Longitudinal Extensive Transverse Myelitis due to Varicella-Zoster Virus Infection in an Undiagnosed HIV-Positive Patient

Introduction Longitudinal extensive transverse myelitis (LETM) has four main causes: inflammatory, malnutrition, vascular, and infectious causes. Among the commonly described viral causes leading to LETM are the Herpesviridae family, HIV, and HTLV-1. Case Presentation. A 43-year-old man presented with asymmetric weakness of the lower limbs (the left side was weaker), urinary retention, and flank pain. The symptoms began five days after shingle eruption and progressed over twelve days. He was diagnosed with longitudinal extensive transvers myelitis extending from T4 to T6, which corresponded to the same dermatome involved in shingles. The PCR result of cerebrospinal fluid was positive for varicella-zoster virus with a viral load of 500 copies/ml. Additionally, the initial HIV enzyme-linked immunosorbent assay (ELISA) test was positive, and his CD4 count was 72 cells/mm3. Other lab results were normal. Based on the appearance of LETM in the thoracic MRI at T4-T6, VZV myelitis was diagnosed, and treatment was initiated with acyclovir (30 mg/kg divided daily for twenty-one days), methylprednisolone (1 g/day for three days), prophylactic antibiotics (trimethoprim/sulfamethoxazole, rifampin, and isoniazid), and antiretroviral therapy (dolutegravir and Truvada). After 2-month follow-up, he was nearly free of symptoms. Conclusion Infection is one of the critical causes of transverse myelitis. When a patient presents with skin shingles along with myelopathy, varicella-zoster myelitis should be considered, and the patient should be evaluated in terms of immune system dysfunction. Treatment with acyclovir has been shown to be effective in reducing clinical symptoms in such cases.

Reactivation of varicella-zoster virus in the posterior root ganglion of the spinal cord, trigeminal ganglion, and other cranial nerves can causes shingles.It is diagnosed by a painful rash and blisters in one or more adjacent dermatomes.In patients with immune system defciencies, skin involvement may be observed in multiple dermatomes, with bilateral involvement, or with spread to the central nervous system [3,4].Central nervous system involvement can lead to meningitis, ventriculitis, encephalitis, and, less frequently, stroke or myelitis [4].
A rare complication of varicella-zoster reactivation is shingles myelitis [4].It may occur at the same time or up to a few weeks after the appearance of a skin rash, or even in the absence of a skin rash.Various mechanisms, including infammatory, vasculitis, or even direct invasion of the virus into the spinal cord, may play a role in its occurrence [5].

Case Presentation
A 43-year-old man presented with asymmetric weakness of the lower limbs (the left side was weaker), urinary retention, and fank pain.Muscle weakness and pain began 12 days before hospitalization (5 days after shingles erupted on the right side), and urinary retention started the day before hospitalization.On the admission day, his blood pressure was 110/75 mmHg, heart rate was 75 Beat/min, and body temperature was 36.8 °C.He had crusted lesions in the T6-7 dermatome region on the right side.Te rest of the systemic examination was normal.He was alert and oriented, and cranial nerve examination and fundoscopy were normal.Te force of the upper limbs was normal.Both proximal lower limbs were asymmetrically weak (left side more than right side), rendering him unable to stand or walk without aid.He also exhibited mild weakness in the distal portions of both lower limbs.Pain perception decreased up to dermatome T7 on the right side and around T5 on the left side, with similar levels of decreased sweating and pain perception on both sides.Te patient's plantar refex on both sides was extensor and deep tendon refexes of the lower limbs were slightly deceased slightly and almost symmetrical.He did not mention any history of previous illness or visit to a doctor.He hailed from Afghanistan, was single, and had been living in Iran for a year.Te patient worked as a construction worker.
He exhibited a triad of myelopathy, prompting a request for a total spinal cord MRI.Due to the appearance of LETM on the thoracic MRI at T4-T6 (Figure 1), which corresponded to the same dermatome involved in shingles (Figure 2), and the positive result of cerebrospinal fuid PCR for varicella (with 500 copies/ml), the diagnosis was shingles myelitis.Treatment with acyclovir (600 mg intravenous every 8 hours) and dexamethasone (4 mg intravenous twice daily) was initiated, and evaluation for immunosuppression began.Te initial serum HIV ELIZA test was positive, and the viral load checked was positive (1800 copy/ml).His CD4 count was 72 cell/mm 3 .Te results of the tuberculosis assessment, which included chest radiography and purifed protein derivative (PPD) testing, were found to be negative.Other lab results are detailed in Table 1.Treatment with dexamethasone was discontinued.To control AIDS, he started taking dolutegravir and Truvada (emtricitabine and tenofovir) daily.Due to a positive Brucella IgG test, he received treatment with trimethoprim/sulfamethoxazole 800/160 BD and rifampin 600 daily for 42 days, along with isoniazid 150 mg per day and vitamin B6 to prevent tuberculosis.On the seventh day after starting acyclovir, the patient's muscle strength signifcantly improved to 4+/5, and he could walk without aid.However, even after removing the internal Foley catheter, he still experienced urinary and fecal incontinence.Blood cultures, urinalysis and culture, and the chest X-ray yielded negative results for infection.Due to persistent urinary retention, the patient received treatment with methylprednisolone 500 mg twice a day for three days.Unfortunately, no immediate sphincter improvement occurred.A reevaluation by MRI requested twelve days after the frst MRI imaging revealed LETM in the previous location with some evidence of myelomalacia and no signs of progression (Figure 3).After two months of follow-up, he regained near-normal gait and urinary continence.

