Atypical HIV-Vacuolar Myelopathy. Case Report and Literature Review.

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Case Report and Literature Review. Mongezi Tau, Sibi Joseph, Jerry George, Lourdes de Fatima Ibañez-Valdés, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-89435/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Feb, 2021 Read the published version in European Journal of Medical Research → Version 1 posted 8 You are reading this latest preprint version Abstract Background: Here, we report an atypical presentation of HIV-vacuolar myelopathy and search the available medical literature about atypical presentations of human immunodeficiency virus associate vacuolar myelopathy (HIVVM) and immunoglobulin therapy response. Case : A 26-year-old lady who was four weeks postpartum presented to us with acute flaccid quadriparesis, with no sensory level. Extensive workup ruled out other causes of myelopathy. She developed a stage 3 acute kidney injury, and MRI showed diffuse cord atrophy involving the lower cervical and thoracic cord. The patient received IV-immunoglobulin, ARV's, and supportive therapy with inadequate response. Unfortunately, she developed nosocomial pneumonia and died. Discussion: In HIV-VM, there is spinal cord atrophy, which mainly involves the thoracic cord. In our case, this pathological process also affected the spinal cord's cervical region, leading to flaccid tetraplegia, no responding to the treatment, including intravenous immunoglobulin. Health Economics & Outcomes Research Internal Medicine Human immunodeficiency virus associated lesions of the nervous system human immunodeficiency virus-associated myelopathy intravenous immunoglobulin administration case report HIV-vacuolar myelopathy. Figures Figure 1 Figure 2 Keynotes Vacuolar myelopathy, HIV, Immunoglobulin therapy, flaccid tetraplegia, hypokalaemia. Renal failure. Background HIV-associated vacuolar myelopathy (HIV-VM) is the most common and primary etiology of myelopathy in HIV/AIDS patients worldwide, leading to progressive spastic paralysis of the limbs, sensory ataxia, and autonomic dysfunction [ 1 ]. It derives its name from its pathological nature: formation of vacuoles in the lateral and posterior columns, mainly on the spinal cord [ 2 ]. Some authors first reported in 1985 [ 3 ]. Initially considered to present when HIV was in its advanced stages, many authors said it earlier, even when the immunity was right [ 3 ]. The prevalence ranges from 22–55% [ 4 ], it does bear a poor prognosis [ 7 ], and due to its high pathological prevalence, it could be underreported in the literature [ 5 ]. Up to date, the pathogenesis is not fully understood; it is essential to note that this is a diagnosis of exclusion requiring evaluation and eliminating other aetiologies [ 1 – 4 ]. Differential diagnosis includes HIV-associated transverse myelitis during seroconversion, Infections, e.g., Viral -Herpes simplex (HSV), Varicella Zoster (VZV), Cytomegalovirus (CMV), Human T-cell Lymphotropic Virus type 1 (HTLV-1/2); Bacterial – mycobacterium tuberculosis, neurosyphilis, Multiple sclerosis, Vitamin B-12 deficiency, and compressive myelopathy among others. MRI scans are useful in diagnosis; T2-weighted images often show symmetric non enhancing high signal areas present on multiple contiguous slices, which result from extensive vacuolation (hence the name). Lesions may be confined to the posterior column, especially the gracile tracts, or be diffuse [ 3 , 7 ]. Currently, there is no definitive treatment; however, most modalities focus on symptomatic therapies, combined Anti-retroviral treatment (cART) [ 9 ], and some authors have found some good outcomes prescribing IV-immunoglobulins [ 3 , 10 ]. Here we report a young female case in her postpartum stage who had an atypical HIV-VM presentation. She was a known HIV patient on cART, morbidly obese, confused, and quadriplegic with a history of renal failure and hypokalaemia that was corrected. Her condition suppressed the viral load, and CD4 + count was high. Unfortunately, she did not respond to IV-immunoglobulin therapy, being a relevant information for the medical community. Our research questions were: How often IVIg is used to treat HIV-VM? How many positive results including atypical presentations have been published? Material And Method We search for publications about HIV-vacuolar myelopathy and intravenous immunoglobulin therapy answer the two previous research questions using the procedure mentioned below and present our patient. Literature search strategy Our literature review utilized the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement and the PRISMA checklist. We suggest searching from 1 st , January 2010 up to 30 th September 2020. We included all studies (case reports, case series, and observational cohort studies) reported HIV-VM and IVIG treatment during the initial search. We also reviewed the following databases for published studies: Medline EMBASE, Scopus online databases, Google Scholar, Science Direct, Scielo, LILACS, BIREME, and Cochrane library to identify articles evaluating HIV-VM and IVIg therapy*. All items about “AIDS-myelopathy* OR primary infectious myelopathy* OR HIV-VM* OR neurological manifestations of HIV/AIDS* OR Nosocomial myelopathy* OR Spinal cord syndrome/HIV/AIDS* OR Neuro-AIDS* OR Unknow cause myelopathy*OR infectious spinal cord disease* where * is the PubMed wildcard for every possible word beginning or ending. We did not consider other neurological manifestations beyond the scope of the current work. Study and cohort selection We select all publications (case reports, case series, and observational cohort studies) reporting HIV-VM, IVIg Therapy during the initial search. Later we progressively s excluded all duplicate studies, those publications not meeting inclusion criteria because reported only HIV/AIDS, Primary myelopathy separately and HIV-VM not related with IVIg therapy, and those without an English translation. Results Between 1st January 2010, and 30th September 2020, our literature search yielded 621 publications. After removing duplicate articles, we retained 457 unique records. Considering the title and abstracts, we discarded 21 journals, keeping 38 items, screening the full text we selected 32 publications regarding COVID-19/Neurological complications. Finally, we found a total of 2 publications referring to HIV-VM and IVIg. From all groups, we did not find any published study about no improvement of HIV-VM after IVIg treatment. See Appendix A: The PRISMA flow diagram of included studies for this review. Case Presentation Ms. N Is a 26-years-old African lady admitted at Nelson Mandela Academic Central Hospital (NMACH) in Mthatha, South Africa. She presented in May 2020 with a history of inability to walk and confusion. We could not establish the duration of symptoms, signs, and the mode of onset in the admission chart, and she gave no further history due to her confusional state. Of note, this patient was still in her puerperal phase. She was admitted in the maternity ward at NMAH two months ago with severe preeclampsia and HELLP syndrome. This entity is a severe form of preeclampsia characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) in a pregnant or puerperal patient (usually within seven days of delivery)]. Her clinical picture worsened by stage 3 acute kidney injury (creatinine was > 3 times the baseline), she had received intermittent hemodialysis, and renal function wholly recovered before discharge. Her medical history was remarkable for HIV, with a CD4:1051cell/µL and a suppressed viral load (< 20copies/ml) on a modified first-line regimen (ABC/3TC/EFV). She is a known hypertensive patient hydrochlorothiazide and Amlodipine, and there is no previous history of target organ damage. However, according to her old chart that she had defaulted on her antihypertensive for about a month. Her family history was non-significant, and she was a non-smoker, never used illicit drugs, and occasionally used alcohol. She did not have any travel history outside Eastern Cape Province in South Africa. On examination, we found her to be obese (BMI 36 kg/m²), with pink mucosal membranes, anicteric, and afebrile. Her vital signs demonstrated a tachycardia (heart rate: 130) and elevated BP: 147/109 mmHg. The patient was confused. No cranial nerve abnormalities or meningeal signs; she had bilateral mild horizontal vestibular nystagmus. Her motor examination revealed the power of 0/5 in all limbs (proximally and distally), with hypotonia in all limbs and absent deep tendons reflexes. The sensory test was exceedingly difficult to perform due to her confusional state, but she seemed to respond to light touch and pain. On her respiratory examination, we confirmed fine crepitation in the right lower zones of the chest. Given her acute presentation of flaccid quadriplegia, our differentials included Landry-Guillain- Barre syndrome and its variants, HIV-related neuropathies, metabolic derangements (hypokalaemia), vitamin B12 deficiency, CMV peripheral neuropathy, inflammatory myopathies, and neuromuscular junction disorders. In her investigations, the MRI brain was completely normal. The MRI spine showed diffuse cord atrophy with dorsal signal abnormality involving the lower cervical and thoracic spine, as shown in Figs. 1 and 2 (Appendix B). These findings made us think of HIV-VM and subacute combined degeneration of the spinal cord. We did an extensive serological and CSF workup to exclude both infectious and non-infectious causes of myelopathy. Blood levels for Vitamin B12 and folate were normal (491 pmol/l and 32,7 nmol/L, respectively), her CD4 was 1051cells/uL with a viral load of < 20copies/ml. Full blood count showed leucocytosis of 17 × 109 /L with mild anemia (Hb 11.6 g/dl) and reactive thrombocytosis (platelet: 506 × 109/L) high C reactive protein of 241 mg/L with negative blood cultures. Her U/E revealed hypokalaemia of 2.1 mmol/L, and calcium, magnesium, and phosphate were normal. Creatine kinase was normal (20 U/L), and her thyroid function tests: TSH: 5.9mIU/L, FT4 12.8 pmol/L. Her CSF demonstrated high protein: 0.69 g/L, glucose 3.5 mmol/L, polymorphs: 0cells/uL, lymphocytes: 4 cells/uL, erythrocytes:240cells/UL. Repeat CSF showed an adverse polymerase chain reaction for viral studies, including herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and JC virus. Serum and CSF cryptococcal antigen testing and Bartonella serology were negative. We did not detect CSF antibodies to aquaporin-4 and oligoclonal immunoglobulin bands. CSF VDRL was non-reactive. We exclude metabolic alkalosis and hypokalaemia, a state of mineralocorticoid excess because of hypertension, and we did a renin/aldosterone ratio. Then, the aldosterone renin ratio was 1.28(< 40), CT scan of adrenal glands was normal. Considering that there is no clear obstructive, vascular, or neoplastic lesion noted on imaging, the likelihood of the pathology being secondary to direct infection by HIV remains high. This patient was complicated by nosocomial pneumonia with type 1 respiratory failure. A gram-negative bacillus was cultured in her repeat blood and CSF. Her treatment included Polygam 40 g daily intravenously for 5days, anti-retroviral: abacavir/lamivudine/efavirenz 1tablet daily orally, Piptaz 4,5 g intravenously six-hourly, Aldactone 100 mg orally bd, slow k 2 tablets po twice daily, Thiamine 100 mg po daily, Pyridoxine 25 mg po daily, and oxygen by facemask. In the management of the patient, the physiotherapists and occupational therapists worked hard. Her situation was discussed with the intensive care unit considering her respiratory failure, but she was declared poor prognosis and not accepted. Her potassium improved to normal, but she remained with power 0/5 in all limbs. Despite IV Immunoglobulin therapy at the higher dosages, the patient did not improve and demise on June 8, 2020. Discussion And Conclusion In HIV-VM, there is spinal cord atrophy, which mainly involves the thoracic cord. Sometimes the cervical cord is involved as well [ 11 ], in which case patients will present with quadriparesis like our patient. HIV-VM has been documented in the past to be associated with HIV-Neurocognitive disorders (HIV-NCD) [ 12 ], and sometimes we can see the same damage of the spinal cord, in the cerebral hemispheres. In our case, the MRI of the brain was completely normal. The spinal cord atrophy results from vacuoles' formation mainly in the posterolateral columns (thereby mostly involving the corticospinal tract and the fasciculus Gracilis and Cuneatus (like vitamin B12 deficiency) leading to subacute combined degeneration of the spinal cord. In which situation, B12 level in serum is low, and those patients respond very well to parenteral B12. The exact pathophysiology resulting in the formation of vacuoles (still unclear), but proposed mechanisms include: 1) Activation of macrophages in the CNS, which can cause the release of myelotoxic substances or impair the metabolism of Vit B12. 2) Oligodendrocyte/myelin injury from the presence of TNF alpha and other cytokines. These will also augment macrophage activity, which can damage myelin. 3) Direct infection of astrocytes [ 13 ]. Investigations made by Petito et al. confirmed that 26.8% of patients who had autopsy proven VM had signs and symptoms of VM [ 14 ]. The usual HIV-VM presentation is progressive spastic paraparesis, ataxic gait, sphincter disturbance, and erectile dysfunction with no sensory level. Usually occurring in the setting of advanced HIV, and sometimes associated with HIV-NCD. To perform laboratory and radiological investigations to exclude other causes of possible spinal cord pathologies is a good recommendation. CSF tests should include cytology, protein level, MCS, CMV, EBV, HSV, TB, JCV, Picornavirus, flavivirus, rhabdovirus, Treponema pallidum, Borellia, and HIV Viral load. Indication of MRI to rule out any other cause of intramedullary/extradural lesions. In the setting of HIV-VM, the MRI may show cord atrophy in the thoracic and cervical regions. The lumbar area can be affected in more rare instances. Also increased T2 weighted signalling of the posterolateral cord usually. CMV polyradiculomyelitis can present a similar to HIV-VM and is usually distinguishable by the absence of spasticity on exam and MRI findings of diffuse, multisegmented signal abnormalities seen in both grey and white matter, with thickening/enhancement of nerve roots [ 15 ]. Somatosensory evoked potential (SSEP) may also be supportive if it shows a functional lesion of the spinal cord, but it does not have any pathognomonic pattern [ 11 ]. HIV-VM is a diagnosis of exclusion. Therefore, to rule out other causes of myelopathy, an extensive workup must be done. A clinical criterion for diagnosing HIV-VM was created by Chong et al. [ 11 ], as shown in Table 1 (Appendix B). Table 1 Criteria for clinical diagnosis of AIDS-associated myelopathy [ 11 ] 1.Male or female, over 18 years old, with documented HIV-1 infection. 