Differential diagnosis
Despite the relative rarity of CES among HIV-positive patients, prompt diagnosis and treatment of the syndrome is crucial due to the potential of persistent debilitating symptoms [
8] (such as permanent loss of bowel/bladder control and paralysis of the legs). It is, thus, necessary to perform an immediate and thorough clinical, imaging, and laboratory investigation in every HIV-positive patient whose symptoms are suggestive of the syndrome in order to identify its cause. An MRI scan of the lumbar spine should be performed within the first few hours of symptom onset [
9]. This aims to quickly identify many of the causes of the syndrome (Table
1), such as simple protrusion of the intervertebral disc, compression of the cauda equina, or focal inflammation (for example, caused by infection) [
8].
Table 1
Causes of cauda equina syndrome in human immunodeficiency virus positive patients
| | Connective tissue disease [ 24, 35] |
Spinal hematoma (for example, from trauma) [ 36] | | Iatrogenic adhesive arachnoiditis [ 38] |
Intervertebral disk hernia [ 28] | | HIV (idiopathic cauda equina syndrome) [ 14] |
Intrathecal disk fragment [ 7] | Herpes simplex virus (mainly HSV-2) [ 19] | |
Pathologic spinal fracture (for example, due to osteoporosis or neoplasia) [ 41] | | |
Spinal neoplasia (especially lymphoma) [ 42‐ 44] | | |
Vertebral canal stenosis [ 46] | | |
| Mycobacterium tuberculosis [ 20] | |
| Varicella zoster virus [ 48, 49] | |
In the general population, CES usually results from compression of spinal nerve roots due to intervertebral disk hernias, vertebral canal stenosis, or spinal neoplasms [
1]. Intervertebral lumbar disc herniation with posterior migration of a disc fragment has been reported as a rare cause of the syndrome in otherwise healthy persons [
7,
10,
11]. As for noncompressive causes, ischemia and spinal arachnoiditis have been described [
1]. These processes could be the cause of CES in HIV-infected individuals, especially in the setting of well-controlled infection under antiretroviral therapy.
The differential diagnosis of CES in immunocompromised patients with HIV infection includes several more, mostly infectious, causes (Table
1). In HIV-infected individuals with advanced HIV/AIDS, the syndrome may present as an acute polyradiculopathy [
12,
13]. When this occurs, it is often caused by CNS infection that affects the cauda equina or conus medullaris. CMV and MTB are the most common infectious causes among HIV-positive patients [
5,
13,
14], which can be in the context of concurrent infection of the retina and other organs [
2,
13].
In order to rule out CMV CNS infection, a lumbar puncture may be performed for CSF analysis, along with serological and molecular testing. CSF laboratory findings suggestive of CMV CNS infection include high cell count with unaltered polymorphonuclear cells (usually >60 %), decreased glucose (<50 % of serum measurement), and significantly increased protein levels, whereas neoplastic cells are absent [
2,
13]. Nevertheless, reports of normal CSF findings in CMV infections have also been published [
13]. Thus, polymerase chain reaction (PCR) of the CSF for CMV DNA is also required before CMV infection is excluded in HIV-positive patients (92 % sensitivity and 94 % specificity) [
15], whereas branched chain DNA (bDNA) assay for CMV DNA and immunoperoxidase staining for CMV antigen can also be considered [
16,
17]; CSF viral cultures are less useful for initial diagnosis, as they lack sensitivity [
13,
15]. In addition to molecular testing, MRI with intravenous gadolinium contrast may be necessary to detect neural CMV lesions [
18].
Myeloradiculitis is usually a complication of tuberculous meningitis or HSV-2 CNS infection that can also lead to CES (even in successfully treated patients) [
4,
19] and yields negative CSF examination results [
20,
21]. Depending on patient history and locally endemic diseases, ruling out HSV-1/2,
varicella zoster virus (VZV), and
Mycobacterium tuberculosis (MTB) should also be considered; molecular testing may also be necessary in these cases, as other testing can be nondiagnostic [
4,
19]; other, more rare causes should be considered on an individualized basis.
