- Email: [email protected]
HIV infection associated neuromyelitis optica spectrum disorder: Clinical features, imaging findings, management and outcomes
Multiple Sclerosis and Related Disorders 27 (2019) 289–293
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
HIV infection associated neuromyelitis optica spectrum disorder: Clinical features, imaging findings, management and outcomes
T
⁎
Thomas Mathewa, , Amrutha Avatia, Delon D’Souzaa, Manjusha Therambila, Anita Angela Baptista, Asha Shajia, Raghunandan Nadiga, Smitha Mary Rockeyb, Gareth Parrya a b
Department of Neurology, St. John's Medical College Hospital, Sarjapura Road, Bengaluru, Karnataka 560034, India Department of Microbiology, St. John's Medical College Hospital, Sarjapura Road, Bengaluru, Karnataka 560034, India
A R T I C LE I N FO
A B S T R A C T
Keywords: HIV infection Neuromyelitis optica Neuromyeltis optica spectrum disorders Anti aquaporin 4 antibody
Introduction: HIV Infection associated NMOSD (HIV-NMOSD) is a recently recognized entity. Management of patients with HIV-NMOSD is a challenge. Here we report our own experience of HIV-NMOSD along with a complete review of all the cases of HIV-NMOSD reported in literature. Objective: Describe the clinical features, radiological findings, treatment patterns and outcomes in patients with HIV-NMOSD. Methods: The details of all cases of HIV- NMOSD were searched from our NMOSD registry. A literature search was also done using the terms NMO, NMOSD and HIV infection in PUBMED, Google Scholar and EMBASE. The details of all the reported cases and cases from our registry were collected and analyzed. Results: Six cases of HIV-NMOSD were identified from the literature and one from our registry. There were four males and three females with age ranging from 8 years to 49 years. Duration of HIV infection ranged from newly detected to 15 years. Optic neuritis followed by myelitis was the commonest presentation, occurring in 5 out of 7 patients. 3 patients were anti-aquaporin 4 antibody positive while 3 were negative and in one anti- aquaporin 4 antibody assay was not done. All patients received immunomodulatory treatment. 5/7 patients had poor recovery from acute attacks but no patient had further relapses while on immunomodulatory treatment and antiretroviral therapy. Conclusion: HIV associated NMOSD is a recently recognized entity. A high index of suspicion is needed to diagnose these patients. In all patients with HIV infection presenting with optic neuritis or/and myelitis, anti aquaporin 4 antibody status should be checked and in all patients of NMOSD, HIV infection should be ruled out.
1. Introduction
NMOSD.
HIV infection is well known to produce an immunodeficiency state, but physicians rarely recognize it as a cause of autoimmunity. A hypo functioning immune state may co-exist with a hyper functioning immune state in the same individual. Though the exact reason for this is unknown it may be due to complicated immune dysregulation in various B and T cell pathways. NMO spectrum disorders are autoimmune inflammatory demyelinating diseases of the central nervous system resulting from auto antibodies attacking the nervous system antigens like aquaporin-4. HIV infection associated Neuromyelitis Optica Spectrum Disorder (HIV-NMOSD) is a recently recognized entity. HIVNMOSD presents an unusual clinical scenario posing several diagnostic and management challenges. Here we describe the clinical features, imaging findings, treatment and outcomes of patients with HIV-
2. Methods
⁎
Case records of all the patients of NMOSD in our NMO/MS clinic was searched for the presence of HIV infection. A literature search was done in Pub med, Google Scholar and Embase using terms HIV, NMO, NMOSD. Clinical features, magnetic resonance imaging findings, treatment strategies and outcomes of all patients were recorded and analyzed. 3. Results From our registry we identified 25 cases of NMOSD from June 2013 to June 2018. Only one patient had HIV infection and NMOSD. A
Corresponding author. E-mail address: [email protected] (T. Mathew).
https://doi.org/10.1016/j.msard.2018.11.014 Received 31 May 2018; Received in revised form 3 November 2018; Accepted 12 November 2018 2211-0348/ © 2018 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 27 (2019) 289–293