2. AIDS-associated myelopathy, with or without neuropathy and dementia, defined as: a. Presence of at least two of the following symptoms : • Paraesthesia and/or numbness in lower extremities or all four limbs • Weakness of the limbs • Unsteady, stiff, or uncoordinated gait • Sensation of electric shock through the back and legs on flexion of the neck (Lhermitte’ sign). • Increased urinary frequency, urgency, incontinence, or retention • Faecal incontinence or retention • Sexual dysfunction with erectile impairment. b. Presence of at least two of the following neurologic signs • Reduction in vibratory and/or position sensation • Brisk deep tendon reflexes • Abnormal plantar response • Lhermitte’ sign • Spastic, ataxic, or ataxo-spastic gait. 3. Signs and symptoms of AIDS-associated myelopathy for at least 6 weeks before consultation. 4. Abnormal somatosensory evoked potential measurement. 5. No other determinable cause for spinal cord disease by serologic and CSF studies Our patient presentation was atypical because she was virologically suppressed (VL < 20copies/ml), and her CD4 was 1051 cells/uL. It is important to remember that the CSF viral load measurement would have been essential to check for 'CSF viral escape.' We did not check for HIV-VL in the CSF looking to 'viral escape,' We did not have a large enough CSF sample to send for this test. Her confusion could have been due to HIV-NCD, but since she had nosocomial sepsis and hypokalaemia, then it was not the only cause. Also, she had flaccid quadriplegia and absent global reflexes, which is not typical for HIV-VM. Bloods showed hypokalaemia, which can explain an associated peripheral neuropathy worsened by HIV infection and subclinical hypothyroidism, but the weakness persisted in the potassium's correction. Vitamin B12 and folate levels were normal; this ruled out a subacute combined degeneration of the spinal cord. We did an extensive blood and CSF workup for other causes of weakness, which all came back negative. The spinal cord MRI supported the clinical suspicion and showed cord atrophy as well as T2 weighted hyperintensity of the cervicothoracic spine. We continued her cART and gave her a trial of IVIg, which did not improve the condition. Unfortunately, she developed nosocomial sepsis and died. Unfortunately, there was no reliable way to confirm vacuolar myelopathy pre-mortem, and the final diagnosis remained a diagnosis of exclusion. Unfortunately, in our center, we currently do not have access to EMG/NCS. The treatment of VM remains an unresolved matter. Therefore, there has been no effective treatment of HIV-VM yet other than anti-retroviral medications. Perhaps, prescribing cART such as Zidovudine/Abacavir, which has an excellent CNS penetration, should be implemented earlier on in patients with HIV-VM. Another option if the patient is poorly responsive would be to send for CSF-VL and to test for mutations in the CSF. Treatment with L-methionine and IVIg so far has not yielded any beneficial results [ 16 , 17 ]. In 2009, Lindkvist et al. studied nine HIV-infected patients with Guillain–Barré syndrome that received the HAART and demonstrated that IVIg administration in high doses (30 g/day for five days) reduce the pool of HIV in the memory of CD4 + T-cells [ 17 ]. At the same time, Cikurel et al . studied a series of patients with VM to evaluate IVIg's efficacy. They demonstrated that all patients reported reduced palsy in the lower limbs, due to the anti-inflammatory effect of IVIg, causing suppression of the complement cascade, inhibition of production of pro-inflammatory cytokines mainly by monocytes, and reinforcing the anti-idiotypic response, leading to neutralization of growth factors (B-cell), and inhibition of the T-cell proliferations with clonal expansion and activation of T-reg cells and downregulation of the Th17 [ 10 ]. Recently, some authors reported that binding of anti-idiotypic antibodies with epitopes (IgG, and IgM) on the B-lymphocytes and thus inhibiting the production of autoimmune antibodies appears to be the most effective action of IVIg increasing the intrathecal production of oligoclonal Ig, which is a marker for the chronic autoimmune inflammatory process in the CNS [ 3 ]. The same author highlighted IVIg treatment's viability in cases presenting HIV-VM, mainly when autoimmune reactions are under suspicion. We like to highlight the study done by Cikurel et al. because it is the only report delivering a number of cases of HIV-VM treated and an important number of improvements (n = 17) after being treated with Ig at the dosage of 2 g/kg for two days of IV infusion but they did not report any improvement of spastic paraparesis and urinary incontinence [ 10 ] and they did not report the method to measure the improved symptoms and signs. Other authors also report a complete recovering of symptoms and signs from HIV-VM after being treated with highly active antiretroviral therapy [ 18 , 19 ] but the procedure to measure the improvements are also questionable. Reviewed in this manuscript is a case where an atypical HIV-VM presentation did not respond when treated with cART and intravenous immunoglobulin (IVIg), which can doubt therapy's efficacy. Even though our patient did not show any signs of improvement after IVIg therapy, to perform a placebo-controlled clinical trial of IVIg in patients with HIV-VM can be other recommendations to confirm or deny the real benefits of this medication. Abbreviations ABC/3TC/EFV - Abacavir/ Lamivudine / Efavirenz BMI – Basal Metabolic Index cART- combined Antiretroviral Therapy CMV – Cytomegalovirus CSF - Cerebro Spinal Fluid CSF-VL – Cerebro Spinal Fluid Viral Load CT – Computed Tomography EBV – Epstein-Barr Virus EMG – Electromyography FT4 – Thyroxine HAART – Highly Active Anti-Retroviral Therapy Hb – Haemoglobin HIV- Human immunodeficiency Virus HIV-NCD - Human Immunodeficiency Virus-associated Neurocognitive Disorders HIV-VL – Human Immunodeficiency Virus-associated Viral Load HIV-VM – Human Immunodeficiency Virus-associated Vacuolar Myelopathy HTLV – Human T-cell Lymphotropic Virus type 1 HSV – Herpes Simplex Virus IVIg – Intravenous Immunoglobulins JCV – John Cunningham Virus MCS -Microscopy, Culture, Sensitivity MRI – Magnetic Resonance Imaging NCS – Nerve Conduction Studies NMACH - Nelson Mandela Academic Central Hospital TSH – Thyroid Stimulating Hormone U/E – Urea and Electrolytes VDRL – Venereal Disease Research Lab Test VL – Viral Load VZV – Varicella-Zoster Virus Declarations Ethical issue and consent to publish: We obtained the written permission from our patient's family, and they agreed to include all necessary information for publication purposes. All authors certify that we did not reveal names, initials, and other identity issues of this patient in this publication, and complete anonymity is guaranteed. Consent for publication: The necessary consent for publication from the family is received. Availability of data: Data used on this study are available on reasonable request from the corresponding author Competing interest: All authors: reported no conflicts of interest. Funding: We did not receive financial support or any contribution to this publication. Author's contribution : All authors contributed equally to the elaboration of this manuscript. MT and SJ collected data and planning this report, JG and LIV wrote the first draft and reviewed bibliographically, TB and HFS wrote the final piece. All authors reviewed the final manuscript, made corrections, and agreed for publications. Acknowledgment: Special thanks to Dr. C. Naidoo and Dr. Oompie from the Department of Radiology, NMACH. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-89435","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case report","associatedPublications":[],"authors":[{"id":3381578,"identity":"bbd12e0a-2e86-4e90-9039-2c6deb2c4efb","order_by":0,"name":"Mongezi Tau","email":"","orcid":"","institution":"Nelson Mandela Academic Hospital/Walter Sisulu Universitylu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mongezi","middleName":"","lastName":"Tau","suffix":""},{"id":3381579,"identity":"3f23d23e-5b46-4c85-8f01-d4cb20c30a03","order_by":1,"name":"Sibi Joseph","email":"","orcid":"","institution":"Nelson Mandela Academic Hospital/Walter Sisulu University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sibi","middleName":"","lastName":"Joseph","suffix":""},{"id":3381580,"identity":"d07267a5-a704-4a1b-8457-e2fc8b133043","order_by":2,"name":"Jerry George","email":"","orcid":"","institution":"Nelson Mandela Academic Hospital/Walter Sisulu University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jerry","middleName":"","lastName":"George","suffix":""},{"id":3381581,"identity":"8bbd68bf-5192-4994-b4d3-a774ea9415be","order_by":3,"name":"Lourdes de Fatima Ibañez-Valdés","email":"","orcid":"","institution":"Nelson Mandela Academic Hospital/ Walter Sisulu University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lourdes","middleName":"de Fatima","lastName":"Ibañez-Valdés","suffix":""},{"id":3381582,"identity":"93e5134d-c519-42c2-8856-8cdb51ea18ad","order_by":4,"name":"Thozama Dubula","email":"","orcid":"","institution":"Walter Sisulu University Faculty of Health Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thozama","middleName":"","lastName":"Dubula","suffix":""},{"id":3381583,"identity":"a77b9f70-e261-414d-b8d3-21f8763daa61","order_by":5,"name":"Humberto Foyaca-Sibat","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-6023-2394","institution":"Walter Sisulu University Faculty of Health Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Humberto","middleName":"","lastName":"Foyaca-Sibat","suffix":""}],"badges":[],"createdAt":"2020-10-07 21:06:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-89435/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-89435/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-021-00483-0","type":"published","date":"2021-02-01T15:02:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2974216,"identity":"542b647f-bb48-46d5-b458-beb4ad153f5d","added_by":"auto","created_at":"2020-10-14 14:41:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57849,"visible":true,"origin":"","legend":"MRI spine Technique: T2W1, T1W1 (pre-and-post contrast) sagittal, axial view thoracic area. The apparent loss of cord volume, more prominent at T5 to T7. Associated bilateral paramedian focal, linear T2W/STIR hyperintensity dorsal cord from the in these regions.","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-89435/v1/312a5da78e928a134df4e639.JPG"},{"id":2974218,"identity":"55a19bde-49a1-4bba-b80d-cc6c67c59280","added_by":"auto","created_at":"2020-10-14 14:41:20","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37171,"visible":true,"origin":"","legend":"MRI of the spine. Technique T2W1, T1W1 (post-contrast), transverse view shows: STIR intensity in the intramedullary segment of the thoracic spinal cord and loss of volume of the spine more of the postero-lateral aspect.","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-89435/v1/9a84728120bbbb7aad12a3bb.JPG"},{"id":13603585,"identity":"ab9ab54d-2f91-4502-b746-a50d817949df","added_by":"auto","created_at":"2021-09-17 05:56:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":365140,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-89435/v1/6b42dd1d-d642-496f-9a99-1405a1279815.pdf"},{"id":2974217,"identity":"d7dabc44-e55d-4580-9d47-826cffa2dfb2","added_by":"auto","created_at":"2020-10-14 14:41:20","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":644908,"visible":true,"origin":"","legend":"PRISMA FLOW DIAGRAM","description":"","filename":"PRISMAFLOWDIAGRAM2.tif","url":"https://assets-eu.researchsquare.com/files/rs-89435/v1/82ef373107ed28ac0dc7387e.tif"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAtypical HIV-Vacuolar Myelopathy.\u0026nbsp;Case Report and Literature Review.\u003c/p\u003e","fulltext":[{"header":"Keynotes","content":"\u003cp\u003eVacuolar myelopathy, HIV, Immunoglobulin therapy, flaccid tetraplegia, hypokalaemia. Renal failure.\u0026nbsp;\u003c/p\u003e"},{"header":"Background","content":" \u003cp\u003eHIV-associated vacuolar myelopathy (HIV-VM) is the most common and primary etiology of myelopathy in HIV/AIDS patients worldwide, leading to progressive spastic paralysis of the limbs, sensory ataxia, and autonomic dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It derives its name from its pathological nature: formation of vacuoles in the lateral and posterior columns, mainly on the spinal cord [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Some authors first reported in 1985 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Initially considered to present when HIV was in its advanced stages, many authors said it earlier, even when the immunity was right [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The prevalence ranges from 22\u0026ndash;55% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], it does bear a poor prognosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and due to its high pathological prevalence, it could be underreported in the literature [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Up to date, the pathogenesis is not fully understood; it is essential to note that this is a diagnosis of exclusion requiring evaluation and eliminating other aetiologies [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Differential diagnosis includes HIV-associated transverse myelitis during seroconversion, Infections, e.g., Viral -Herpes simplex (HSV), Varicella Zoster (VZV), Cytomegalovirus (CMV), Human T-cell Lymphotropic Virus type 1 (HTLV-1/2); Bacterial \u0026ndash; mycobacterium tuberculosis, neurosyphilis, Multiple sclerosis, Vitamin B-12 deficiency, and compressive myelopathy among others. MRI scans are useful in diagnosis; T2-weighted images often show symmetric non enhancing high signal areas present on multiple contiguous slices, which result from extensive vacuolation (hence the name). Lesions may be confined to the posterior column, especially the gracile tracts, or be diffuse [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Currently, there is no definitive treatment; however, most modalities focus on symptomatic therapies, combined Anti-retroviral treatment (cART) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and some authors have found some good outcomes prescribing IV-immunoglobulins [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere we report a young female case in her postpartum stage who had an atypical HIV-VM presentation. She was a known HIV patient on cART, morbidly obese, confused, and quadriplegic with a history of renal failure and hypokalaemia that was corrected. Her condition suppressed the viral load, and CD4\u0026thinsp;+\u0026thinsp;count was high. Unfortunately, she did not respond to IV-immunoglobulin therapy, being a relevant information for the medical community.\u003c/p\u003e \u003cp\u003eOur research questions were: How often IVIg is used to treat HIV-VM? How many positive results including atypical presentations have been published?