A 31-year-old man presented to the emergency department with a 3-day history of headache along with nausea and vomiting, 5 h of confusion followed by generalized tonic-clonic seizures and fevers to 38.9 C. His seizures occurred twice within an hour, lasting about 5 min and 2 min each and resolving spontaneously. The patient did not have personal or family history of seizures. His past medical history was significant for an AML with t (8; 21) (q22; q22.1)/RUNX1-RUNX1T1 6 months prior. Meanwhile, when he was first diagnosed with AML, he also had a widespread papular rash with vesicles in the lip, trunk, and extremities, which suggested varicella with VZV infection. With the diagnosis of AML, the patient received a standard 7 + 3 IA regimen (idarubicin 10 mg/m2 for 3 days, cytarabine 100 mg/m2 for 7 days) as induction chemotherapy which achieved complete remission. Considering the VZV infection, the patient simultaneously received intravenous acyclovir and foscarnet sodium, after which the skin lesions were fully recovered. During regular chemotherapy, although the CSF pressure and routine analysis were normal, the intrathecal chemotherapy with cytarabine, methotrexate, and dexamethasone was prophylactically given. Consolidation chemotherapy with another cycle of IA and 2 cycles of high dose cytarabine was administered, and he remained in complete remission. An outline of the episodes is described in Figure 1.
On admission, his vital signs included a temperature of 37.5 C. A skin examination revealed a few scattered erythematous rash and varicella in the lip and extremities. In the neurologic examination, the patient was confused and unable to follow complicated commands. Withdrawal reflex response was elicited by noxious stimuli to the upper and lower extremities. Pupils were reactive, but he displayed impaired left eye adduction and right eye abduction. He had signs of meningeal irritation in the form of neck stiffness, positive Kernig's, and Lesage's sign. Movement and sensory examination were unreliable due to the patient's altered level of consciousness. He had a palpable bladder. The Babinski sign was positive bilaterally. CT scans of the head showed no acute abnormalities. Considering the skin varicella, intravenous acyclovir (at a dose of 10 mg/kg q8 h) therapy was instituted on day 1 after admission. However, it is doubtful whether the skin varicella on admission was the reactivation of VZV.
Based on the initial presentation, a broad differential diagnosis was considered. First, we should consider the localization for his presentation. The symptoms of headache, confusion, and seizures clinically suggested a central rather than peripheral etiology. Neck stiffness indicates involvement of the meninges, and generalized tonic-clonic seizures suggest diffuse cortical involvement. The urinary retention suggests either bi-hemispheric lesions or a spinal cord lesion; Second, we should consider the etiology of his presentation. The differential etiology included infection (e.g., meningoencephalitis, meningomyelitis, and progressive multifocal leukoencephalopathy), intracranial malignancy (e.g., CNS leukemia, leptomeningeal carcinomatosis, and paraneoplastic syndromes), toxic encephalopathy (e.g., chemotherapy-induced), inflammatory etiologies (e.g., autoimmune encephalitis and acute disseminated encephalomyelitis), and vascular (e.g., cerebral venous sinus thrombosis).
On day 2 after admission, the lumbar puncture revealed xanthochromic CSF with a slow flow rate. The patient's CSF opening pressure was normal (140 mm H2O). CSF analysis showed pleocytosis (630 total nucleated cells/mul with 70% mononuclear cells), marked elevation in protein at 10.326 g/L, normal glucose/chloride, negative Gram stain, negative Cryptococcal antigen, negative PCR for Mycobacterium tuberculosis, and negative bacterial cultures. Immunoglobulin M (IgM) antibodies for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus were negative.
On day 5 after admission, the cytology testing of CSF revealed 4% lymphocytes, 2% monocytes, and 94% atypical cells (Figure 2A). Brain MRI with contrast was reported as multiple abnormal signals in the cortex, extensive pachymeningeal enhancement, and irregular thickening (Figure 3A). The Magnetic resonance venography and diffusion-weighted imaging were normal. MRI of the cervical and thoracic spine showed T2 hyperintense lesions located at C2-C3 and T6-T9, with partial enhancement (Figure 3E).