T. Mathew et al.
literature search identified six further cases. There were four males and three females with age ranging from 8 years to 49 years. Duration of HIV infection ranged from newly detected to 15 years. 3 patients were African American in ethnicity, one was African, two were Caucasians and one was Asian in origin. Four patients were on antiretroviral therapy while three were drug naïve. 4. Case description A 37-year-old woman presented with painful eye movements and impaired vision in the left eye of 3 days duration. On examination visual acuity on the left was finger counting at one meter and there was an afferent pupillary defect with a normal disc on fundoscopy. The right eye was normal and there were no other neurological deficits. A diagnosis of retrobulbar neuritis was made. She had known HIV infection for the past 11 years and was on anti-retroviral therapy with tenofovir, lamivudine and efavirenz for the past 2 years. Her CD4 count at admission was 290 cells /cmm. MRI Brain with contrast was normal. Visual Evoked Potential study showed prolonged P 100 latency in the left eye. Cerebrospinal fluid (CSF) analysis was normal. CSF polymerase chain reaction for Herpes simplex, cytomegalovirus, Epstein-Barr virus, JC virus, Toxoplasma and Mycobacterium tuberculosis was negative. CSF VDRL was negative. India ink stain for cryptococcus and cryptococcal antigen assay were negative in CSF. She was treated with Methylprednisolone I gm intravenous (IV) daily for five days followed by oral prednisone, tapered over 2 weeks. She recovered completely by 4 weeks. After 2 months she presented to us again with hiccups, vomiting, tingling of upper limbs, urinary urgency, frequency and constipation. On examination power was normal but she had bilateral brisk reflexes with extensor plantar responses. MRI spinal cord showed longitudinally extensive transverse myelitis (LETM) extending from upper dorsal spinal cord to medulla, predominantly involving the central cord. MRI brain was normal. In view of LETM a diagnosis of NMOSD was considered and serum aquaporin 4 antibody assay was performed. Aquaporin assay was done using a cell based immune assay using transfected cell lines for in vitro determination in serum/plasma for qualitative/ semi quantitative determination of human IgG antibodies to Aquaporin −4 receptor. (Euroimmune, Indirect immunofluorescence on transfected cells at a titer of 1:10 dilution). The serum aquaporin antibody assay was positive. MOG antibody assay was not performed as it was not available. Her CD 4 count during the current admission was 180 cells/cmm and serum HIV viral load was less than 40 copies/ml. ANA, double stranded DNA, anti SSA and anti SSB antibody were all negative. Serum Angiotensin Converting Enzyme levels were normal. A diagnosis of HIV associated NMOSD was made and she was again treated with IV Methylprednisolone 1 g/day for 5 days followed by prednisolone 60 mg/day for 2 weeks followed by a taper by 10 mg/ week. After reaching 10 mg/day she was maintained on the same dose for another one month. After that prednisolone was further reduced to 7.5 mg/day. While she was on prednisolone 7.5 mg/day she developed recurrence of upper back pain and bilateral upper limb and lower limb weakness. The interval between the first attack of myelitis and second attack of myelitis was six months. Repeat MRI spine showed enhancing cervical spinal cord lesion suggestive of recurrence of LETM. She was treated again with IV methylprednisolone 1 g per day for another 5 days and followed by prednisolone 60 mg/day. After few weeks of therapy, she started developing steroid related side effects and developed Cushingoid features. Azathioprine 50 mg/day was added as a steroid sparing agent. After 4 days of azathioprine patient came back with severe hair loss and oral ulcers. She also developed pancytopenia and was treated with broad spectrum antibiotics and granulocyte monocyte colony stimulating factor. Azathioprine induced pancytopenia was considered and it was stopped. Patient improved over 10 days and was given steroids alone. At one year of follow up she was doing well on prednisone 15 mg/day. At 2 year follow up she is doing very well,
Fig. 1. Clinical attacks and corresponding CD4 counts.
without any relapse on a maintenance dose of prednisolone 10 mg/day. Her CD4 counts during various clinical attacks are shown in Fig. 1. The details of all the other cases of HIV-NMOSD collected from literature search are summarized in Table 1. The most common presentation was optic neuritis followed by myelitis seen in 5/7 patients. One patient had myelitis followed by optic neuritis and another patient had only recurrent myelitis. Three were anti aquaporin 4 antibody positive and three were negative and in one antibody was not tested. Two patients were treated with steroids, two with rituximab, two with azathioprine and one with mycophenolate mofetil while one was treated with anti retroviral therapy alone. All the newly diagnosed cases were treated with antiretroviral drugs along with immune modulatory treatment. Though most acute attacks (5/7) had resulted in a permanent disability, there were no relapses after immune modulatory treatment and antiretroviral therapy. 5. Discussion Although physicians usually consider HIV infection as an immunodeficiency state, autoimmune diseases like Guillain-Barre syndrome, Chronic Inflammatory Demyelinating Polyneuropathy, Systemic Lupus Erythematosis, Sarcoid and Anti-Phospholipid Antibody syndrome are known to occur in these patients. Autoimmune disorders may occur at the time of seroconversion, when immune competence is still active, or can occur after anti-retroviral therapy is started, when the CD 4 count improves, a phenomenon called Immune Reconstitution syndrome (IRIS). IRIS has classically been described with respect to opportunistic infections or malignancies. But literature review reveals various case reports/series of autoimmune conditions like Graves disease (Vos et al., 2006; Chen et al., 2005), Sarcoidosis (Gomez et al., 2000; Foulon et al., 2004) and Autoimmune hepatitis (O'Leary et al., 2008) which have been noted after initiation of HAART and improving CD4 counts. However, autoimmune diseases were described in HIV infected patients before the use of anti retroviral therapy suggesting that autoimmunity may not be entirely related to IRIS (Blanche et al., 2000). The case of HIV-NMOSD described here developed clinical attacks when the CD4 counts were dropping (Fig. 1), suggesting that the autoimmunity may be directly related to the viral activity and not IRIS. The exact mechanism of autoimmunity in HIV infection is not clear but immune dysregulation is a characteristic feature of HIV infection. The hallmark of the disease, the loss of CD4+ T cells, may result from this immune activation. HIV-1 production generates alloantigens that 290
291
Male
Male
Female
8
37
Male
32
45
Male
46
Female
Female
41
49
Sex
Age
Indian
Caucasian
African American
African American
African American
Caucasian
African
Ethnicity
11 years
New
New
15 years
5 years
12 years
11 years
Duration of HIV
On ART for 2 years
Not on ART
Not on ART
On ART
On ART
On ART
Not on ART
ART treatment
290/mm < 40
430,000
1134/mm3
3
583,451
< 3000
>350/mm3
109/ mm3
41,000
1029/mm3
<3000
1150
499/mm3
>350/mm3
Viral Load (RNA/ml)
CD4 count
Table 1 Details of all cases of HIV –NMOSD from literature with the current case.