\u003c/p\u003e "},{"header":"Material And Method","content":"\u003cp\u003eWe search for publications about HIV-vacuolar myelopathy and intravenous immunoglobulin therapy answer the two previous research questions using the procedure mentioned below and present our patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLiterature search strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur literature review utilized the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement and the PRISMA checklist. We suggest searching from 1\u003csup\u003est\u003c/sup\u003e, January 2010 up to 30\u003csup\u003eth\u003c/sup\u003e September 2020. We included all studies (case reports, case series, and observational cohort studies) reported HIV-VM and IVIG treatment during the initial search. We also reviewed the following databases for published studies: Medline EMBASE, Scopus online databases, Google Scholar, Science Direct, Scielo, LILACS, BIREME, and Cochrane library to identify articles evaluating HIV-VM and IVIg therapy*. All items about \u0026ldquo;AIDS-myelopathy* OR primary infectious myelopathy* OR HIV-VM* OR neurological manifestations of HIV/AIDS* OR Nosocomial myelopathy* OR Spinal cord syndrome/HIV/AIDS* OR Neuro-AIDS* OR Unknow cause myelopathy*OR infectious spinal cord disease* where * is the PubMed wildcard for every possible word beginning or ending. We did not consider other neurological manifestations beyond the scope of the current work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy and cohort selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe select all publications (case reports, case series, and observational cohort studies) reporting HIV-VM, IVIg Therapy during the initial search. Later we progressively s excluded all duplicate studies, those publications not meeting inclusion criteria because reported only HIV/AIDS, Primary myelopathy separately and HIV-VM not related with IVIg therapy, and those without an English translation.\u003c/p\u003e"},{"header":"Results","content":" \u003cp\u003eBetween 1st January 2010, and 30th September 2020, our literature search yielded 621 publications. After removing duplicate articles, we retained 457 unique records. Considering the title and abstracts, we discarded 21 journals, keeping 38 items, screening the full text we selected 32 publications regarding COVID-19/Neurological complications. Finally, we found a total of 2 publications referring to HIV-VM and IVIg. From all groups, we did not find any published study about no improvement of HIV-VM after IVIg treatment. See Appendix A: The PRISMA flow diagram of included studies for this review.\u003c/p\u003e "},{"header":"Case Presentation","content":" \u003cp\u003eMs. N Is a 26-years-old African lady admitted at Nelson Mandela Academic Central Hospital (NMACH) in Mthatha, South Africa. She presented in May 2020 with a history of inability to walk and confusion. We could not establish the duration of symptoms, signs, and the mode of onset in the admission chart, and she gave no further history due to her confusional state.\u003c/p\u003e \u003cp\u003eOf note, this patient was still in her puerperal phase. She was admitted in the maternity ward at NMAH two months ago with severe preeclampsia and HELLP syndrome. This entity is a severe form of preeclampsia characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) in a pregnant or puerperal patient (usually within seven days of delivery)]. Her clinical picture worsened by stage 3 acute kidney injury (creatinine was \u0026gt;\u0026thinsp;3 times the baseline), she had received intermittent hemodialysis, and renal function wholly recovered before discharge.\u003c/p\u003e \u003cp\u003eHer medical history was remarkable for HIV, with a CD4:1051cell/\u0026micro;L and a suppressed viral load (\u0026lt;\u0026thinsp;20copies/ml) on a modified first-line regimen (ABC/3TC/EFV). She is a known hypertensive patient hydrochlorothiazide and Amlodipine, and there is no previous history of target organ damage. However, according to her old chart that she had defaulted on her antihypertensive for about a month. Her family history was non-significant, and she was a non-smoker, never used illicit drugs, and occasionally used alcohol. She did not have any travel history outside Eastern Cape Province in South Africa.\u003c/p\u003e \u003cp\u003eOn examination, we found her to be obese (BMI 36\u0026nbsp;kg/m\u0026sup2;), with pink mucosal membranes, anicteric, and afebrile. Her vital signs demonstrated a tachycardia (heart rate: 130) and elevated BP: 147/109\u0026nbsp;mmHg. The patient was confused. No cranial nerve abnormalities or meningeal signs; she had bilateral mild horizontal vestibular nystagmus. Her motor examination revealed the power of 0/5 in all limbs (proximally and distally), with hypotonia in all limbs and absent deep tendons reflexes. The sensory test was exceedingly difficult to perform due to her confusional state, but she seemed to respond to light touch and pain. On her respiratory examination, we confirmed fine crepitation in the right lower zones of the chest.\u003c/p\u003e \u003cp\u003eGiven her acute presentation of flaccid quadriplegia, our differentials included Landry-Guillain- Barre syndrome and its variants, HIV-related neuropathies, metabolic derangements (hypokalaemia), vitamin B12 deficiency, CMV peripheral neuropathy, inflammatory myopathies, and neuromuscular junction disorders.\u003c/p\u003e \u003cp\u003eIn her investigations, the MRI brain was completely normal. The MRI spine showed diffuse cord atrophy with dorsal signal abnormality involving the lower cervical and thoracic spine, as shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (Appendix B). These findings made us think of HIV-VM and subacute combined degeneration of the spinal cord.\u003c/p\u003e \u003cp\u003eWe did an extensive serological and CSF workup to exclude both infectious and non-infectious causes of myelopathy. Blood levels for Vitamin B12 and folate were normal (491\u0026nbsp;pmol/l and 32,7\u0026nbsp;nmol/L, respectively), her CD4 was 1051cells/uL with a viral load of \u0026lt;\u0026thinsp;20copies/ml. Full blood count showed leucocytosis of 17\u0026thinsp;\u0026times;\u0026thinsp;109 /L with mild anemia (Hb 11.6\u0026nbsp;g/dl) and reactive thrombocytosis (platelet: 506\u0026thinsp;\u0026times;\u0026thinsp;109/L) high C reactive protein of 241\u0026nbsp;mg/L with negative blood cultures. Her U/E revealed hypokalaemia of 2.1\u0026nbsp;mmol/L, and calcium, magnesium, and phosphate were normal. Creatine kinase was normal (20\u0026nbsp;U/L), and her thyroid function tests: TSH: 5.9mIU/L, FT4 12.8\u0026nbsp;pmol/L.\u003c/p\u003e \u003cp\u003eHer CSF demonstrated high protein: 0.69\u0026nbsp;g/L, glucose 3.5\u0026nbsp;mmol/L, polymorphs: 0cells/uL, lymphocytes: 4 cells/uL, erythrocytes:240cells/UL.\u003c/p\u003e \u003cp\u003eRepeat CSF showed an adverse polymerase chain reaction for viral studies, including herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and JC virus. Serum and CSF cryptococcal antigen testing and Bartonella serology were negative. We did not detect CSF antibodies to aquaporin-4 and oligoclonal immunoglobulin bands. CSF VDRL was non-reactive.\u003c/p\u003e \u003cp\u003eWe exclude metabolic alkalosis and hypokalaemia, a state of mineralocorticoid excess because of hypertension, and we did a renin/aldosterone ratio. Then, the aldosterone renin ratio was 1.28(\u0026lt;\u0026thinsp;40), CT scan of adrenal glands was normal.\u003c/p\u003e \u003cp\u003eConsidering that there is no clear obstructive, vascular, or neoplastic lesion noted on imaging, the likelihood of the pathology being secondary to direct infection by HIV remains high.\u003c/p\u003e \u003cp\u003eThis patient was complicated by nosocomial pneumonia with type 1 respiratory failure. A gram-negative bacillus was cultured in her repeat blood and CSF.