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:

• Large disc prolapse
• Spondylopathies
• Spinal canal stenosis due to trauma/degeneration
• Spinal injury: due to trauma or ischemia
• Guillain-Barre syndrome: GBS variant in HIV and GBS cannot be differentiated clinically; hence all patients presenting with GBS must be tested for HIV. It may also be preceded by viral infections like Campylobacter jejuni in HIV negative patients. CSF shows albumino-cytological dissociation.
• 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.[45]
• Miller Fischer syndrome: GBS variant associated with ophthalmoplegia and ataxia, with a history of preceding viral infection.[45]
• Neurosyphilis: late sequelae of syphilis in immunocompetent patients, confirmed with serology[46]
• 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[47][48][49]
• Inflammatory polyradiculopathy: associated with systemic lupus erythematosus[45]; or Sjogren syndrome; or paraproteinemias[50]
• Leptomeningeal carcinomatosis: should be considered in lumbosacral polyradiculopathy picture with no structural lesion on imaging and presence of malignant cells in CSF.[51]
• Vertebral artery dissection: may present as cervical radiculopathy with prominent upper limb involvement[52]
• Lyme disease: Mimics GBS with similar CSF picture, diagnosis confirmed with positive serology for Lyme disease[53]
• 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[54]
• 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[55]
• Hypertriglyceridemia: Polyradiculoneuropathy secondary to hypertriglyceridemia is uncommon. However, it is an important differential, since the resulting neurological deficits are irreversible. It presents with neuropathy and/or radiculopathy, with unremarkable imaging as well as lab findings other than exceptionally deranged lipid profile.[56]
• Post-bariatric surgery complication: Rarely as 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.[57]
• Diabetic Polyradiculopathy: Seen mostly with type 2 diabetes mellitus. The patient presents with either thoracic radiculopathy presenting with chronic unexplained abdominal pain with abdominal protrusion and weight loss, or it can be accompanied by lumbosacral radiculopathy simultaneously.[58]

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:

• in adults: 20 to 40 mg/dL OR 0.15 to 0.45 g/L
• in children (Up to 4 years of age): 24 mg/dL
• in children (Up to 6 days of age): 70 mg/dL

5. Leukocyte count:

• in adults: 0 to 5/mm 
• children younger than 1 year: 0 not 30/mm
• Children 1 to 4 years: 0 to 20/mm
• Children 5 years to puberty: 0 to 10/mm

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.