Optic neuritis followed by myelitis
Recurrent myelitis Unilateral Optic neuritis followed by myelitis Unilateral Optic neuritis followed by myelitis Bilateral optic neurtitis followed by myelitis Myelitis followed by Optic Neuritis
Unilateral Optic neuritis followed by myelitis
Clinical features
Positive
Negative
Negative in CSF (not tested in serum)
Positive
Negative
Positive
Not done
Serum Anti Aquaporin 4 antibody
Methylprednisolone
Corticosteroids// Plasma exchange/IVIG
Mehtylprednisolone
Methylpredisolone/ Plasma exchange
Methylpredisolone/ Plasma exchange
None
Mehtylprednisolone
Acute Treatment
Steroids (Azathioprine produced hair loss and bone marrow suppression)
Rituximab and ART
Ritonavir, atazanavir, and emtricitabine-tenofavir
Mycophenolate Mofetil
Rituximab
Azathioprine
Steroids + LamivudineZidovudine/Nelfinavir
Disease modifying therapy
No relapse after rituximab and ART Good / No recurrence after 2 years/Predisolone 15 mg/day
No recovery of left eye blindness/ paraplegia, but no relapse No recovery of right eye blindness/ mild recovery of spastic paraplegia No recovery for vision, myelopathy improved significantly. Had paraplegia did not recover
Good/No recurrence at 5 months/ predisolone 15 mg alternate days Good
Outcome
Mathew et al 2018
Olson et al., 2015
Delgado et al., 2014
Feyissa et al., 2013
Salazar et al., 2013 Feyissa et al., 2013
Blanche et al., 2000
Study
T. Mathew et al.
Multiple Sclerosis and Related Disorders 27 (2019) 289–293
Multiple Sclerosis and Related Disorders 27 (2019) 289–293
T. Mathew et al.
synthesis. HIV virion protein Nef has been shown to promote proliferation of B cells into immunoglobulin producing plasma cells causing hypergammaglobulinemia. Another proposed mechanism is stimulation of CD27 memory B cells by HIV activated T cells to become plasma cell-like cells which produce immunoglobulins (Delgado et al., 2014). This autoimmunity appears to be unrelated to IRIS as it has been described in ART naïve patients (Berger et al., 1989; Olson et al., 2015). An alternative mechanism of HIV related NMOSD is that infection of astrocytes with the HIV virus and consequent damage to the astrocytes (Feyissa et al., 2013). NMOSD can be associated with a wide range of autoimmune diseases but clinicians rarely diagnose NMOSD in cases of HIV infection and HIV-associated NMOSD is rarely mentioned in the conventional classification of NMOSD. Viral infections like herpes zoster are known to trigger NMOSD (Heerlein et al., 2009; Park et al., 2013). Similarly HIV may also trigger NMOSD because of its ability to dysregulate immune system. HIV-NMOSD needs to be added to the list of HIV-associated neurological disorders and NMO spectrum disorders. Unless there is a high index of suspicion the diagnosis of NMOSD may be missed in a case of HIV infection. In all patients of HIV related optic neuritis or myelitis, aquaporin-4 antibody assay should be done to diagnose HIV-NMOSD. It will also be prudent to check HIV status in all patients with NMOSD.
trigger the immune system directly. HIV-1 components may directly stimulate immune cells, typical example being the stimulation of monocytes and macrophages by Nef and Vpr. HIV-1 RNA interacts with the pattern recognition receptors TLR-7 and TLR-9 in plasmacytoid dendritic cells and induces the production of Interferon (IFN)-a by these cells. In addition, it has been suggested recently that the presence of HIV DNA in the cytoplasm of target cells leads to caspase-1 activation and to the release of pro-inflammatory cytokines including interleukin (IL)−1b (Younas et al., 2016). The HIV-1 envelope triggers signal transduction through binding to chemokine receptors on the surface of the target cell. CCR5 or CXCR4 engagement by HIV envelope results in altered chemotaxis and trafficking as well as alterations of cell cycle. CCR5 cross-linking on monocytes and macrophages triggers production of IL-1β and TNF-α (Boasso et al., 2009). Laboratory markers of T cell activation and B cell activation, activation of monocytes and dendritic cells (DCs), and natural killer cells are typically and persistently elevated during untreated infection . After the commencement of antiretroviral therapies as circulating CD4+ T cell numbers rise, these inflammatory markers improve yet in many, and especially among those who fail to restore circulating CD4+ T cell numbers, persistent immune activation persist. It is plausible to attribute much of the activation/inflammation in untreated infection directly to HIV replication. Though HIV replication is attenuated dramatically in most ART-treated patients, with sensitive enough assays, low levels of virus often can be found in plasma. HIV RNA can be found in lymph node and gut mucosal tissues of patients on anti retro viral therapies. These viral products can drive activation of both adaptive and innate immune responses (Lederman et al., 2013). Mere presence of HIV viral DNA in the cytoplasm of target cells, might induce immune activation (Younas et al., 2016). The first report of HIV associated demyelinating disorders were by Berger et al., in 1989 where he described 7 cases of MS like illness which probably was NMOSD (Berger et al., 1989), but anti aquaporin-4 antibodies had not been discovered at that time. A case of HIV-associated NMOSD was described by Blanche