\u003c/p\u003e \u003cp\u003eHer treatment included Polygam 40\u0026nbsp;g daily intravenously for 5days, anti-retroviral: abacavir/lamivudine/efavirenz 1tablet daily orally, Piptaz 4,5\u0026nbsp;g intravenously six-hourly, Aldactone 100\u0026nbsp;mg orally bd, slow k 2 tablets po twice daily, Thiamine 100\u0026nbsp;mg po daily, Pyridoxine 25\u0026nbsp;mg po daily, and oxygen by facemask. In the management of the patient, the physiotherapists and occupational therapists worked hard. Her situation was discussed with the intensive care unit considering her respiratory failure, but she was declared poor prognosis and not accepted.\u003c/p\u003e \u003cp\u003eHer potassium improved to normal, but she remained with power 0/5 in all limbs. Despite IV Immunoglobulin therapy at the higher dosages, the patient did not improve and demise on June 8, 2020.\u003c/p\u003e "},{"header":"Discussion And Conclusion","content":" \u003cp\u003eIn HIV-VM, there is spinal cord atrophy, which mainly involves the thoracic cord. Sometimes the cervical cord is involved as well [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], in which case patients will present with quadriparesis like our patient. HIV-VM has been documented in the past to be associated with HIV-Neurocognitive disorders (HIV-NCD) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and sometimes we can see the same damage of the spinal cord, in the cerebral hemispheres. In our case, the MRI of the brain was completely normal.\u003c/p\u003e \u003cp\u003eThe spinal cord atrophy results from vacuoles' formation mainly in the posterolateral columns (thereby mostly involving the corticospinal tract and the fasciculus Gracilis and Cuneatus (like vitamin B12 deficiency) leading to subacute combined degeneration of the spinal cord. In which situation, B12 level in serum is low, and those patients respond very well to parenteral B12. The exact pathophysiology resulting in the formation of vacuoles (still unclear), but proposed mechanisms include:\u003c/p\u003e \u003cp\u003e1) Activation of macrophages in the CNS, which can cause the release of myelotoxic substances or impair the metabolism of Vit B12.\u003c/p\u003e \u003cp\u003e2) Oligodendrocyte/myelin injury from the presence of TNF alpha and other cytokines. These will also augment macrophage activity, which can damage myelin.\u003c/p\u003e \u003cp\u003e3) Direct infection of astrocytes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInvestigations made by Petito et al. confirmed that 26.8% of patients who had autopsy proven VM had signs and symptoms of VM [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe usual HIV-VM presentation is progressive spastic paraparesis, ataxic gait, sphincter disturbance, and erectile dysfunction with no sensory level. Usually occurring in the setting of advanced HIV, and sometimes associated with HIV-NCD.\u003c/p\u003e \u003cp\u003eTo perform laboratory and radiological investigations to exclude other causes of possible spinal cord pathologies is a good recommendation. CSF tests should include cytology, protein level, MCS, CMV, EBV, HSV, TB, JCV, Picornavirus, flavivirus, rhabdovirus, Treponema pallidum, Borellia, and HIV Viral load. Indication of MRI to rule out any other cause of intramedullary/extradural lesions. In the setting of HIV-VM, the MRI may show cord atrophy in the thoracic and cervical regions. The lumbar area can be affected in more rare instances. Also increased T2 weighted signalling of the posterolateral cord usually.\u003c/p\u003e \u003cp\u003eCMV polyradiculomyelitis can present a similar to HIV-VM and is usually distinguishable by the absence of spasticity on exam and MRI findings of diffuse, multisegmented signal abnormalities seen in both grey and white matter, with thickening/enhancement of nerve roots [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSomatosensory evoked potential (SSEP) may also be supportive if it shows a functional lesion of the spinal cord, but it does not have any pathognomonic pattern [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHIV-VM is a diagnosis of exclusion. Therefore, to rule out other causes of myelopathy, an extensive workup must be done.\u003c/p\u003e \u003cp\u003eA clinical criterion for diagnosing HIV-VM was created by Chong et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003e(Appendix B).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCriteria for clinical diagnosis of AIDS-associated myelopathy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1.Male or female, over 18\u0026nbsp;years old, with documented HIV-1 infection.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. AIDS-associated myelopathy, with or without neuropathy and dementia,\u003c/p\u003e \u003cp\u003edefined as:\u003c/p\u003e \u003cp\u003ea. \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ePresence of at least two of the following symptoms\u003c/span\u003e:\u003c/p\u003e \u003cp\u003e\u0026bull; Paraesthesia and/or numbness in lower extremities or all four limbs\u003c/p\u003e \u003cp\u003e\u0026bull; Weakness of the limbs\u003c/p\u003e \u003cp\u003e\u0026bull; Unsteady, stiff, or uncoordinated gait\u003c/p\u003e \u003cp\u003e\u0026bull; Sensation of electric shock through the back and legs on flexion of the neck (Lhermitte\u0026rsquo; sign).\u003c/p\u003e \u003cp\u003e\u0026bull; Increased urinary frequency, urgency, incontinence, or retention\u003c/p\u003e \u003cp\u003e\u0026bull; Faecal incontinence or retention\u003c/p\u003e \u003cp\u003e\u0026bull; Sexual dysfunction with erectile impairment.\u003c/p\u003e \u003cp\u003eb. \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ePresence of at least two of the following neurologic signs\u003c/span\u003e\u003c/p\u003e \u003cp\u003e\u0026bull; Reduction in vibratory and/or position sensation\u003c/p\u003e \u003cp\u003e\u0026bull; Brisk deep tendon reflexes\u003c/p\u003e \u003cp\u003e\u0026bull; Abnormal plantar response\u003c/p\u003e \u003cp\u003e\u0026bull; Lhermitte\u0026rsquo; sign\u003c/p\u003e \u003cp\u003e\u0026bull; Spastic, ataxic, or ataxo-spastic gait.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Signs and symptoms of AIDS-associated myelopathy for at least 6 weeks before consultation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Abnormal somatosensory evoked potential measurement.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. No other determinable cause for spinal cord disease by serologic and CSF studies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOur patient presentation was atypical because she was virologically suppressed (VL\u0026thinsp;\u0026lt;\u0026thinsp;20copies/ml), and her CD4 was 1051 cells/uL. It is important to remember that the CSF viral load measurement would have been essential to check for 'CSF viral escape.' We did not check for HIV-VL in the CSF looking to 'viral escape,' We did not have a large enough CSF sample to send for this test. Her confusion could have been due to HIV-NCD, but since she had nosocomial sepsis and hypokalaemia, then it was not the only cause. Also, she had flaccid quadriplegia and absent global reflexes, which is not typical for HIV-VM. Bloods showed hypokalaemia, which can explain an associated peripheral neuropathy worsened by HIV infection and subclinical hypothyroidism, but the weakness persisted in the potassium's correction. Vitamin B12 and folate levels were normal; this ruled out a subacute combined degeneration of the spinal cord. We did an extensive blood and CSF workup for other causes of weakness, which all came back negative. The spinal cord MRI supported the clinical suspicion and showed cord atrophy as well as T2 weighted hyperintensity of the cervicothoracic spine. We continued her cART and gave her a trial of IVIg, which did not improve the condition. Unfortunately, she developed nosocomial sepsis and died.\u003c/p\u003e \u003cp\u003eUnfortunately, there was no reliable way to confirm vacuolar myelopathy pre-mortem, and the final diagnosis remained a diagnosis of exclusion.