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HIV CNS escape syndrome is characterized by high viral load in the CNS despite having low serum viral load.
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The neurological manifestation of HIV CNS escape syndrome include acute onset of headache, tremors, cognitive impairment, focal neurologic deficit, seizures, behavioral disturbance, and dysarthria.
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New onset refractory status epilepticus is a rare sequalae of HIV CNS escape syndrome.
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It is critical to consider HIV CNS escape syndrome early on during the investigation of NORSE as it requires changing anti-viral treatment.
]. The neurological manifestations of CNS viral escape syndrome that have been reported include insidious or acute onset of headache, tremors, cognitive impairment, focal neurologic deficit, seizures, behavioral disturbance, and dysarthria [
]. We report a unique case of HIV CNS escape syndrome in a 47-year-old female with controlled HIV who presented with new-onset refractory status epilepticus (NORSE), that was seronegative for all the commercially available testing for autoimmune and paraneoplastic encephalitides. Our case underscores the diverse neurological manifestations of HIV CNS escape syndrome, that should include NORSE, in otherwise well-controlled HIV patients. Early diagnosis of HIV CNS escape syndrome requires a change in cART which can potentially change neurological outcomes. Therefore, HIV CNS escape syndrome should be considered early in the investigation of NORSE in HIV patients.
2. Case
A 47-year-old female woman with past medical history of HIV on combination antiviral therapy (cART) (Bictegravir, Emtricitabine & Tenofovir) who presented to the hospital due to with a 6-day history of lethargy and decreased oral intake. She reportedly had episodes of staring-off for several months prior to presentation. She was diagnosed with HIV infection in 2002 and had been on cART with good compliance. In the emergency room, she had two episodes of generalized tonic-clonic seizures. Clinical examination revealed spastic tone in the right side, right hemiparesis (power of 3/5 in right upper and lower extremities, according to the Medical Research Council (MRC) grading), consistent with Todd's paralysis.
Brain MRI showed areas of restricted diffusion in the left temporal region (Fig. 1) with correlating, and EEG showing showed increased epileptogenicity in the epileptiform discharges in the left temporal region. EEG monitoring later captured frequent focal seizures, consistent with nonconvulsive status epilepticus, arising from the left temporal area (Fig. 2). These were resistant to multiple antiepileptic drugs (AEDs) medications including levetiracetam, valproate, lacosamide and perampanel, leading to use of intravenous sedation. Electrographic seizures continued to persist for longer than 24 h despite using use of four AEDs and midazolam infusion, making the seizures consistent with super-refractory status epilepticus. Finally, seizure control was achieved with the use of pentobarbital infusion, which was maintained for two days. As Pentobarbital was gradually weaned off, electrographic seizures controlled with five AEDs at day 10 of hospitalization.
Fig. 1Brain MRI: (A) coronal and (B) axial images show FLAIR hyperintensity in left temporal lobe. Images (C) and (D) demonstrates diffusion restriction in the left hippocampus (white circled) and left insular cortex (blue arrow) suggestive of post-ictal changes.
Further work-up revealed that the CD4 count was 134 cells/uL and serum HIV viral load was 33 copies/mL. First CSF analysis showed 31 leukocytes/mm3 (97% lymphocytes), elevated protein (110 mg/dL), and normal glucose levels. CSF culture was sterile. CSF PCR testing for bacterial and viral meningitis was negative. CSF culture was sterile. CSF PCR testing for bacterial and viral meningitis were all was negative including JC virus. Extensive workup was done to rule out autoimmune and paraneoplastic etiologies of the NORSE, and was negative. A wide array of autoimmune and paraneoplastic antibodies in both serum and CSF, including Antibodies tested for in serum and CSF included (but were not limited to) anti-N-methyl-d-aspartate receptor (NMDAR), CRMP-5-IgG, AGNA-1, Amphiphysin Ab, DPPX Ab IFA, anti-amphiphysin, and anti-voltage-gated potassium channel-complex (VGKC), were negative. CT scans of chest, abdomen and pelvis, as well as pelvic ultrasound were unrevealing for malignancies.
She initially received a 3-day course of intravenous methylprednisolone, and 5-day course of IVIG for a presumed autoimmune/paraneoplastic encephalitis. However, she remained comatose even after seizures were controlled. After extensive workup for most known causes of NORSE was unrevealing, CSF HIV load was checked, and was surprisingly elevated at 34,949 copies/mL. HIV genotype resistance analysis from the CSF revealed methionine replacing valine mutation at position 184 (M184V). However, infectious disease team believes that the poor penetrance of her prior HIV medication was reason for the escape syndrome. Consequently, antiretroviral medications were switched to Abacavir and Lamivudine, darunavir, and dolutegravir to improve the CNS penetrance. The subsequent CSF analyses after medication changes continued to show lymphocytic pleocytosis with reduction in HIV load (1860 copies/mL).. At the time of discharge to a long-term acute care facility, she remained comatose despite being seizure free. A 3-month follow-up showed no change in neurological state.
3. Discussion
While 5–10% of patients compliant with cART have detectable HIV viral load in CSF, only a small minority are symptomatic. [
]. However, reports of NORSE from HIV escape syndrome in the literature are scarce. Moloney et al. reports two cases of HIV CNS viral escape syndrome presenting with seizures in which NMDA antibodies were detected. One of their patients sustained non-convulsive status epilepticus similar to our case [
HIV CNS viral escape syndrome is a diagnosis of exclusion in HIV infection patients presenting with neurologic symptoms. Such patients require extensive evaluation to rule out opportunistic infections and collaboration with an infectious disease specialist. In addition to testing for opportunistic infections, appropriate investigations should include MRI brain, lumbar puncture for a quantitative CSF HIV viral load, serum HIV viral load, and EEG. To diagnose, CSF HIV load should be 0.5 log higher than plasma HIV load, or HIV must be detectable in CSF and undetectable in plasma and other possible etiologies must be ruled out [
Treatment of HIV CNS viral escape syndrome requires changing cART to a combination with improved CNS penetration. Studies have shown that most patients with HIV viral escape syndrome improve or have resolution of their neurologic symptoms after changing their cART [
]. Unfortunately, our patient did not show any significant clinical improvement, possibly due to prolonged status epilepticus.
CNS viral escape syndrome should be in the differential for HIV patients with a variety of neurologic symptoms, including seizure. Neurologist should be cognizant of this syndrome, as it requires specific testing (CSF HIV load), which is otherwise not commonly performed, as well as treatment change in cART.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
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