et al. (2000). Their case was of a 41 year old lady, with HIV infection of 11 years duration, with a normal CD4 count. She was not on treatment with anti-retroviral drugs at the time of presentation. Secondary causes of optic neuritis and myelitis were ruled out. Aquaporin-4 antibody assay was not available at that time. However, this case again indicates that HIV-NMOSD is an independent entity and not a part of IRIS. Except the case of Olson et al., all the patients were infected with HIV for more than 5 years (Olson et al., 2015). Of the 7 patients, 3 were aquaporin- antibody positive, three were negative and in one it was not done, indicating that in HIV-infected patients, both seropositive and seronegative NMOSD can occur. There were no features distinguishing aquaporin positive HIV-NMOSD from aquaporin negative HIV-NMOSD. The phenotype of NMOSD in this series of patients did not differ from those without HIV infection. Five had optic neuritis followed by myelitis while one had myelitis followed by optic neuritis. One patient had only recurrent myelitis but the aquaporin-4 antibody was positive (Salazar et al., 2013). Management of these patients does not differ from patients with NMOSD without HIV infection but it may be prudent to treat them with steroids at the lowest possible dose or rituximab for preventing future attacks. The safety of broad spectrum immunosuppressants like azathioprine and mycophenolate in HIV-infected patients is not known but they have been used in individual cases (Chamberlain et al., 2014). Our patient had severe bone marrow suppression with azathioprine and was later successfully managed with oral steroids. TPMT test was done in our patient prior to initiation of azathioprine as the test was not available. The exact mechanism of HIV-NMOSD is not known. NMOSD is a Bcell mediated disease that appears to occur due to hyperactivation of B cells most probably due to a T cell regulatory dysfunction secondary to HIV infection. T cell regulatory dysfunction in HIV causes an increase of cytokines IL- 6 and IL- 10 resulting in polyclonal immunoglobulin
6. Conclusion HIV associated NMOSD may be an under recognized entity. In all HIV patients presenting with optic neuritis or myelitis, serum aquaporin-4 antibody assay should be done and in all patients with NMOSD, HIV status should be tested. Management of these patients should be individualized with appropriate therapy with antiretroviral drugs and immunomodulators like steroids and rituximab. Prognosis of these patients is variable; residual neurological deficits were common but treatment prevented further attacks. Increased awareness of this association will lead to earlier diagnosis, early treatment and prevention of disability. The spectrum of HIV associated NMOSD may also expand to include non-optico-spinal forms. Conflict of interest No conflict of interest to declare. Financial disclosure None. References Berger, J.R., Sheremata, W.A., Resnick, L., Atherton, S., Fletcher, M.A., Norenberg, M., 1989. Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 39, 324–329. Blanche, P., Diaz, E., Gombert, B., et al., 2000. Devic's neuromyelitis optica and HIV-1 infection. J. Neurol. Neurosurg. Psychiatry 68, 795–796. Boasso, A., Shearer, G.M., Chougnet, C., 2009. Immune dysregulation in human immunodeficiency virus infection: know it, fix it, prevent it? J. Intern Med. 265 (1), 78–96. Chamberlain, F.E., Naila, D., Singh, G.K.J., Mark, B., Mark, N., 2014. Azathioprine can be safely used in HIV-infected individuals. AIDS 28 (3), 447–448. Chen, F., Day, S.L., Metcalfe, R.A., Sethi, G., Kapembwa, M.S., Brook, M.G., Churchill, D., de Ruiter, A., Robinson, S., Lacey, C.J., Weetman, A.P., 2005. Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine (Baltimore). 84 (2), 98–106. Delgado, S.R., Maldonado, J., Rammohan, K.W., 2014. CNS demyelinating disorder with mixed features of neuromyelitis optica and multiple sclerosis in HIV-1 infection. Case report and literature review. J. NeuroVirol. 20, 531–537. Feyissa, A.M., Singh, P., Smith, R.G., 2013. Neuromyelitis optica in patients with coexisting human immunodeficiency virus infections. Mult. Scler. J. 19 (10), 1363–1366. Foulon, G., Wislez, M., Naccache, J.-M., et al., 2004. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin. Infect. Dis. 38, 418–425. Gomez, V., Smith, P.R., Burack, J., et al., 2000. Sarcoidosis after antiretroviral therapy in
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boy with ascending paralysis. J. Pediatric Infect. Dis. Soc. 4, 385–388. Park, Jin-Sung, Hwang, Sun-Jae, Shin, Jin-Hong, Kim, Dae-Seong, 2013. A recurrent longitudinally extensive transverse myelitis with Aquaporin-4(AQP4) antibody after herpes zoster. J. Neurol. Sci. 334 69–7. Salazar, R., Cerghet, M., Shada, A., Markowitz, N.P., 2013. NMO-IgG positive relapsing longitudinally extensive transverse myelitis (LETM) in a seropositive HIV patient. Clin. Neurol. Neurosurg. 115, 1873–1875. Vos, F., Pieters, G., Keuter, M., van der Ven, A., 2006. Graves' disease during immune reconstitution in HIV-infected patients treated with HAART. Scand. J. Infect. Dis. 38 (2), 124–126. Younas, M., Psomas, C., Reynes, J., Corbeau, P., 2016. Immune activation in the course of HIV-1 infection: causes, phenotypes and persistence under. HIV Med. 17, 89–105.