\u003c/p\u003e \u003cp\u003eUnfortunately, in our center, we currently do not have access to EMG/NCS.\u003c/p\u003e \u003cp\u003eThe treatment of VM remains an unresolved matter. Therefore, there has been no effective treatment of HIV-VM yet other than anti-retroviral medications. Perhaps, prescribing cART such as Zidovudine/Abacavir, which has an excellent CNS penetration, should be implemented earlier on in patients with HIV-VM. Another option if the patient is poorly responsive would be to send for CSF-VL and to test for mutations in the CSF. Treatment with L-methionine and IVIg so far has not yielded any beneficial results [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2009, Lindkvist \u003cem\u003eet al.\u003c/em\u003e studied nine HIV-infected patients with Guillain\u0026ndash;Barr\u0026eacute; syndrome that received the HAART and demonstrated that IVIg administration in high doses (30\u0026nbsp;g/day for five days) reduce the pool of HIV in the memory of CD4\u0026thinsp;+\u0026thinsp;T-cells [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. At the same time, Cikurel \u003cem\u003eet al\u003c/em\u003e. studied a series of patients with VM to evaluate IVIg's efficacy. They demonstrated that all patients reported reduced palsy in the lower limbs, due to the anti-inflammatory effect of IVIg, causing suppression of the complement cascade, inhibition of production of pro-inflammatory cytokines mainly by monocytes, and reinforcing the anti-idiotypic response, leading to neutralization of growth factors (B-cell), and inhibition of the T-cell proliferations with clonal expansion and activation of T-reg cells and downregulation of the Th17 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, some authors reported that binding of anti-idiotypic antibodies with epitopes (IgG, and IgM) on the B-lymphocytes and thus inhibiting the production of autoimmune antibodies appears to be the most effective action of IVIg increasing the intrathecal production of oligoclonal Ig, which is a marker for the chronic autoimmune inflammatory process in the CNS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The same author highlighted IVIg treatment's viability in cases presenting HIV-VM, mainly when autoimmune reactions are under suspicion. We like to highlight the study done by Cikurel et al. because it is the only report delivering a number of cases of HIV-VM treated and an important number of improvements (n\u0026thinsp;=\u0026thinsp;17) after being treated with Ig at the dosage of 2\u0026nbsp;g/kg for two days of IV infusion but they did not report any improvement of spastic paraparesis and urinary incontinence [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and they did not report the method to measure the improved symptoms and signs. Other authors also report a complete recovering of symptoms and signs from HIV-VM after being treated with highly active antiretroviral therapy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] but the procedure to measure the improvements are also questionable.\u003c/p\u003e \u003cp\u003eReviewed in this manuscript is a case where an atypical HIV-VM presentation did not respond when treated with cART and intravenous immunoglobulin (IVIg), which can doubt therapy's efficacy. Even though our patient did not show any signs of improvement after IVIg therapy, to perform a placebo-controlled clinical trial of IVIg in patients with HIV-VM can be other recommendations to confirm or deny the real benefits of this medication.\u003c/p\u003e"},{"header":"Abbreviations","content":" \u003cp\u003eABC/3TC/EFV - Abacavir/ Lamivudine / Efavirenz\u003c/p\u003e \u003cp\u003eBMI \u0026ndash; Basal Metabolic Index\u003c/p\u003e \u003cp\u003ecART- combined Antiretroviral Therapy\u003c/p\u003e \u003cp\u003eCMV \u0026ndash; Cytomegalovirus\u003c/p\u003e \u003cp\u003eCSF - Cerebro Spinal Fluid\u003c/p\u003e \u003cp\u003eCSF-VL \u0026ndash; Cerebro Spinal Fluid Viral Load\u003c/p\u003e \u003cp\u003eCT \u0026ndash; Computed Tomography\u003c/p\u003e \u003cp\u003eEBV \u0026ndash; Epstein-Barr Virus\u003c/p\u003e \u003cp\u003eEMG \u0026ndash; Electromyography\u003c/p\u003e \u003cp\u003eFT4 \u0026ndash; Thyroxine\u003c/p\u003e \u003cp\u003eHAART \u0026ndash; Highly Active Anti-Retroviral Therapy\u003c/p\u003e \u003cp\u003eHb \u0026ndash; Haemoglobin\u003c/p\u003e \u003cp\u003eHIV- Human immunodeficiency Virus\u003c/p\u003e \u003cp\u003eHIV-NCD - Human Immunodeficiency Virus-associated Neurocognitive Disorders\u003c/p\u003e \u003cp\u003eHIV-VL \u0026ndash; Human Immunodeficiency Virus-associated Viral Load\u003c/p\u003e \u003cp\u003eHIV-VM \u0026ndash; Human Immunodeficiency Virus-associated Vacuolar Myelopathy\u003c/p\u003e \u003cp\u003eHTLV \u0026ndash; Human T-cell Lymphotropic Virus type 1\u003c/p\u003e \u003cp\u003eHSV \u0026ndash; Herpes Simplex Virus\u003c/p\u003e \u003cp\u003eIVIg \u0026ndash; Intravenous Immunoglobulins\u003c/p\u003e \u003cp\u003eJCV \u0026ndash; John Cunningham Virus\u003c/p\u003e \u003cp\u003eMCS -Microscopy, Culture, Sensitivity\u003c/p\u003e \u003cp\u003eMRI \u0026ndash; Magnetic Resonance Imaging\u003c/p\u003e \u003cp\u003eNCS \u0026ndash; Nerve Conduction Studies\u003c/p\u003e \u003cp\u003eNMACH - Nelson Mandela Academic Central Hospital\u003c/p\u003e \u003cp\u003eTSH \u0026ndash; Thyroid Stimulating Hormone\u003c/p\u003e \u003cp\u003eU/E \u0026ndash; Urea and Electrolytes\u003c/p\u003e \u003cp\u003eVDRL \u0026ndash; Venereal Disease Research Lab Test\u003c/p\u003e \u003cp\u003eVL \u0026ndash; Viral Load\u003c/p\u003e \u003cp\u003eVZV \u0026ndash; Varicella-Zoster Virus\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eEthical issue and consent to publish:\u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003e We obtained the written permission from our patient's family, and they agreed to include all necessary information for publication purposes. All authors certify that we did not reveal names, initials, and other identity issues of this patient in this publication, and complete anonymity is guaranteed.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eConsent for publication:\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003eThe necessary consent for publication from the family is received.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eAvailability of data: \u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003eData used on this study are available on reasonable request from the corresponding author\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eCompeting interest: \u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003eAll authors: reported no conflicts of interest.\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eFunding: \u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003eWe did not receive financial support or any contribution to this publication.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eAuthor's contribution\u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003e: All authors contributed equally to the elaboration of this manuscript. MT and SJ collected data and planning this report, JG and LIV wrote the first draft \u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan lang=\"EN-GB\"\u003eand reviewed bibliographically, TB and HFS wrote the final piece. All authors reviewed the final manuscript, made corrections, and agreed for publications.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan lang=\"EN-GB\"\u003eAcknowledgment: \u003c/span\u003e\u003c/strong\u003e\u003cspan lang=\"EN-GB\"\u003eSpecial thanks to Dr. C. Naidoo and Dr. Oompie from the Department of Radiology, NMACH. Mthatha, South Africa, for the radiological investigations done and we inform about it.