Why Is This Diabetes Patient With CKD Having Seizures?

A 69-year-old man presents at the hospital with interstitial pneumonia due to amiodarone treatment for paroxysmal atrial fibrillation. The patient has chronic kidney disease (CKD) and type 2 diabetes, and a history of herpes encephalitis.

He is admitted to the hospital – amiodarone is discontinued, and he is treated with high-dose intravenous methylprednisolone (1,000 mg daily) for three days. On day 4, his steroid treatment is changed to prednisolone (60 mg daily), and later decreased to a dose of 40 mg daily.

Forty days after being admitted, the patient develops seizures. Although these resolve quickly, he remains in a semi-comatose state. On examination, the patient has no neck or limb stiffness and no evidence of paralysis affecting his extremities. However, he continues to have impaired levels of consciousness.

Vital signs include:

• Glasgow Coma Scale score 11/15 (E3, V3, M5)
• blood pressure 137/59 mmHg
• pulse rate 116 beats/min
• peripheral capillary oxygen saturation 96% in room air
• body temperature 37.4 °C

Laboratory tests identify a creatinine concentration of 1.20 mg/dL and hemoglobin A1c level of 9.3%, but he has normal levels of inflammatory markers and electrolytes, and no evidence of hypoglycemia.

To identify the reason for this patient's seizures, a computed tomography (CT) scan of the head is performed, which reveals an area of low-density in the left temporal lobe.

Figure 1. CT imaging of the head. (A) Head CT performed after a seizure showing a low-density area in the left temporal lobe. (B) Bilateral low-density areas in the forehead region of the frontal lobes on head, CT performed following discontinuation of acyclovir (arrow), which were suspected to be due to hematoma or edema.

Due to suspected symptomatic epilepsy related to the patient's history of herpes encephalitis, the patient is placed under observation and his medications – including antiepileptic drugs – are discontinued.

One day following the onset of the seizures, a nurse observes an erythematous rash with raised vesicles on his genital region, distributed in the area of the third to fourth sacral dermatomes (S3–S4). Similar rashes are more widely distributed on his left thigh and abdomen.

The patient explains that he knew of but did not report the "embarrassing" rash, which had developed along with mild pain the week prior to the onset of the seizures. He is provisionally diagnosed with disseminated herpes zoster (DHZ).

Lab tests including analysis of cerebrospinal fluid (CSF) reveal a white blood cell count of 287/μL (proportion of segmented neutrophils, 80%), a CSF protein level of 481 mg/dL, and a CSF glucose level of 69 mg/dL (blood glucose 129 mg/dL).

Bacterial cultures of the CSF and herpes simplex virus polymerase chain reaction (PCR) are negative. Although positive serum levels of varicella zoster virus IgM and IgG and intrathecal IgG are detected, the antibody titer of herpes simplex virus in the CSF is negative.

Diagnosis and treatment

Based on these findings, DHZ-induced meningoencephalitis is identified as the probable cause of the patient's seizures and impaired levels of consciousness. Intravenous acyclovir treatment is started before DHZ is confirmed. He continues to exhibit impaired levels of consciousness; based on his clinical course, this is thought to be secondary to acyclovir-related neurotoxicity. After 14 days, the acyclovir is discontinued.

Outcome

Seven days later, his level of consciousness deteriorates further, prompting another CT scan (Figure 1B) and CSF analysis, which shows a white blood cell count of 741 per μL (mononuclear cells 94%), and a CSF protein level of 213 mg/dL. Based on suspicion of a prolonged course of DHZ-related meningoencephalitis, treatment with acyclovir is resumed. However, the patient does not recover but dies of respiratory failure due to aspiration pneumonia.

Discussion

Clinicians reporting this case¹ note that in immunosuppressed patients, the initial symptom of DHZ may be seizures due to meningoencephalitis. As well, steroid treatment may cause susceptibility to DHZ and meningoencephalitis, which may not respond to antiviral treatment and thus, be fatal.

Opportunistic Infection Risks

In this case, they note that their initial suspicion of symptomatic epilepsy caused by a past history of herpes encephalitis may have delayed the diagnosis of DHZ. They observe that this patient's diabetes and chronic renal failure, combined with steroid pulse therapy followed by 40 mg daily of oral prednisolone led to severe immunosuppression, which in turn may have accelerated progression of DHZ and death, despite acyclovir treatment.

Risk factors for DHZ include HIV/AIDS and human T-cell leukemia virus type 1.^2,3

Other factors associated with an increased risk of opportunistic infection include prednisolone (≥10 mg/day; 1.6 times higher), diabetes mellitus (1.8 times higher), and steroid use.⁴ Furthermore, case authors noted that mortality rate is approximately 55% in patients who have DHZ accompanied by disseminated intravascular coagulation, meningoencephalitis, and pneumonia.⁵

Diagnostic considerations

Patients with suspected zoster infection without a skin rash may be diagnosed with combined serological and CSF studies using PCR. Notably, varicella zoster virus (VZV) is the third most common cause of viral meningitis, and 44% of these patients present without a skin rash.⁶

While combining molecular testing for herpes simplex virus and VZV infection, including polymerase chain reaction (PCR) assay with antibody tests, is useful for the diagnosis and exclusion of virus-induced neurologic disease, results of routine antibody tests may show false-positive reactions or reactions due to prior infection.⁷

In this case, for example, authors note that the presence of VZV IgG could have been related to persistent titers from the previous disease, with a false positive VZV IgM, or reactivation of VZV IgM due to a systemic illness not due to DHZ.

Noting that the meningoencephalitis is comparatively less likely to be due to DHZ than it is to HSV,⁸ clinicians reporting this case explained that HSV PCR was performed for the analysis of the CSF and VZV PCR was not performed. Although a positive serum IgM and intrathecal IgG was consistent with the diagnosis of DHZ, they noted that VZV PCR of the CSF should be performed to obtain a definite diagnosis.

Conclusion

In immunosuppressed patients who present with seizures and impaired levels of consciousness, case authors stress the importance of performing a thorough skin examination, including the genital area, to avoid a delay in diagnosis.

References

1. Fujisato S et al. A fatal case of atypical disseminated herpes zoster in a patient with meningoencephalitis and seizures associated with steroid

immunosuppression. Am J Case Rep 2018; 19: 1162-1167

2. Mabuchi T et al. Case of disseminated vesicles of herpes zoster developing one day before the onset of local eruption in a hospitalized immunocompromised patient. Tokai J Exp Clin Med 2013; 38: 52–54

3. Fujii N et al. Disseminated herpes zoster with multifocal neurologic involvement in an HTLV-1 carrier. Intern Med 1993; 32: 854–56

4. Greenberg JD et al. Association of methotrexate and

tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry. Ann Rheum Dis 2010; 69: 380–86

5. Schiller GJ et al. Abdominal presentation of varicella-zoster infection in recipients of allogeneic bone marrow transplantation. Bone Marrow Transplant 1991; 7: 489–91

6. Becerra JC 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: e529–34

7. DeBiasi RL et al. Use of PCR for the diagnosis of herpes virus infections of the central nervous system. J Clin Virol 2002; 25 (Suppl. 1): S5–11

8. Wada-Isoe K et al. Epidemiological study of acute encephalitis in Tottori Prefecture Japan. Eur J Neurol 2008; 15: 1075–79

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