a patient with acquired immunodeficiency syndrome. Clin. Infect. Dis. 31, 1278–1280. Heerlein, K., Jarius, S., Jacobi, C., Rohde, S., Storch-Hagenlocher, B., Wildemann, B., 2009. Aquaporin-4 antibody positive longitudinally extensive transverse myelitis following varicella zoster infection. J. Neurol. Sci. 15 (276), 184–186. Lederman, M.M., Funderburg, N.T., Sekaly, R.P., Klatt, N.R., Hunt, P.W., 2013. Residual immune dysregulation syndrome in treated HIV infection. Adv. Immunol. 119, 51–83. O'Leary, J.G., Zachary, K., Misdraji, J., Chung, R.T., 2008. De novo autoimmune hepatitis during immune reconstitution in an HIV-infected patient receiving highly active antiretroviral therapy. Clin. Infect. Dis. 46 (1), 12–14. Olson, D., Moen, A., Barr, E., Mirsky, D., Schreiner, T., Abzug, M.J., 2015. An 8 year old
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Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
HIV infection associated neuromyelitis optica spectrum disorder: Clinical features, imaging findings, management and outcomes
T
⁎
Thomas Mathewa, , Amrutha Avatia, Delon D’Souzaa, Manjusha Therambila, Anita Angela Baptista, Asha Shajia, Raghunandan Nadiga, Smitha Mary Rockeyb, Gareth Parrya a b
Department of Neurology, St. John's Medical College Hospital, Sarjapura Road, Bengaluru, Karnataka 560034, India Department of Microbiology, St. John's Medical College Hospital, Sarjapura Road, Bengaluru, Karnataka 560034, India
A R T I C LE I N FO
A B S T R A C T
Keywords: HIV infection Neuromyelitis optica Neuromyeltis optica spectrum disorders Anti aquaporin 4 antibody
Introduction: HIV Infection associated NMOSD (HIV-NMOSD) is a recently recognized entity. Management of patients with HIV-NMOSD is a challenge. Here we report our own experience of HIV-NMOSD along with a complete review of all the cases of HIV-NMOSD reported in literature. Objective: Describe the clinical features, radiological findings, treatment patterns and outcomes in patients with HIV-NMOSD. Methods: The details of all cases of HIV- NMOSD were searched from our NMOSD registry. A literature search was also done using the terms NMO, NMOSD and HIV infection in PUBMED, Google Scholar and EMBASE. The details of all the reported cases and cases from our registry were collected and analyzed. Results: Six cases of HIV-NMOSD were identified from the literature and one from our registry. There were four males and three females with age ranging from 8 years to 49 years. Duration of HIV infection ranged from newly detected to 15 years. Optic neuritis followed by myelitis was the commonest presentation, occurring in 5 out of 7 patients. 3 patients were anti-aquaporin 4 antibody positive while 3 were negative and in one anti- aquaporin 4 antibody assay was not done. All patients received immunomodulatory treatment. 5/7 patients had poor recovery from acute attacks but no patient had further relapses while on immunomodulatory treatment and antiretroviral therapy. Conclusion: HIV associated NMOSD is a recently recognized entity. A high index of suspicion is needed to diagnose these patients. In all patients with HIV infection presenting with optic neuritis or/and myelitis, anti aquaporin 4 antibody status should be checked and in all patients of NMOSD, HIV infection should be ruled out.
1. Introduction
NMOSD.
HIV infection is well known to produce an immunodeficiency state, but physicians rarely recognize it as a cause of autoimmunity. A hypo functioning immune state may co-exist with a hyper functioning immune state in the same individual. Though the exact reason for this is unknown it may be due to complicated immune dysregulation in various B and T cell pathways. NMO spectrum disorders are autoimmune inflammatory demyelinating diseases of the central nervous system resulting from auto antibodies attacking the nervous system antigens like aquaporin-4. HIV infection associated Neuromyelitis Optica Spectrum Disorder (HIV-NMOSD) is a recently recognized entity. HIVNMOSD presents an unusual clinical scenario posing several diagnostic and management challenges. Here we describe the clinical features, imaging findings, treatment and outcomes of patients with HIV-
2. Methods
⁎
Case records of all the patients of NMOSD in our NMO/MS clinic was searched for the presence of HIV infection. A literature search was done in Pub med, Google Scholar and Embase using terms HIV, NMO, NMOSD. Clinical features, magnetic resonance imaging findings, treatment strategies and outcomes of all patients were recorded and analyzed. 3. Results From our registry we identified 25 cases of NMOSD from June 2013 to June 2018. Only one patient had HIV infection and NMOSD. A
Corresponding author. E-mail address: [email protected] (T. Mathew).
https://doi.org/10.1016/j.msard.2018.11.014 Received 31 May 2018; Received in revised form 3 November 2018; Accepted 12 November 2018 2211-0348/ © 2018 Published by Elsevier B.V.
