Human immunodeficiency virus (HIV) is a type of RNA virus, retrovirus of genera lentivirus. It can be classified into two types, HIV 1 and HIV 2, of which HIV 1 is more virulent and globally prevalent. Peripheral neuropathy is the commonest neurological complication associated with HIV1.[1] It can present in 6 patterns, which are distal sensory polyneuropathy, mononeuritis, mononeuropathy multiplex, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, and autonomic neuropathy.[2][3]
Progressive polyradiculopathy in HIV infection is seen clinically as gradual sensory, motor, reflex, and sphincter disturbances in a radicular pattern. Although frequently appearing in advanced stages of the disease, it may sometimes be a presenting feature with rapid progression leading to irreversible deficits or a fatal outcome, unless treated promptly.[3]
HIV virus is neuroinvasive, neurotropic, and neurovirulent for cells of the central as well as the peripheral nervous system. However, underlying etiologies for neuropathy depend on the immune status in HIV patients. Inflammatory neuropathies occur at a higher CD4 count, and opportunistic infections occur at lower CD4 count.[4][5]
Classically, progressive polyradiculopathy is associated with cytomegalovirus (CMV) infection in HIV patients. Nevertheless, its association with other infectious etiologies has also been demonstrated, such as a varicella-zoster virus (VZV), mycobacterium tuberculosis (Mtb), treponema pallidum, Epstein-Barr virus, toxoplasma, cryptococcus, and herpes simplex virus.[4][6][7][8][9] Non-infectious etiologies such as primary lymphoma, metastasis from systemic lymphoma, paraneoplastic polyradiculopathy, and lymphomatous meningitis have also been observed.[9][10][11]
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, two 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.[12]
A clinical course with milder features was also observed in a few studies, which was more benign and had lesser neurological deficits and with 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 important to exclude etiologies with a similar presentation in the general population as well, especially in patients with a well-controlled disease under highly active antiretroviral therapy (HAART).[11]
Since the advent of HAART, HIV has altered from a progressive and fatal disease to a chronic condition, so the overall population of HIV patients is aging, and the prevalence of HIV associated complications is also increasing. Even though 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 advanced acquired immunodeficiency syndrome (AIDS) patients.[13]
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 risk factors for the development of neuropathies in HIV patients.[14][3] Literature indicates that prompt treatment with antivirals is associated with mortality reduction from 100 to 22%.[15]
The studies have failed to demonstrate evidence of the direct effect of HIV infection in the spinal cord and nerves. It is hypothesized that it can either be 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. Moreover, mitochondrial DNA damage has been observed in affected neurons in HIV patients.[3]
CMV shows maximum mortality and morbidity in HIV neuropathies. Regardless of neural or non-neural infection, human 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.[16] As per the study by Mahieux and colleagues, the necrosis and inflammation of the spinal cord and roots by direct subpial and subependymal infection of CMV virus are responsible for the symptoms. CMV encodes its DNA polymerase; however, it uses host RNA polymerase for replication, which happens in a specialized compartment in the host cell nucleus, evident as inclusion bodies.[17]
Eidelberg and colleagues proposed that infected ependymal cells detach and travel via CSF pathways to implant caudally.[18] It was found that the UL146, 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 as well as gains lifelong latency in leucocyte progenitors.[19]
Tubercular polyradiculopathy may either start as an extension from 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.[7]
Non-infectious polyradiculopathy cases show the infiltration of the leptomeninges, spinal cord, and spinal roots with lymphoma cells.[10] 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.[20]
Post mortem examination discloses extensive inflammation and necrosis predominantly involving roots and cords in HIV patients with 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.[13] Subarachnoid space granulomas may be seen in TB polyradiculopathy.
Taking into account the high prevalence of distal sensory paraesthesia in HIV patients, the co-existence of more than one neuropathic conditions is highly probable. 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 not often seen.