Based on the above examinations, we have a debate about the diagnosis. The fever and apparent immunocompromise support infectious causes. CSF profile of pleocytosis, high protein level, and normal glucose/chloride helped to confine the differential diagnosis to virus, bacteria, tuberculosis, and fungi. The serum and CSF screens for bacteria, tuberculosis, and fungi were normal. Thus, we excluded the CNS infections with bacteria, tuberculosis, and fungi. The varicella infection supported the suspicion of meningoencephalitis associated with VZV. However, brain MRI of our patient showed obvious enhancement and thickening of pachymeninges. The pachymeningeal enhancement was different from the typical MRI imaging of viral meningitis, which often presented with diffuse enhancement along the leptomeninges. Furthermore, his CSF analysis showed marked elevation in protein at 10.326 g/L, which is rare in viral infections. Moreover, CSF cytology suggested 94% atypical cells. Based on his past medical history, the suspected presence of atypical cells in CSF raised the concern for CNS leukemia. The above diagnostic workup was unable to differentiate between VZV infections and CNS leukemia. Thus, additional testing should be performed.
The flow cytometric analysis was proved to be a sensitive test for detecting CNS involvement when compared to traditional CSF cytology. On day 7 after admission, cell phenotypes of immune cells were detected by flow cytometry from CSF. The cell-surface markers used in flow cytometry include CD45, CD14, CD64, CD117, CD3, CD4, and CD19, which showed a predominance of mature lymphocytes (93.6%) and rare monocytes (0.7%). No myeloblasts and no cells of the prior leukemic immunophenotype were identified. Thus, we speculated that the atypical cells in CSF cytology do not belong to the malignant clone but are reactive. Furthermore, the AML1-ETO fusion gene in CSF and bone marrow was also negative. The negative results of flow cytometry and AML1-ETO fusion gene from CSF should cast doubt on the diagnosis of CNS leukemia.
Given the strong suspicion for viral meningoencephalitis, other CSF tests were also conducted on day 7 after admission. On this set of CSF studies, metagenomic next-generation sequencing (mNGS) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to further assess for an infectious cause. The mNGS has the capability of rapid, sensitive, and accurate pathogen identification. The sequencing detection identified 15,281 (out of 16,544) sequence reads uniquely aligned to the VZV genome, and these reads covered a high percentage (92.37%) of the VZV (Figure 4). The presence of VZV DNA in CSF was further verified by VZV-specific qRT-PCR. The CSF qRT-PCR was positive for VZV.
Based on the positive mNGS and confirmatory qRT-PCR test, a final diagnosis of VZV meningoencephalitis with meningomyelitis was made. The patient received an additional foscarnet sodium (3g q12 h) on day 7 after admission. The combined use of acyclovir and foscarnet sodium resulted in a steady improvement in symptoms. After combination therapy, repeated CSF studies on day 19 after admission revealed 95% lymphocytes and 5% monocytes. Meanwhile, no atypical cells were found in the cytology testing of CSF (Figure 2B). On day 7 after admission, the skin varicella showed gradual recovery. A repeated MRI on day 29 after admission showed less meningeal enhancement (Figures 3B,F). During the entire treatment course of hospitalization, we did not use steroids.
By the time of discharge (hospital day 62), the patient was conscious, and denied headache fever. No fever and seizure occur during hospitalization. Examination revealed normal eye movements, normal strength/sensation, normal coordination/gait testing, and no nuchal rigidity. But the Kernig's sign and left-sided Babinski's sign were still positive. Repeated CSF studies revealed a clear appearance, pleocytosis (18 total nucleated cells/mul), and elevated protein (1.2 g/L). Compared with the CSF on admission, the pleocytosis and elevated protein were significantly alleviated. A repeated brain MRI revealed obvious resolution of the previous abnormal pachymeningeal enhancement (Figure 3C). At the 6-month follow-up visit, he denied headache, nausea, vomiting, diplopia, and confusion. Repeated CSF studies revealed normal cell count and protein (Table 1). The repeated brain MRI revealed no abnormal meningeal enhancement (Figure 3D).