\u003c/span\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWuliji N, Mandell MJ, Lunt JM, Merando A. HIV-Associated Vacuolar Myelopathy, and HIV-Associated Dementia as the Initial Manifestation of HIV/AIDS. Case Report 2019; 3842425:4-11. doi.org/10.1155/2019/3842425.\u003c/li\u003e\n\u003cli\u003eRobinson-Papp, J., George, M.C., Nmashie, A., Weisz, D. and Simpson, D.M., Lower-extremity Dynamometry as a Novel Outcome Measure in a Double-blind, Placebo-controlled, Feasibility Trial of Intravenous Immunoglobulin (IVIG) for HIV-associated Myelopathy. Inn Clin Neur.2018;15(1):28.\u003c/li\u003e\n\u003cli\u003ePrakhova LN, Ilves AG, Kizhlo SN, Savintseva ZI. Successful treatment of human immunodeficiency virus associated highly active anti-retroviral therapy-resistant vacuolar myelopathy with intravenous immunoglobulin. Ann Indian Acad Neurol 2020; 23:220-222.\u003c/li\u003e\n\u003cli\u003eGarg RK, Hardeep M, Neeraj N. Approach to a case of myeloneuropathy. Ann Ind Acad Neurol. 2016; 19:183-187.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eMadden GR, Fleece ME, Gupta A, Lopes MBS, Heysell S, Arnold CJ, Wispelwey B. HIV-Associated Vacuolar Encephalomyelopathy, Open Forum Inf Dis. 2019;6(10):366. \u003ca href=\"https://doi.org/10.1093/ofid/ofz366\"\u003ehttps://doi.org/10.1093/ofid/ofz366\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eBrew BJ. Chapter two. In: The Neurology of HIV Infection. Amsterdam, Nederland. Elsevier; Ed 1, 2018.\u003c/li\u003e\n\u003cli\u003ePandey K, MD. Chief Editor: Niranjan N Singh. HIV-Associated Vacuolar Myelopathy. Updated April 2018. \u003ca href=\"https://emedicine.medscape.com/article/1167064\"\u003ehttps://emedicine.medscape.com/article/1167064\u003c/a\u003e. (We did the last review on August 30, 2020).\u003c/li\u003e\n\u003cli\u003eTyor WR, Wesselingh SL, Griffin JW, McArthur JC, and Griffin D. A unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. J Acq Imm Def Syn Hum Retrovirol. 1995;9(4):379-388.\u003c/li\u003e\n\u003cli\u003eRobinson-Papp J, George MC, Nmashie A, Weisz D, Simpson DM. Lower-extremity Dynamometry as a Novel Outcome Measure in a Double-blind, Placebo-controlled, Feasibility Trial of Intravenous Immunoglobulin (IVIG) for HIV-associated Myelopathy. Innov Clin Neurosci. 2018;15(1-2):28-32.\u003c/li\u003e\n\u003cli\u003eCikurel K, Schiff L, Simpson DM, Pilot study of intravenous immunoglobulin in HIV-associated myelopathy. AIDS Patient Care and STDs. 2009;23(2):75\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eChong J, Di Rocco A, Tagliati A, F. Danisi D, Simpson M, Atlas SW. MR findings in AIDS-associated myelopathy. Am J Neuroradiol. 1999;20(8):1412\u0026ndash;1416.\u003c/li\u003e\n\u003cli\u003eWuliji N, Mandell MJ Lunt JM, Morando A. HIV-associated vacuolar myelopathy and HIV-associated dementia as the initial manifestation of HIV/AIDS. Case Report Inf Dis. 2019; 19:384.\u003c/li\u003e\n\u003cli\u003eTan SV, R J Guiloff RJ. Hypothesis about the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. Psychiatry. 1998; \u003cstrong\u003e65:23\u003c/strong\u003e\u0026ndash;28.\u003c/li\u003e\n\u003cli\u003ePetito CK, Navia BA, Cho ES, Jordan BD, George DC, Price RW. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. New Eng J Med. 1985;312(14):874\u0026ndash;879.\u003c/li\u003e\n\u003cli\u003eP. Portegies, L. Solod, P. Cinque, et al., \"Guidelines for the diagnosis and management of neurological complications of HIV infection,\" Eur J Neurol. 2004;11(5):297\u0026ndash;304.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eDi Rocco A, Werner P, Bottiglieri T, et al. Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study. Neurology, 2004; 63:1270\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eLindkvist A, Ed\u0026eacute;n A, Norstr\u0026ouml;m MM, Gonzalez VD, Nilsson S, Svennerholm B,\u0026nbsp;\u003cem\u003eet al.\u003c/em\u003e\u0026nbsp;Reduction of the HIV-1 reservoir resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: A proof-of-concept study. AIDS Res Ther. 2009; 6:15.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eStaudinger R, Henry K. Remission of HIV myelopathy after highly active antiretroviral therapy.\u0026nbsp;Neurology.\u0026nbsp;2000; 54:267\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eDi Rocco A, Tagliati M. Remission of HIV myelopathy after highly active antiretroviral therapy.\u0026nbsp;Neurology.\u0026nbsp;2000; 55:456.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Human immunodeficiency virus, associated lesions of the nervous system, human immunodeficiency virus-associated myelopathy, intravenous immunoglobulin administration, case report, HIV-vacuolar myelopathy.","lastPublishedDoi":"10.21203/rs.3.rs-89435/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-89435/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u0026nbsp;\u003c/strong\u003eHere, we report an atypical presentation of HIV-vacuolar myelopathy and search the available medical literature about atypical presentations of human immunodeficiency virus associate vacuolar myelopathy (HIVVM) and immunoglobulin therapy response.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase\u003c/strong\u003e: A 26-year-old lady who was four weeks postpartum presented to us with acute flaccid quadriparesis, with no sensory level. Extensive workup ruled out other causes of myelopathy.\u0026nbsp;\u003c/p\u003e\u003cp\u003eShe developed a stage 3 acute kidney injury, and MRI showed diffuse cord atrophy involving the lower cervical and thoracic cord. The patient received IV-immunoglobulin, ARV's, and supportive therapy with inadequate response. Unfortunately, she developed nosocomial pneumonia and died.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eDiscussion:\u0026nbsp;\u003c/strong\u003eIn HIV-VM, there is spinal cord atrophy, which mainly involves the thoracic cord. In our case, this pathological process also affected the spinal cord's cervical region, leading to flaccid tetraplegia, no responding to the treatment, including intravenous immunoglobulin.\u003c/p\u003e","manuscriptTitle":"Atypical HIV-Vacuolar Myelopathy.\u0026nbsp;Case Report and Literature Review.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-14 14:37:13","doi":"10.21203/rs.3.rs-89435/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-11-27T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-19T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-11-19T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewersInvited","content":"","date":"2020-11-12T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-10-07T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-10-06T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-06T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63788008-858a-497e-a2ac-27cce0508d01","owner":[],"postedDate":"October 14th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":778389,"name":"Health Economics \u0026 Outcomes Research"},{"id":778390,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2021-02-07T15:03:36+00:00","versionOfRecord":{"articleIdentity":"rs-89435","link":"https://doi.org/10.1186/s40001-021-00483-0","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2021-02-01 15:02:54","publishedOnDateReadable":"February 1st, 2021"},"versionCreatedAt":"2020-10-14 14:37:13","video":"","vorDoi":"10.1186/s40001-021-00483-0","vorDoiUrl":"https://doi.org/10.1186/s40001-021-00483-0","workflowStages":[]},"version":"v1","identity":"rs-89435","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-89435","identity":"rs-89435","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}