The patient usually presents with lower back pain with acute or subacute motor weakness involving multiple roots, sometimes with the involvement of more distal sites, which may progress to paraparesis or flaccid paraplegia or quadriplegia. 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 in shock-like pain in dermatomal spread occurring either spontaneously or elicited by movement. Rarely sacral dysesthesias are seen. The involvement of the upper limbs or cranial nerves is scarce. The upper limb association is seen in the cervical region involvement.[4] The patient might have a previous history of other signs and symptoms indicating immunodeficiency or encephalitis or meningitis.
HIV associated PP may occur due to various causes; however, the clinical picture is similar in all. And the time of presentations may vary according to etiology, for example, infectious PP is seen in late stages of HIV infection, CIDP is seen mid to late stages whereas AIDP/GBS variant is seen at seroconversion.[13]
Additionally, sphincter action may be spared in inflammatory-PP, whereas CIDP may show a relapsing-remitting course.[21] In the case of CMV-PP, concomitant non-neurologic CMV infection is common and may be subclinical. In syphilis, PP has been observed only in early infection, prior to the development of classical manifestations of secondary syphilis when the patient may be seronegative.[8]
In HIV patients, opportunistic infections are seen at lower CD4 counts. If absolute lymphocyte count is less than 950 cells/mm3, then CD4 count will be low enough (less than 200 cells/microliter) to cause immunosuppression for the risk of opportunistic infections.[22]
For the diagnosis of CMV, clinical examination alone is not sufficient, and laboratory identification of the virus is necessary. CSF studies show CSF pleocytosis with polymorphonuclear leucocyte predominance (usually >60% of normal CSF count); hypoglycorrhachia: CSF glucose<40mg/dl or CSF: serum glucose level </=0.5; significantly increased protein levels; and absent neoplastic cells.[23][24]
Histopathological diagnosis is the gold standard; it shows evidence of CMV related inclusion bodies. But quantitative PCR assay is the preferred method for viral detection.[25] 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 it improves with treatment, thus useful for monitoring disease progression, evaluating treatment regimen or drug failure. In immunocompromised patients, viral levels could be undetectable and thus may not be reliable.[26][27][28] CMV-pp67 antigenemia assay is useful for the diagnosis and monitoring of CMV infection in HIV positive patients. CMV pp67 mRNA in CSF detects active infection only, whereas DNA PCR may also detect latent disease virus. CSF culture is insensitive.[16]
Usually, imaging studies are most useful to exclude focal spinal lesions. Plain radiographs offer limited information about the underlying soft tissue pathology. CT and MRI have similar sensitivity, but MRI can distinguish between inflammatory, neoplastic, and vascular lesions better than CT. MRI is the imaging modality of choice, as well as 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 or if MRI is contraindicated or if the patient has surgical spinal hardware, CT myelography (intrathecal contrast) is used. Spinal T1-weighted MRI with gadolinium-DTPA shows enhancement of the pial lining of the affected nerve roots.[29][30]
When MRI is not conclusive, electrophysiological studies are warranted to aid diagnosis. These diagnostic tests, such as EMG and NCT, are accurate only after three weeks of persistent symptoms. EMG may reveal multifocality, asymmetry, radicular involvement, chronicity, and neuromuscular junction, and muscle disease.[29][31] Electrodiagnostic studies in CMV-PP show axonal loss of spinal roots leading to denervation potentials in concerned myotomes, whereas inflammatory-PP shows axonal loss with superimposed delayed latencies and conduction blocks suggesting predominant demyelinating pathology.[13][29]
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.[32] 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 albumino-cytological dissociation is seen.[13][20]
In order to prevent irreversible damage or improve physical function and quality of life in patients with HIV associated progressive polyradiculopathy, a multidisciplinary approach should be followed. Early empirical treatment must be considered with ganciclovir, acyclovir, and antimycobacterial drugs, depending on the patient's history and local endemicity. However, it is advised that the treatment should be specific unless the syndrome cannot be recognized.[32] Considering the frequency of CMV-PP, prophylaxis should be targeted at CD4 count below 0.1x10(9)/L.[33]
The HAART regimen should be started speedily to suppress viral load and raise CD4 count, accompanied by relevant therapy for underlying etiology.[34] 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.[35]
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 six months or until CD4 count is increased more than 0.1x10(9)/L.[35] 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.
