brucella[60]
• Hypertriglyceridemia: Polyradiculoneuropathy secondary to hypertriglyceridemia is uncommon. However, it is an important differential since the resulting neurological deficits are irreversible. It presents with neuropathy or radiculopathy, unremarkable imaging, and lab findings other than an exceptionally deranged lipid profile.[61]
• Post-bariatric surgery complication: Rarely, a neurological complication between 6 months to 2 years from the bariatric surgery may present as acute or subacute progressive motor and sensory axonal polyradiculopathy mainly in the lower limb, areflexia, and ataxia with normal CSF picture and predominant axonal degeneration. Sometimes, autoimmune antibodies may also be detected in these patients.[62]
• Diabetic Polyradiculopathy: Seen mostly with type 2 diabetes mellitus. The patient presents either thoracic radiculopathy with chronic unexplained abdominal pain with abdominal protrusion and weight loss, or it can be accompanied by lumbosacral radiculopathy simultaneously.[63]

Prognosis

Misdiagnosis and underdiagnosis of HIV-1-associated radiculopathy are common. Consequently, HIV-associated progressive polyradiculopathy has 100% mortality without prompt diagnosis and treatment. Even with the advent of HAART, reducing the morbidity and mortality in neurological complications of HIV infection, the prognosis of progressive polyradiculopathies is poor in HIV patients due to severe immunosuppression. CMV-associated polyradiculopathy is rapidly fatal without treatment, but the mortality for this particular form is as high as 22% even with treatment.[12] CMV blood detection is considered a poor prognostic marker for CMV morbidity and survival.[64] Also, commonly associated infections like CMV and HSV show latent infection. Thus, recurrence and relapses are quite common. Even after completion of therapy, a residual neurological deficit is seen, which may lead to disabilities and handicaps and negatively impact the socio-economic aspects of the patient's life.

Complications

Since patients with HIV-associated polyradiculopathy are at a high risk of opportunistic infections, the most important factor to be considered is the drug interaction between antivirals and HAART. Careful regimen selection and monitoring are essential parts of the treatment plan to prevent or minimize complications. Initial symptoms worsening after beginning antiviral therapy may be observed. This usually resolves spontaneously throughout treatment; however, when vital structures are involved, adjuvant corticosteroids, tapered over time, are suggested to reduce morbidity and mortality in these cases. In many infectious etiologies, concomitant involvement of other neurological (myelitis, encephalitis, ventriculitis, etc) and non-neurological (retinitis, esophagitis, pneumonitis, etc) tissues may be seen at presentation or during disease progression by the involved or other opportunistic pathogens. In neoplastic etiologies, expansion of primary lesion or metastasis or drug interaction with chemotherapeutic agents may accelerate the worsening of the disease.[12]