Discussion
Our patient's symptoms started with shingles in the thoracic region.Within fve days after the onset of skin symptoms, he had paraparesis, which progressively worsened over ten days, followed by sphincteric symptoms.When a patient with myelopathy presents with fever, confusion, meningismus, rash, concomitant systemic infection, and lymphadenopathy or resides in an endemic area for parasitic infections, suspicion of infectious myelopathy increases [6].Due to the similar clinical presentation and CSF pattern, distinguishing neuromyelitis optica spectrum disorders from direct infectious myelitis is often challenging.Te most reliable evidence of direct infection occurs when a pathogen is isolated from cerebrospinal fuid (CSF), when PCR results are positive, or when both acute and convalescent CSF and serum antibody titers demonstrate a signifcant increase or change.Tis suggests an ongoing or recent infection [6].
It is uncommon for immunocompetent patients to develop myelopathy as a result of varicella-zoster infection, although there are a few documented cases [3].So, it is necessary to carefully evaluate the immune system defciency in these patients.A positive HIV test established immunodefciency of our patient.
Te most signifcant risk of neurologic complications of disseminated herpes zoster is in patients with HIV whose CD4 cell count is less than 200 cells/mm 3 [7].Varicellazoster virus causes diferent neurological syndromes in patients with immunodefciency, including multifocal leukoencephalopathy, CNS vasculitis, ventriculitis, myelitis and myeloradiculitis, optic neuritis, cranial nerve palsies, focal brain-stem lesions, and aseptic meningitis [4].
In our case, based on the typical manifestations of myelopathy, MRI fndings of the spinal cord, history of shingles skin scarring before the onset of symptoms, and the detection of virus DNA by PCR in the cerebrospinal fuid, LETM was diagnosed as a result of varicella-zoster virus infection.
Tere is no agreed-upon standard for treating myelitis caused by varicella zoster in patients with weakened immune systems.A PubMed search from 1992 to December 2023 revealed only a few cases of VZV myelitis in HIV-positive patients, with information on their treatment plan and longterm outcome.
De La Blanchardiere et al. conducted a multicenter case series of 34 HIV-positive patients with varicella zosterrelated neurological complications.Among them, only eight had myelitis, which was associated with a high rate of mortality and severe neurological sequelae (72%), compared to other neurological manifestations (27%).Te treatment methods varied across the patients, and the authors did not specify the treatment for myelitis cases [8].
Lameiras et al. reported a case of shingles rash, fever, paraparesis, sphincteric disorder, and meningismus.MRI detected a LETM lesion, and PCR confrmed VZV in the cerebrospinal fuid.Te patient was treated with acyclovir 2 Case Reports in Neurological Medicine (10 mg/kg) and dexamethasone 4 mg three times daily for a month, followed by an oral prednisolone taper starting at 20 mg for another month.After the treatment, the patient experienced brief motor recovery [9].Our patient had a lower CD4 level, a lower varicella viral load, mild CSF pleocytosis, no meningismus signs, less severe initial symptoms, and a faster and more complete recovery than Lameiras' case.Tis suggests that the severity of the immune system response has a greater infuence on the spinal cord infammation and damage than the viral load.Te only major diference in treatment was the administration of a high-dose corticosteroid injection (methylprednisolone) in our patient versus low-dose corticosteroid injection in their patient, which might have afected the fnal outcome.Weiss et al. described a case of VZV myelitis in an HIVpositive patient with poor adherence to antiretroviral therapy.Te CSF HIV viral load was 1,030 copies/mL, suggesting "secondary" HIV CSF escape.She underwent intravenous acyclovir treatment for four weeks and was followed by oral famciclovir, then valacyclovir for six weeks.She also got dexamethasone to reduce infammation.Tey reported a signifcant improvement in motor symptoms in their patient, but she still exhibited some weakness in the afected limb after six months of follow-up [10], whereas our patient had no residual motor symptoms after two months.
