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A 44-year-old previously healthy woman presents to the medical center with a crippling, dull frontal headache that has been constant for the past 3-4 days. The patient rates the severity of the pain as 10/10.

There is no significant past medical history. As well, the headache does not seem to be linked to any activity; in fact, she notes that it has made her incapable of performing her normal daily functions.

The pain is non-radiating. However, she says that when she is standing the headache becomes a "driving knifelike pain in the head." The patient explains that the headache began 3 days previously, and was so intense that after suffering with it for 24 hours, she sought help at an urgent care clinic.

3 days previously ...

The patient's assessment at the urgent care clinic included a computed tomography (CT) scan of her head, which showed no evidence of any intracranial process. She was sent home with a prescription for acetaminophen/butalbital/caffeine and Meloxicam. The medications "didn't even make a dent in her pain," she explains -- which is why she is at the clinic.

Clinical history and examination

Her recent clinical history includes feeling mildly sick to her stomach, and being sensitive to light and sound. She is not experiencing any confusion and her eyes and eyesight are normal.

Her headache is not associated with auras, fortification spectrum, vertigo, or seizures. And she reports being free of fevers, chills, neck stiffness, or rash. Likewise, she is not experiencing body aches, weakness, or tingling or numbness of the extremities.

Physical examination yields nothing out of the ordinary. Vital signs are within normal limits on presentation, including blood pressure of 97/55 mm Hg and temperature of 37°C. Neurological assessment notes the patient has no scalp tenderness, jaw claudication, nuchal rigidity, or photophobia.

Results of the jolt test and Kernig's and Brudzinski's signs are negative. Her cranial nerves are intact and she has no evidence of focal weakness. Results of tests of range of movement, sensation to soft touch, and cerebellar signs are all unremarkable. Triceps, patellar, and Achilles deep tendon reflexes were 1+ and equal bilaterally.

She has no sign of rashes, lesions, or erythema anywhere on her body, including her genitalia.

Clinicians perform another CT scan and a CTA (computed tomography angiography) of the patient's head and there is no evidence of intracranial pathology. Similarly, there is no evidence of tumors, sinus thrombosis, or periventricular plaques that might suggest multiple sclerosis from a brain MRI with and without contrast.

Results of a complete metabolic panel and complete blood count are unremarkable. She is not pregnant nor does she have HIV. A lumbar puncture is performed that shows:

• normal red blood cell (RBC) count
• elevated white blood cell (WBC) count of 422 cells/μL (normal <5 cells) with lymphocytic predominance
• glucose of 35 mg/dL (ref range: 45–80 mg/dL)
• protein of 225 mg/dL (ref range: 14–45 mg/dL)

Serum glucose drawn before the lumbar puncture was performed and is 110 mg/dL; her CSF-to-serum glucose ratio is 0.3. Gram staining of spinal fluid does not show any organisms and cultures remained negative.

Diagnosis

Meningitis panel by polymerase chain reaction (PCR) is positive for varicella zoster virus. Results of additional CSF studies are unremarkable. Based on the positive findings of VZV meningitis, the patient is started on treatment with intravenous (IV) acyclovir. Her symptoms begin to improve fairly quickly. After 5 days of IV acyclovir, she is discharged with a prescription for oral valacyclovir 1,000 mg, 3 times per day for 14 days.

Follow-up finds that her headache has completely resolved without any neurological complications.

Discussion

Clinicians reporting this uncommon ¹ of varicella zoster virus (VZV) meningitis in a 44-year-old immunocompetent woman note that VZV meningitis typically affects immunocompromised hosts, with symptoms of fever and rash.

A member of the herpes virus family, varicella zoster virus or chickenpox is responsible for approximately 1.5–3 infections per 1,000 persons annually in the U.S. An estimated 90% of all adults have serological markers indicating prior VZV infection.^2,3

They caution that VZV meningitis should be considered as a differential diagnosis of patients with headaches, even if they present without the suggestive rash, fevers, or neurological signs. Importantly, VZV meningitis can occur concomitantly with chickenpox or shingles, or as in this case, can occur in its own without any rash or skin manifestation.

Chickenpox is easily spread -- typically during childhood -- through respiratory droplets or direct contact with its hallmark itchy vesicular rash. Following chickenpox infections, the virus migrates along sensory nerves to the dorsal ganglia of sensory nerves,⁴ where it remains dormant, usually for many years.

Secondary VZV infection occurs as a result of reactivation of the dormant virus. When the virus is reactivated as secondary VZV, symptoms include abnormal skin sensations including tingling, itching, and pain. In many cases, a maculopapular rash eventually develops in a unilateral pattern often involving the thoracic and lumbar dermatomes.

Clinical meningitis with negative bacterial cultures, known as aseptic meningitis, can be caused by a variety of non-bacterial infections. Enterovirus infection⁵ is the most common cause of aseptic meningitis. However, varicella zoster is involved in 8% to 13% of cases of aseptic meningitis.⁶

VZV Meningitis

Meningitis is a rare complication of varicella zoster virus (VZV) reactivation, affecting approximately 0.5% of patients who have had a recent zoster infection.⁷ The pathway by which the nature of VZV spreads to the central nervous system has been theorized to involve afferent nerve fibres or hematologic pathways⁸ -- it remains a subject of debate.