Multiple Sclerosis and Related Disorders 27 (2019) 289–293
T. Mathew et al.
literature search identified six further cases. There were four males and three females with age ranging from 8 years to 49 years. Duration of HIV infection ranged from newly detected to 15 years. 3 patients were African American in ethnicity, one was African, two were Caucasians and one was Asian in origin. Four patients were on antiretroviral therapy while three were drug naïve. 4. Case description A 37-year-old woman presented with painful eye movements and impaired vision in the left eye of 3 days duration. On examination visual acuity on the left was finger counting at one meter and there was an afferent pupillary defect with a normal disc on fundoscopy. The right eye was normal and there were no other neurological deficits. A diagnosis of retrobulbar neuritis was made. She had known HIV infection for the past 11 years and was on anti-retroviral therapy with tenofovir, lamivudine and efavirenz for the past 2 years. Her CD4 count at admission was 290 cells /cmm. MRI Brain with contrast was normal. Visual Evoked Potential study showed prolonged P 100 latency in the left eye. Cerebrospinal fluid (CSF) analysis was normal. CSF polymerase chain reaction for Herpes simplex, cytomegalovirus, Epstein-Barr virus, JC virus, Toxoplasma and Mycobacterium tuberculosis was negative. CSF VDRL was negative. India ink stain for cryptococcus and cryptococcal antigen assay were negative in CSF. She was treated with Methylprednisolone I gm intravenous (IV) daily for five days followed by oral prednisone, tapered over 2 weeks. She recovered completely by 4 weeks. After 2 months she presented to us again with hiccups, vomiting, tingling of upper limbs, urinary urgency, frequency and constipation. On examination power was normal but she had bilateral brisk reflexes with extensor plantar responses. MRI spinal cord showed longitudinally extensive transverse myelitis (LETM) extending from upper dorsal spinal cord to medulla, predominantly involving the central cord. MRI brain was normal. In view of LETM a diagnosis of NMOSD was considered and serum aquaporin 4 antibody assay was performed. Aquaporin assay was done using a cell based immune assay using transfected cell lines for in vitro determination in serum/plasma for qualitative/ semi quantitative determination of human IgG antibodies to Aquaporin −4 receptor. (Euroimmune, Indirect immunofluorescence on transfected cells at a titer of 1:10 dilution). The serum aquaporin antibody assay was positive. MOG antibody assay was not performed as it was not available. Her CD 4 count during the current admission was 180 cells/cmm and serum HIV viral load was less than 40 copies/ml. ANA, double stranded DNA, anti SSA and anti SSB antibody were all negative. Serum Angiotensin Converting Enzyme levels were normal. A diagnosis of HIV associated NMOSD was made and she was again treated with IV Methylprednisolone 1 g/day for 5 days followed by prednisolone 60 mg/day for 2 weeks followed by a taper by 10 mg/ week. After reaching 10 mg/day she was maintained on the same dose for another one month. After that prednisolone was further reduced to 7.5 mg/day. While she was on prednisolone 7.5 mg/day she developed recurrence of upper back pain and bilateral upper limb and lower limb weakness. The interval between the first attack of myelitis and second attack of myelitis was six months. Repeat MRI spine showed enhancing cervical spinal cord lesion suggestive of recurrence of LETM. She was treated again with IV methylprednisolone 1 g per day for another 5 days and followed by prednisolone 60 mg/day. After few weeks of therapy, she started developing steroid related side effects and developed Cushingoid features. Azathioprine 50 mg/day was added as a steroid sparing agent. After 4 days of azathioprine patient came back with severe hair loss and oral ulcers. She also developed pancytopenia and was treated with broad spectrum antibiotics and granulocyte monocyte colony stimulating factor. Azathioprine induced pancytopenia was considered and it was stopped. Patient improved over 10 days and was given steroids alone. At one year of follow up she was doing well on prednisone 15 mg/day. At 2 year follow up she is doing very well,
Fig. 1. Clinical attacks and corresponding CD4 counts.
without any relapse on a maintenance dose of prednisolone 10 mg/day. Her CD4 counts during various clinical attacks are shown in Fig. 1. The details of all the other cases of HIV-NMOSD collected from literature search are summarized in Table 1. The most common presentation was optic neuritis followed by myelitis seen in 5/7 patients. One patient had myelitis followed by optic neuritis and another patient had only recurrent myelitis. Three were anti aquaporin 4 antibody positive and three were negative and in one antibody was not tested. Two patients were treated with steroids, two with rituximab, two with azathioprine and one with mycophenolate mofetil while one was treated with anti retroviral therapy alone. All the newly diagnosed cases were treated with antiretroviral drugs along with immune modulatory treatment. Though most acute attacks (5/7) had resulted in a permanent disability, there were no relapses after immune modulatory treatment and antiretroviral therapy. 5. Discussion Although physicians usually consider HIV infection as an immunodeficiency state, autoimmune diseases like Guillain-Barre syndrome, Chronic Inflammatory Demyelinating Polyneuropathy, Systemic Lupus Erythematosis, Sarcoid and Anti-Phospholipid Antibody syndrome are known to occur in these patients. Autoimmune disorders may occur at the time of seroconversion, when immune competence is still active, or can occur after anti-retroviral therapy is started, when the CD 4 count improves, a phenomenon called Immune Reconstitution syndrome (IRIS). IRIS has classically been described with respect to opportunistic infections or malignancies. But literature review reveals various case reports/series of autoimmune conditions like Graves disease (Vos et al., 2006; Chen et al., 2005), Sarcoidosis (Gomez et al., 2000; Foulon et al., 2004) and Autoimmune hepatitis (O'Leary et al., 2008) which have been noted after initiation of HAART and improving CD4 counts. However, autoimmune diseases were described in HIV infected patients before the use of anti retroviral therapy suggesting that autoimmunity may not be entirely related to IRIS (Blanche et al., 2000). The case of HIV-NMOSD described here developed clinical attacks when the CD4 counts were dropping (Fig. 1), suggesting that the autoimmunity may be directly related to the viral activity and not IRIS. The exact mechanism of autoimmunity in HIV infection is not clear but immune dysregulation is a characteristic feature of HIV infection. The hallmark of the disease, the loss of CD4+ T cells, may result from this immune activation. HIV-1 production generates alloantigens that 290
291
Male
Male
Female
8
37
Male
32
45
Male
46
Female
Female
41
49
Sex
Age
Indian
Caucasian
African American
African American
African American
Caucasian
African
Ethnicity
11 years
New
New
15 years
5 years
12 years
11 years
Duration of HIV
On ART for 2 years
Not on ART
Not on ART
On ART
On ART
On ART
Not on ART
ART treatment
290/mm < 40
430,000
1134/mm3
3
583,451
< 3000
>350/mm3
109/ mm3
41,000
1029/mm3
<3000
1150
499/mm3
>350/mm3
Viral Load (RNA/ml)
CD4 count
Table 1 Details of all cases of HIV –NMOSD from literature with the current case.