Progression of neurological symptoms is controlled within two weeks, and virological tests become negative in three weeks course, but residual neurological deficits are still commonly seen after treatment completion. The antivirals prevent further replication of the virus; however, they do not cure the latent infection; thus relapses are frequently seen. Hence, many studies suggest an indefinite course of ganciclovir in HIV patients.[15][24][36] Foscarnet is a valuable alternative drug in acyclovir-resistant herpes virus infection as well.[9] For other infectious causes, a relevant antibiotic course should be given accompanied by steroids if necessary to prevent worsening of symptoms, as in the treatment of TB, radiculopathy may also initially cause exacerbation of symptoms and needs steroids to control worsening.
In the case of neoplastic or paraneoplastic etiology, remission is seen with chemo/radiotherapy.[10] Plasmapheresis and IVIG have both been used to treatment of GBS and other inflammatory pathologies in HIV patients.[20] 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.[37]
In radiculopathy patients, supportive measures are advised to relieve pain, improve function, and better coping with the disease physically and psychologically. In some cases, interventions like epidural steroid injections and percutaneous spinal decompression are performed.[38][39][40] 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.[41][42][43][44]
For the presentation of progressive sensorimotor polyradiculopathy, following differentials are to be considered:
Misdiagnosis or non-diagnosis is quite common in radiculopathies since they usually present with concomitant peripheral neuropathies, and without prompt diagnosis and proper treatment, HIV associated progressive polyradiculopathy has 100% morality. 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 blood detection is considered a poor prognostic marker for CMV morbidity and survival.[59] 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 have a negative impact on the socio-economic aspect of the patient's life.
Since the 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 an important part of the treatment plan to prevent or minimize complications.
After beginning antiviral therapy, the worsening of the symptoms may be observed initially. This usually resolves spontaneously over the course of 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.), as well as 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.[11]
Practices for prevention of the spread of the responsible pathogens, including HIV, HSV, CMV, Tb, etc. are essential for the patient as well as the primary caretaker of the patient. The greatest risk of spread is by contact with the mucosal surface or body secretions. Optimal hygiene practices are effective in prevention. Good compliance with HAART and routine checkup for CD4 cell count has prognostic importance in HIV positive patients.
In patients with CD4 count less than 100 cells/microliter or CMV viremia or previous history of CMV infection, asymptomatic fundoscopic screening is recommended.[60] In all the infectious and non-infectious complications of HIV, early diagnosis and prompt treatment are essential to reduce the long term morbidity and mortality in the patient. Thus, the patient themselves must be vigilant and visit the clinic soon after the presentation of symptoms.
The reference range for CSF lab values:
1. Opening pressure - 90 to 180 mmH2O (with the patient lying in lateral position)
2. Specific gravity: 1.006 to 1.008
3. Glucose: 45 to 80 mg/dL OR 2.8 to 4.2 mmol/L
4. Proteins:
5. Leukocyte count:
HIV-associated progressive polyradiculopathy often has diagnostic ambiguity due to two reasons. First, the clinical syndrome in all infectious, non-infectious, and neoplastic causes is identical and may pose difficulty in early diagnosis; at the same time, the usually concomitant distal peripheral neuropathy is present as a part of disease progression or adverse drug reaction. In most cases, radiculopathy is seen in the advanced late stage of HIV, but sometimes it may be the presenting complaint of HIV. The presentation of polyradiculopathy can be observed in the clinical examination; however, for etiological specificity, imaging and lab evaluation is essential.
While the infectious disease physician is almost always involved in the care of patients with HIV and complications of HIV, it is important to consult with an interprofessional team of specialists that include a neurologist, pathologist, radiologist, and microbiologist. Training primary care providers for early referrals is beneficial. The nurses are also vital members of the interprofessional group as they can assist with the management as well as the education of the patient and family. During the treatment period, for symptomatic relief and monitoring and treatment of drug interaction, the pharmacist will ensure that the patient is on the right analgesics, antiemetics, and appropriate antibiotics.
The outcomes of radiculopathy associated with HIV depend on the etiology and appropriate therapy. However, to improve outcomes, prompt consultation with an interprofessional group of specialists is recommended.
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