Also, impaired immune response in HIV-positive patients with syphilis can cause an atypical, aggressive form of neurosyphilis, which can manifest as painful polyradiculopathy [
22]; rapidly progressive, asymmetrical sensorimotor abnormalities of the lower limbs, bladder and sphincter are the hallmark of this form of neurosyphilis. In the full-blown syndrome, the patient may present with sensory loss of the lower body’s dorsal surface, bilateral sciatic nerve pain, paresthesia, decreased strength of the lower limbs or chronic flaccid paraplegia, absence of deep tendon reflexes, and bladder/sphincter dysfunction [
1]. Lymphomas have also been reported to cause CES in HIV-positive patients [
5,
23]. Finally, primary CES in these patients is a benign, idiopathic form of the syndrome that has a slow clinical progression, mild neurologic deficits, and a generally better prognosis, which may explain those cases where no anatomical causes, infectious agents or neoplastic cells can be identified [
24]. CSF examination results in the primary syndrome reveal moderate mononuclear pleocytosis and mildly increased protein levels.
A systematic meta-analysis of more than 200 individual cases of CES found that the majority (84 %) of patients experience a progressive development of symptoms, beginning with sensory-motor findings in the lower extremities (early CES) [
25]. Bowel and sphincter symptoms tend to develop later on, in what the authors of the study describe as “incomplete CES” and “CES in retention” [
25]. Thus, suspecting CES when bilateral lower limb and/or perineal sensorimotor findings are present could lead to more rapid diagnosis and subsequent management in both well-controlled and advanced HIV infection.
Treatment
Treatment should always be specific, unless the cause of the syndrome cannot be identified. In the case of the latter, short-term alleviation of symptoms and long-term complete neurological recovery of the patient are sought.
In the case of lumbar disk herniation causing CES in HIV-positive patients, surgery is considered more effective than medical management in the short term [
26]. In the single relevant study, no significant difference in the response of HIV-infected individuals to surgical treatment of lumbar disk herniation was found, as compared to uninfected patients [
27]. It is estimated that 1–3 % of all patients with intervertebral lumbar disc herniation may manifest with CES [
28,
29]. These cases of the syndrome, as well as those caused by other anatomical compressive phenomena, undergo surgical decompression that is performed within the first 24 hours of symptom presentation, in order to achieve maximum postoperative neurological recovery [
29,
30]. Delayed surgical decompression (more than 48 hours after symptom onset versus treatment within 24–48 hours) has been correlated with a much higher rate of postoperative bladder and anal sphincter dysfunction, serious motor deficits, sexual dysfunction, and persistent pain [
29].
In HIV-positive patients, when CES is due to CMV CNS infection, treatment may consist of intravenous administration of ganciclovir for 2–3 weeks; foscarnet can also be added to the treatment regimen when there is an increased risk for treatment failure, as in patients who have previously received ganciclovir, or in those with persistent polymorphonuclear pleocytosis, decreased glucose, and/or detection of CMV in serial CSF tests [
3,
31]. In ganciclovir-resistant cases, foscarnet infusion can be performed alone or in combination with cidofovir. Progression of neurological symptoms is usually controlled within 2 weeks of treatment, while serious defects may persist even after treatment completion [
2,
12]. Contrarily, in idiopathic CES spontaneous resolution of the syndrome is most often the case [
12].
Initiation of empirical treatment may be considered in advanced HIV/AIDS patients with CES until the etiology is revealed, in order to prevent irreversible progression of neurological deficits [
4]. Given the high occurrence of
Herpesviridae and MTB infections leading to CES among HIV-infected patients, it may be reasonable to consider ganciclovir, acyclovir, and antimycobacterials in empirical regimens, while patient history and findings will further guide the empirical treatment selection [
4].