Optic neuritis followed by myelitis
Recurrent myelitis Unilateral Optic neuritis followed by myelitis Unilateral Optic neuritis followed by myelitis Bilateral optic neurtitis followed by myelitis Myelitis followed by Optic Neuritis
Unilateral Optic neuritis followed by myelitis
Clinical features
Positive
Negative
Negative in CSF (not tested in serum)
Positive
Negative
Positive
Not done
Serum Anti Aquaporin 4 antibody
Methylprednisolone
Corticosteroids// Plasma exchange/IVIG
Mehtylprednisolone
Methylpredisolone/ Plasma exchange
Methylpredisolone/ Plasma exchange
None
Mehtylprednisolone
Acute Treatment
Steroids (Azathioprine produced hair loss and bone marrow suppression)
Rituximab and ART
Ritonavir, atazanavir, and emtricitabine-tenofavir
Mycophenolate Mofetil
Rituximab
Azathioprine
Steroids + LamivudineZidovudine/Nelfinavir
Disease modifying therapy
No relapse after rituximab and ART Good / No recurrence after 2 years/Predisolone 15 mg/day
No recovery of left eye blindness/ paraplegia, but no relapse No recovery of right eye blindness/ mild recovery of spastic paraplegia No recovery for vision, myelopathy improved significantly. Had paraplegia did not recover
Good/No recurrence at 5 months/ predisolone 15 mg alternate days Good
Outcome
Mathew et al 2018
Olson et al., 2015
Delgado et al., 2014
Feyissa et al., 2013
Salazar et al., 2013 Feyissa et al., 2013
Blanche et al., 2000
Study
T. Mathew et al.
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synthesis. HIV virion protein Nef has been shown to promote proliferation of B cells into immunoglobulin producing plasma cells causing hypergammaglobulinemia. Another proposed mechanism is stimulation of CD27 memory B cells by HIV activated T cells to become plasma cell-like cells which produce immunoglobulins (Delgado et al., 2014). This autoimmunity appears to be unrelated to IRIS as it has been described in ART naïve patients (Berger et al., 1989; Olson et al., 2015). An alternative mechanism of HIV related NMOSD is that infection of astrocytes with the HIV virus and consequent damage to the astrocytes (Feyissa et al., 2013). NMOSD can be associated with a wide range of autoimmune diseases but clinicians rarely diagnose NMOSD in cases of HIV infection and HIV-associated NMOSD is rarely mentioned in the conventional classification of NMOSD. Viral infections like herpes zoster are known to trigger NMOSD (Heerlein et al., 2009; Park et al., 2013). Similarly HIV may also trigger NMOSD because of its ability to dysregulate immune system. HIV-NMOSD needs to be added to the list of HIV-associated neurological disorders and NMO spectrum disorders. Unless there is a high index of suspicion the diagnosis of NMOSD may be missed in a case of HIV infection. In all patients of HIV related optic neuritis or myelitis, aquaporin-4 antibody assay should be done to diagnose HIV-NMOSD. It will also be prudent to check HIV status in all patients with NMOSD.
trigger the immune system directly. HIV-1 components may directly stimulate immune cells, typical example being the stimulation of monocytes and macrophages by Nef and Vpr. HIV-1 RNA interacts with the pattern recognition receptors TLR-7 and TLR-9 in plasmacytoid dendritic cells and induces the production of Interferon (IFN)-a by these cells. In addition, it has been suggested recently that the presence of HIV DNA in the cytoplasm of target cells leads to caspase-1 activation and to the release of pro-inflammatory cytokines including interleukin (IL)−1b (Younas et al., 2016). The HIV-1 envelope triggers signal transduction through binding to chemokine receptors on the surface of the target cell. CCR5 or CXCR4 engagement by HIV envelope results in altered chemotaxis and trafficking as well as alterations of cell cycle. CCR5 cross-linking on monocytes and macrophages triggers production of IL-1β and TNF-α (Boasso et al., 2009). Laboratory markers of T cell activation and B cell activation, activation of monocytes and dendritic cells (DCs), and natural killer cells are typically and persistently elevated during untreated infection . After the commencement of antiretroviral therapies as circulating CD4+ T cell numbers rise, these inflammatory markers improve yet in many, and especially among those who fail to restore circulating CD4+ T cell numbers, persistent immune activation persist. It is plausible to attribute much of the activation/inflammation in untreated infection directly to HIV replication. Though HIV replication is attenuated dramatically in most ART-treated patients, with sensitive enough assays, low levels of virus often can be found in plasma. HIV RNA can be found in lymph node and gut mucosal tissues of patients on anti retro viral therapies. These viral products can drive activation of both adaptive and innate immune responses (Lederman et al., 2013). Mere presence of HIV viral DNA in the cytoplasm of target cells, might induce immune activation (Younas et al., 2016). The first report of HIV associated demyelinating disorders were by Berger et al., in 1989 where he described 7 cases of MS like illness which probably was NMOSD (Berger et al., 1989), but anti aquaporin-4 antibodies had not been discovered at that time. A case of HIV-associated NMOSD was described by Blanche et al. (2000). Their case was of a 41 year old lady, with HIV infection of 11 years duration, with a normal CD4 count. She was not on treatment with anti-retroviral drugs at the time of presentation. Secondary causes of optic neuritis and myelitis were ruled out. Aquaporin-4 antibody assay was not available at that time. However, this case again indicates that HIV-NMOSD is an independent entity and not a part of IRIS. Except the case of Olson et al., all the patients were infected