Falcone et al. described a case of AIDS manifesting as VZV meningomyeloradiculitis.He had positive CSF-VZV PCR.He received methylprednisolone and acyclovir for 14 days and then switched to famciclovir, which aggravated his symptoms.He resumed acyclovir for four weeks and then continued with valacyclovir for eight weeks, which eventually improved his motor symptoms signifcantly [11].Tis case highlights the importance of long-term antiviral treatment and suggests that the favorable motor prognosis of the patient is related to the efective anti-infammatory treatment in the beginning.Stefan Polen described a patient who developed paraplegia in the lower limbs and weakness in the upper limbs within three days, three weeks after having zoster rash and histoplasmosis.Te patient was given ganciclovir for fve days (then switched to acyclovir for 36 days) and briefy improved in motor symptoms but had a seizure 12 days after starting treatment, which MRI revealed as encephalitis and worsening of cord involvement.Te patient received methylprednisolone pulse (one gram daily) for fve days and then intravenous dexamethasone (8 mg/daily) for eleven days, followed by oral prednisolone (80 milligrams daily, slowly tapered) for fve weeks.During this time, the patient's motor symptoms deteriorated, and MRI showed that brain infammation had subsided, but extensive intramedullary hematoma had formed at the previous myelitis site in the neck [12].Tis case suggests that the delayed anti-infammatory treatment could not prevent the infammatory vasculopathy induced by the virus, and that the efective delay dose of anti-infammatory treatment did not improve the patient's fnal outcome.
A patient with HIV, who contracted Crohn's disease after shingles, also experienced myelitis zoster.He received acyclovir for 14 days and pulse methylprednisolone (1 gram daily) for fve days.Although the patient had a partial recovery at discharge, the long-term prognosis was not reported.Tese cases suggest that short-term treatment with corticosteroid and acyclovir may be inefective in improving the short-term prognosis [13].
Bagat et al. described an HIV-positive patient with AIDS who developed paraparesis and urinary and fecal sphincter impairment after zoster involvement in the sacral region.Te patient's myelitis slowly improved with acyclovir and dexamethasone (44 milligrams daily), but during hospitalization, he experienced unexplained fevers and eosinophilia.Extensive clinical tests eventually led to the diagnosis of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).Te patient improved upon discontinuation of acyclovir [14].
In recent years, a new treatment method has been proposed.Some viral diseases may improve with superinfection, which blocks or weakens the primary virus.For example, chickens and mice coinfected with IBDV and another virus had better outcomes than those infected with only one virus [15].Tis concept may also apply to VZV infection in HIV patients, but more research is necessary.
Te primary and most efective method for preventing infection is through vaccination.While the use of weakened virus vaccines is not recommended for patients with immune system defciencies, there has been recent success with recombinant vaccines in this patient population.Tese recombinant vaccines have proven highly efective in preventing shingles and mitigating other complications associated with varicella zoster infection, including vasculitis, disseminated disease, ophthalmic issues, neurological complications, and visceral manifestations [16].For people with HIV who have severe or complicated varicella, it seems the initial treatment recommendation is intravenous acyclovir 10 mg/kg every 8 hours for 4 weeks.
Currently, there is insufcient conclusive pathological evidence directly linking acute myelitis to varicella zoster infection.In a case report during the subacute stage of the disease, a patient with shingles neuralgia exhibited a hyperintense lesion in the MRI region corresponding to the afected dermatome in the spinal cord.Pathological examination revealed the presence of CD68+ macrophages and CD8+ lymphocytes but no signs of demyelination, axonal loss, or vasculitis [17].In another case series involving nine postmortem patients, fve exhibited either focal or difuse necrosis, while two displayed mild infammation.Additionally, two patients displayed cord thinning and mild vascular proliferation [18].Based on the pathology fndings, early corticosteroid treatment before the onset of necrosis and vasculitis changes appears more efective.However, initiating anti-infammatory treatment after the development of vasculitis and hemorrhagic necrosis may not signifcantly impact the longterm prognosis.
Although in immunocompromised patients, the initiation of corticosteroids is associated with a higher risk of opportunistic infections due to the increased risk [19], early treatment with a high dose of methylprednisolone appears to be more efective in reducing neurologic sequelae.
Delayed diagnosis, a high varicella zoster viral load in CSF, and severe initial infammatory symptoms appear to be risk factors for poor neurologic recovery.

Conclusion
One of the critical causes of transverse myelitis is infection.In a patient who has skin shingles along with myelopathy, varicella-zoster myelitis should be considered, and the patient should be evaluated for immune system dysfunction.Treatment with acyclovir and corticosteroids is efective in reducing the patient's clinical symptoms.

Figure 2 :Figure 1 :
Figure 2: Image of the patient's rash around dermatomes T8-9 showed crusted lesions and some pustular lesions, as seen around dermatome T5 (indicated by the arrow).

Table 1 :
Laboratory data.BS � blood sugar measured at the same time as CSF puncture.mIU/mL � milli-international units per milliliter.mcL � microliter.
ỻ Serum total protein measured at the same time as CSF puncture.*