Varicella zoster meningitis in a pregnant woman with uncontrolled type 1 diabetes mellitus

Abstract

We report the case of retrograde varicella zoster virus (VZV) reactivation presenting as aseptic meningitis without rash in a generally healthy pregnant patient. A 27-year-old nulliparous woman at 25 weeks of gestation presented to the emergency department with a 1-day history of severe headache associated with nausea, photophobia and neck stiffness. After ruling out a space-occupying lesion by brain imaging, lumbar puncture was performed. Cerebrospinal fluid analysis by PCR revealed the presence of VZV, making the diagnosis of acute varicella meningitis. The patient had immunoglobulin studies consistent with a history of primary VZV infection, thus confirming reactivation of VZV rather than primary infection. The patient was treated with acyclovir for 14 days and recovered fully. Her neonate was delivered full term without any evidence of vertical transmission. This is only the second reported case of VZV meningitis in a pregnant patient in the medical literature, and the first case in the US that was reported.

Background

Varicella zoster virus (VZV) is a highly contagious double-stranded DNA virus. Primary varicella infection results in a diffuse vesicular pruritic rash commonly known as chickenpox. Once infected by VZV, whether via primary infection or vaccination, VZV lies dormant in the host dorsal root ganglia with the potential for future reactivation. Reactivated VZV is currently believed to be rare in the general healthy population; however, the literature regarding diagnosis of isolated neurologic VZV reactivation without the presence of rash is increasing. This is only the second reported case of VZV meningitis in a healthy pregnant patient in the medical literature, and the first reported case was in the USA.

Case presentation

A 27-year-old nulliparous woman at 25 weeks gestation presented at the emergency department with a 1-day history of severe holocephalic headache. She described the headache as throbbing, worsened with movement and ‘the worst headache of’ her life. Associated symptoms included nausea, photophobia and neck stiffness. The patient denied a history of migraines. Her medical history is significant for type 1 diabetes mellitus, which was poorly controlled on insulin therapy. On admission, the patient was afebrile with stable vital signs, including blood pressure 128/69 mm Hg. The neurologic examination identified a Kernig sign, but was otherwise unremarkable. Physical examination was negative for rash.

Investigations

Initial laboratory studies were remarkable for a leucocytosis of 22.2×10⁹/L and an elevated C-Reactive Protein of 26.5 mg/L. Random blood glucose was 92 mg/dL and haemoglobin A1c (HbA1c) 7.8%. Comprehensive metabolic panel was within normal limits. HIV, hepatitis B and syphilis tests were negative. Initial symptomatic treatment with acetaminophen, fioricet and oxycodone were unsuccessful. Magnetic resonance imaging (MRI), as well as magnetic resonance angiography and venography (MRA and MRV), of the brain were performed and were negative for subarachnoid haemorrhage, thrombosis or other acute processes.

A lumbar puncture was performed with the cerebrospinal fluid (CSF) demonstrating a cell count of 12×10⁹/L, protein 22 mg/dL and glucose 88 mg/dL. Cell differential demonstrated a lymphocytic predominance. The patient was empirically started on antibiotics, steroids and acyclovir while awaiting PCR results. PCR was positive for VZV, while negative for cytomegalovirus, herpes virus, West Nile virus and Epstein-Barr virus. CSF and blood cultures were negative for bacteria. CSF varicella IgM and IgG were undetectable. Serum varicella IgG was 1338 mg/dL and the IgM was 0.91 mg/dL.

Treatment

The antibiotics and steroids were discontinued on hospital day 2 following diagnosis of viral meningitis, with continuation of intravenous acyclovir for a total of 14 days.

Outcome and follow-up

The patient made an uneventful recovery with slow resolution of her presenting symptoms. She was discharged from the hospital on day nine with a peripheral inserted central catheter in place to complete a 14-day course of intravenous acyclovir. Repeat leucocyte count at that time was 14.5×10⁹/L. There were no residual symptoms or neurologic deficits at the time of discharge. She subsequently delivered a full-term healthy male neonate without any clinical evidence of vertical transmission or any related sequelae. The absence of vertical transmission was confirmed by negative CSF culture following neonatal lumbar puncture.

Discussion

VZV is a highly contagious double-stranded DNA virus.^{1 2} Primary varicella infection results in a diffuse vesicular pruritic rash commonly known as chickenpox. The vast majority of cases of primary VZV occur in children, though rates have declined significantly since the development of the varicella vaccine in 1995. Primary infection provides lifelong immunity in about 90% of individuals.²

While primary VZV is rare in pregnancy, it puts both the mother and fetus at risk for serious morbidity and mortality.² Infection prior to 20 weeks gestation places the fetus at risk for congenital varicella syndrome, which is characterised by limb hypoplasia, skin lesions, neurologic abnormalities and structural eye damage. When primary varicella is acquired immediately before or after delivery, the neonate is at risk for neonatal varicella, which may be life-threatening for the neonate.²