with HIV for more than 5 years (Olson et al., 2015). Of the 7 patients, 3 were aquaporin- antibody positive, three were negative and in one it was not done, indicating that in HIV-infected patients, both seropositive and seronegative NMOSD can occur. There were no features distinguishing aquaporin positive HIV-NMOSD from aquaporin negative HIV-NMOSD. The phenotype of NMOSD in this series of patients did not differ from those without HIV infection. Five had optic neuritis followed by myelitis while one had myelitis followed by optic neuritis. One patient had only recurrent myelitis but the aquaporin-4 antibody was positive (Salazar et al., 2013). Management of these patients does not differ from patients with NMOSD without HIV infection but it may be prudent to treat them with steroids at the lowest possible dose or rituximab for preventing future attacks. The safety of broad spectrum immunosuppressants like azathioprine and mycophenolate in HIV-infected patients is not known but they have been used in individual cases (Chamberlain et al., 2014). Our patient had severe bone marrow suppression with azathioprine and was later successfully managed with oral steroids. TPMT test was done in our patient prior to initiation of azathioprine as the test was not available. The exact mechanism of HIV-NMOSD is not known. NMOSD is a Bcell mediated disease that appears to occur due to hyperactivation of B cells most probably due to a T cell regulatory dysfunction secondary to HIV infection. T cell regulatory dysfunction in HIV causes an increase of cytokines IL- 6 and IL- 10 resulting in polyclonal immunoglobulin
6. Conclusion HIV associated NMOSD may be an under recognized entity. In all HIV patients presenting with optic neuritis or myelitis, serum aquaporin-4 antibody assay should be done and in all patients with NMOSD, HIV status should be tested. Management of these patients should be individualized with appropriate therapy with antiretroviral drugs and immunomodulators like steroids and rituximab. Prognosis of these patients is variable; residual neurological deficits were common but treatment prevented further attacks. Increased awareness of this association will lead to earlier diagnosis, early treatment and prevention of disability. The spectrum of HIV associated NMOSD may also expand to include non-optico-spinal forms. Conflict of interest No conflict of interest to declare. Financial disclosure None. References Berger, J.R., Sheremata, W.A., Resnick, L., Atherton, S., Fletcher, M.A., Norenberg, M., 1989. Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 39, 324–329. Blanche, P., Diaz, E., Gombert, B., et al., 2000. Devic's neuromyelitis optica and HIV-1 infection. J. Neurol. Neurosurg. Psychiatry 68, 795–796. Boasso, A., Shearer, G.M., Chougnet, C., 2009. Immune dysregulation in human immunodeficiency virus infection: know it, fix it, prevent it? J. Intern Med. 265 (1), 78–96. Chamberlain, F.E., Naila, D., Singh, G.K.J., Mark, B., Mark, N., 2014. Azathioprine can be safely used in HIV-infected individuals. AIDS 28 (3), 447–448. Chen, F., Day, S.L., Metcalfe, R.A., Sethi, G., Kapembwa, M.S., Brook, M.G., Churchill, D., de Ruiter, A., Robinson, S., Lacey, C.J., Weetman, A.P., 2005. Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine (Baltimore). 84 (2), 98–106. Delgado, S.R., Maldonado, J., Rammohan, K.W., 2014. CNS demyelinating disorder with mixed features of neuromyelitis optica and multiple sclerosis in HIV-1 infection. Case report and literature review. J. NeuroVirol. 20, 531–537. Feyissa, A.M., Singh, P., Smith, R.G., 2013. Neuromyelitis optica in patients with coexisting human immunodeficiency virus infections. Mult. Scler. J. 19 (10), 1363–1366. Foulon, G., Wislez, M., Naccache, J.-M., et al., 2004. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin. Infect. Dis. 38, 418–425. Gomez, V., Smith, P.R., Burack, J., et al., 2000. Sarcoidosis after antiretroviral therapy in
292
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T. Mathew et al.
boy with ascending paralysis. J. Pediatric Infect. Dis. Soc. 4, 385–388. Park, Jin-Sung, Hwang, Sun-Jae, Shin, Jin-Hong, Kim, Dae-Seong, 2013. A recurrent longitudinally extensive transverse myelitis with Aquaporin-4(AQP4) antibody after herpes zoster. J. Neurol. Sci. 334 69–7. Salazar, R., Cerghet, M., Shada, A., Markowitz, N.P., 2013. NMO-IgG positive relapsing longitudinally extensive transverse myelitis (LETM) in a seropositive HIV patient. Clin. Neurol. Neurosurg. 115, 1873–1875. Vos, F., Pieters, G., Keuter, M., van der Ven, A., 2006. Graves' disease during immune reconstitution in HIV-infected patients treated with HAART. Scand. J. Infect. Dis. 38 (2), 124–126. Younas, M., Psomas, C., Reynes, J., Corbeau, P., 2016. Immune activation in the course of HIV-1 infection: causes, phenotypes and persistence under. HIV Med. 17, 89–105.
a patient with acquired immunodeficiency syndrome. Clin. Infect. Dis. 31, 1278–1280. Heerlein, K., Jarius, S., Jacobi, C., Rohde, S., Storch-Hagenlocher, B., Wildemann, B., 2009. Aquaporin-4 antibody positive longitudinally extensive transverse myelitis following varicella zoster infection. J. Neurol. Sci. 15 (276), 184–186. Lederman, M.M., Funderburg, N.T., Sekaly, R.P., Klatt, N.R., Hunt, P.W., 2013. Residual immune dysregulation syndrome in treated HIV infection. Adv. Immunol. 119, 51–83. O'Leary, J.G., Zachary, K., Misdraji, J., Chung, R.T., 2008. De novo autoimmune hepatitis during immune reconstitution in an HIV-infected patient receiving highly active antiretroviral therapy. Clin. Infect. Dis. 46 (1), 12–14. Olson, D., Moen, A., Barr, E., Mirsky, D., Schreiner, T., Abzug, M.J., 2015. An 8 year old
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