Other complications of herpes zoster include post-herpetic neuralgia, eye involvement, motor neuropathy, and superimposed bacterial skin infections. Risk of complications increase with age. They may develop in about 1 in 9 people within about 60 days of the infection, according to one review.⁹

Diagnostic challenges

Varicella zoster meningitis presents primarily with headache,¹⁰ but may also cause fever, neck stiffness, or rash. Notably, some isolated cases present with severe headaches and additional signs such as nausea and vomiting.^11,12

Diagnosis of varicella zoster meningitis can be especially difficult in patients who, as in this case, do not develop the characteristic rash. Literature of VZV-reactivation related infections suggest this absence of rash occurs in 33-60% of cases. Until the development of CSF polymerase chain reaction (PCR), standard cerebral spinal fluid (CSF) studies were rarely able to identify specific viral etiological agents.¹³ A large multicenter retrospective study found that CSF PCR was positive for VZV in 100% of cases, while CSF culture was only positive in 33%.¹⁴

As well, polymerase chain reaction (PCR) of the CSF shows hypoglycorrhachia, with elevated CSF WBC and protein, case authors note. Among 620 patients with meningitis, 19% had hypoglycorrhachia on CSF PCR. Of those meningitis patients, 15% of cases were due to a viral infection with West Nile virus (WNV), herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and acute HIV infection. Authors of that note that hypoglycorrhachia (CSF glucose <45 mg/dL) has been identified as a prognostic factor in patients with meningitis.¹⁵

Because hypoglycorrhachia has been noted in patients with nonbacterial meningitis, authors recommend that in appropriate settings, PCR be performed on CSF analysis to ensure nonbacterial causes. The cause of hypoglycorrhachia is unknown but likely multifactorial, case authors note. Affected patients appear to be more likely to be immunosuppressed, present with vesicular/petechial rash, and have a positive history of intravenous drug use.

Various recommended treatments of VZV meningitis include valacyclovir 2 g three times per day¹⁶ to oral valacyclovir 1 g three times per day, to maintain a therapeutic concentration of acyclovir in the CSF.^17,18

Case authors note that this patient was effectively treated with a lower dose of valacyclovir, with no clinical complications, and had resolution of symptoms on follow-up.

Conclusion

Further studies are needed to establish the pathophysiology of hypoglycorrhachia in viral meningitis, as well as the appropriate dosage for treatment with valacyclovir, authors conclude. This case of VZV meningitis in an immunocompetent young female patient presenting with a debilitating headache but no meningeal signs or dermatologic manifestations highlights the subtle presentation of VZV meningitis and the diagnostic challenge it can present.

References

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3. Gnann JW, Whitely RK: Herpes Zoster. New Engl J Med, 2002; 347(5): 340–46

4. Ku CC et al: Varicella-Zoster Virus pathogenesis and immunobiology: New concepts emerging from investigations with the SCIDhu mouse model. J Virol, 2005; 79(5): 2651–58

5. Ihekwaba UK et al: Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among Herpes Simplex Virus, Varicella Zoster Virus, and Enterovirus infections. Clin Infect Dis, 2008; 47(6): 783–89

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7. Gupta P et al: Meningitis with polymerase chain reaction for Varicella Zoster positivity in cerebrospinal fluid of a young immunocompetent adult. J Neurosci Rural Pract, 2016; 7(4): 591–93

8. Grahn A, Studahl M: Varicella-Zoster Virus infections of the central nervous system – prognosis, diagnostics and treatment. J Infect, 2015; 71(3):281–93

9. Mantero, Vittorio, De Toni F et al: Varicella-Zoster Meningoencephaloradiculoneuropathy in an Immunocompetent Young Woman. J Clin Virol, 2013;57(4): 361–62

10. Becerra JCL et al: Infection of the central nervous system caused by Varicella Zoster Virus reactivation: A retrospective case series study. Int J Infect Dis, 2013; 17(7): 529–34

11. Habib AA et al: Varicella Zoster Virus meningitis with hypoglycorrhachia in the absence of rash in an immunocompetent woman. J Neurovirol, 2009; 15(2): 206–8

12. Pasedag T et al: Varicella Zoster Virus meningitis in a young immunocompetent adult without rash: A misleading clinical presentation. Case Rep Neurol Med, 2014; 2014: 686218

13. Debia RL, Tyler KL: Molecular methods for diagnosis of viral encephalitis. Clin Microbiol Rev, 2004; 17(4): 903–25

14. De La Blanchardiere A et al: Neurological complications of Varicella-Zoster Virus infection in adults with Human Immunodeficiency Virus infection. Scand J Infect Dis, 2000; 32(3): 263–69

15. Shrikanth V et al: Hypoglycorrhachia in adults with community-acquired meningitis: Etiologies and prognostic significance. Int J Infect Dis, 2015; 39: 39–43

16. Cunha BA, Baron J: The pharmacokinetic basis of oral valacyclovir treatment of Herpes Simplex Virus (HSV) or Varicella Zoster Virus (VZV) meningitis, meningoencephalitis or encephalitis in adults. J Chemother, 2017; 29(2): 122–25

17. Lycke J et al: Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir. Antimicrob Agents Chemother, 2003; 47(8): 2438–41

18. Pouplin T et al: Valacyclovir for herpes simplex encephalitis.Antimicrob Agents Chemother, 2011; 55(7): 3624–62.01023-10

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