Once infected, VZV lies dormant in the dorsal root ganglia.^{3 4} Reactivation of the virus may occur later in life, leading most often to herpes zoster, a painful vesicular skin rash in a dermatomal distribution known as shingles.^{1 5} Both those immunised by the VZV vaccine and those previously infected by the wild-type virus can later develop herpes zoster.^{5 6} Most cases of VZV reactivation occur in elderly or immunosuppressed individuals due to a decline in VZV-specific cell-mediated immunity.^{3 7} The lack of adequate immunity allows reactivated VZV to travel along the ganglia in either an anterograde or retrograde fashion. Anterograde reactivation, in which herpes zoster develops due to VZV travel from the dorsal root ganglia to the neural tissue of the skin, occurs in the majority of cases. Retrograde reactivation involves direct spread from sensory ganglia to the central nervous system.⁷ Anterograde and retrograde propagation can occur simultaneously, leading to the presence of a dermatome-distributed rash as well as central neurologic symptoms. However, in a minority of cases retrograde reactivation alone may occur, leading to an atypical presentation involving neurologic disorder without the presence of a rash.^{4 7 8} In recent years, shingles rates have been increasing in the USA. The reason for this epidemiological change has not been determined.³

The most common VZV-associated central nervous system complications are aseptic meningitis and encephalitis, though a large variety of neurologic sequelae have been described.⁹ This spectrum makes the diagnosis very challenging, particularly because the complications of VZV reactivation can be indistinguishable from other viral central nervous system (CNS) infections, as well as other unrelated aetiologies.^{7 9} There have been several recent case reports in which patients without rash were diagnosed with VZV meningitis.1 4 9–11 There is only one other, very recent, case report in the literature describing VZV meningitis presenting in a generally healthy pregnant patient.¹¹ Herpes zoster in pregnancy is rare, though there are reports in the literature. Unlike in the case of primary VZV infection, there has been no evidence of fetal or neonatal complications resulting from VZV reactivation leading to herpes zoster.¹² Additionally, there is no evidence that suggests the risk of maternal complications is higher with VZV reactivation in pregnancy.¹³

It remains controversial whether pregnancy, in and of itself, represents a clinically significant state of immunocompromise for the host. However, this could be an explanation for the occurrence of herpes zoster in young, pregnant women. The patient presented in this case had uncontrolled diabetes, which is a well-known cause of immunosuppression and increased susceptibility to infection. Diabetic patients have both impaired innate and adaptive immunity, including a reduction of regulatory T cells to control reactivation of latent viral infections.¹⁴ Therefore, in the present case, it is reasonable to assume that both pregnancy-related immunosuppression and that from uncontrolled diabetes contributed to VZV reactivation. As the prevalence of diabetes continues to rise rapidly, an increasing number of pregnancies are likely to be affected by the vast array of complications of this disease, including CNS infections.

In the past, the diagnosis of VZV meningitis was established with the use of VZV specific immunoglobulins detected in the CSF. More recently, VZV DNA detection with PCR methodologies have become the preferred approach.^{3 9} Given this more sensitive diagnostic tool, more cases in the future will be identified in patients who have undergone CSF sampling when presenting with meningitis-like symptoms.

Varicella meningitis has been reported in approximately 5%–11% of cases of viral, or aseptic, meningitis.⁹ Presenting symptoms include fever, headache, neck stiffness, photophobia, drowsiness, nausea, irritability and lethargy.^{7 15} Non-specific CSF findings may include elevated opening pressure, a mild-to-moderate lymphocytic pleocytosis, mildly elevated protein and normal glucose levels. Brain imaging studies are typically unremarkable in cases of isolated meningitis. Of interest, only about 50% of patients have evidence of systemic inflammation such as leucocytosis or elevated CRP.⁹ Viral meningitis typically resolves completely without lasting deficits.^{7 15} However, long-term morbidities, such as seizure disorders or sensorineural hearing loss, have been reported, although most occur in elderly or immunocompromised patients.⁸

Treatment with acyclovir should be started empirically in all patients with suspected meningitis or encephalitis. Intravenous acyclovir 5–10 mg/kg every 8 hours for 10–14 days is the currently recommended regimen.¹⁵ Additionally, appropriate therapy for presumed bacterial meningitis may be initiated until bacterial sources are ruled out. The exact duration or preferred route of acyclovir administration has not been clearly elucidated, and there have been some recent cases reporting successful treatment with oral acyclovir.¹ Acyclovir is used frequently in pregnancy both for acute treatment of herpes simplex virus (HSV) as well as for prophylaxis against recurrent HSV. In pregnant women with a known history of HSV, the use of acyclovir suppression therapy from 36 weeks gestation to the time of delivery has been shown to reduce the risks of neonatal HSV transmission.¹⁶ While the risk of adverse pregnancy outcomes related to acyclovir use during pregnancy are not entirely known, studies thus far have shown no increased risk of fetal malformations, preterm delivery or spontaneous abortion with systemic acyclovir use.^{16 17}

Given the current standard recommendation for childhood vaccination against VZV, additional data are needed regarding long-term sequelae such as the occurrence of shingles or other reactivation events. While this was, to the best of our knowledge, the first reported case of varicella meningitis in a pregnant patient in the USA, another case was recently reported in the UK.¹¹ It may be that this atypical presentation is not so rare, but has previously gone unrecognised due to the lack of PCR testing. With the introduction of a sensitive PCR-based diagnostic testing, it is anticipated that this will become a more commonly established diagnosis, and lumbar puncture may be considered for patients with severe intractable headache and no other obvious aetiology.

Learning points.

• In pregnant women with severe headache of unknown origin, consider performing lumbar puncture to rule out viral meningitis.

• Varicella meningitis, in general, may be more common in the healthy population than previously believed and diagnosis may increase with the proper use of PCR.

• While adverse fetal outcomes with primary varicella infection in pregnancy are well described, to date there is no known fetal consequences for women with varicella zoster virus reactivation.