Herpes Encephalitis
CASE
A 70 year-old male, with a past medical history of hypertension, gastroesophageal reflux disease, chronic lymphocytic leukemia on Ibrutinib, and coronary artery disease, presented with right hand weakness since waking that morning. He reported that he felt the strength of his grip was not at baseline, and his wife also noted that, while eating breakfast, the patient dropped his bagel, a dish towel, and his utensils. His last known well was 10:00 PM the night before, although he also endorsed two weeks of persistent right hand numbness and burning paresthesias in his right hand. He denied headache, fever/chills, chest/back/abdominal pain, nausea/vomiting, urinary symptoms, or diarrhea, as well as any visual symptoms, speech changes, or gait problems.
His symptoms were initially concerning for a possible stroke, but CT angiography for an emergent large vessel occlusion (CTA ELVO) was negative. Labwork, including a basic metabolic panel, complete blood count, troponin, urinalysis, and urine drug screen were all negative. The patient was admitted to the hospital and received an MRI that was notable for an abnormal signal intensity involving the left postcentral gyrus, which was thought to represent subacute infarct. He was seen by neurology and discharged the next day with a diagnosis of subacute cerebral infarct with persistent paraesthesia of the right upper extremity.
Unfortunately, the patient returned the next day with hand spasms. He felt like his right hand was involuntarily closing and he continued to be uncoordinated, weak, numb, and was dropping things. One hour prior to arrival he also had dysarthria and word finding difficulty. On arrival, he felt nauseated and lightheaded, and also endorsed new urinary incontinence.
In the emergency department, patient had an episode during which his right arm became flexed, his head turned to the right, and he was noted to have clonic shaking of arm. This lasted for 30 seconds to 1 minute. He had impaired speech during this time. Afterward, the patient was fully alert and oriented, with mild dysarthria and stuttering speech. Cranial nerve exam was normal; however, patient had persistent, intermittent rhythmic clonic flexion of his right arm every 2-3 seconds. He was unaware of this movement and could not suppress it. Right upper extremity strength was 0/5, but left upper extremity strength was 5/5 LUE. He had full strength in his lower extremities. The patient also had no sensation to pain or light touch in his right upper extremity.
He was given Ativan and Keppra, however, the clonic movements persisted. He was started on broad antibiotics and antivirals for possible meningitis/encephalitis. A CT brain was negative, and a lumbar puncture was subsequently performed. The cerebrospinal fluid (CSF) results showed more than 30,000 RBC, a protein of 113 mg/dL, and herpes simplex virus (HSV) PCR was positive. He was loaded with more Keppra and Depakote.
DIAGNOSIS
HSV encephalitis (HSVE)
DISCUSSION
While both HSV-1 and HSV-2 can cause encephalitis, HSV-1 constitutes 90% of encephalitis in adults and children. It is bimodal, being most common under 3 years of age and over 50 years of age. Despite a seropositivity of HSV-1 between 60-90% by late adulthood, the incidence of HSVE remains low at 2 to 4 cases per 1,000,000. The exact route of CNS transmission remains uncertain.
In one review, the three most common presenting signs of HSVE were seizures (32%), abnormal behavior (23%), and loss of consciousness or confusion/disorientation (tied for 13%). Classically, we are taught to think of HSVE when a patient presents with altered mental status and seizures; however, the absence of seizures does not rule out HSVE, since only about half of patients ultimately have seizures. To complicate things, immunocompromised patients -- like the patient above -- are less likely to present with focal neurologic deficits, may have atypical CSF results, and are up to six times more likely to die than non-immunocompromised patients.
Typical CSF findings include elevated protein, leukocytosis, and normal glucose. More useful is the HSV PCR assay, which is typically positive within 24 hours of symptom onset and is both highly sensitive and specific (98% and 94%, respectively). Neuroimaging with CT may be normal and therefore falsely reassuring in the early stages of HSVE. One study identified MRI abnormalities in 21% of patients with herpes encephalitis who had normal CT scans.
In addition to supportive management and seizure prophylaxis, early IV acyclovir continues to be the treatment of choice but morbidity and mortality remains high. Nearly 20% of patients require mechanical ventilation with around 11-15% in-hospital mortality (improved from 70% mortality in the years prior to the advent of IV acyclovir). One year mortality between 5-15% with survivors having high rates of neuropsychological abnormalities or persistent seizure disorders. Recurrence of HSVE is uncommon, and is more predominant in patients who are treated with shorter regimens.
CASE RESOLUTION
The patient was admitted to neurology and continued on acylovir. A repeat MRI showed a new diffusion-weighted imaging (DWI) abnormality in left insular cortex, left frontal lobe, and left thalamus. There was also left ACA territory DWI changes without ACD or FLAIR correlate or enhancement. Patient had an EEG with ongoing seizures refractory to Keppra, Valproate, carbamazepime, Lacosamide, and benzodiazepines. He also had progressively worsening hypoxia and tachypnea requiring intubation. He was unable to be weaned from the ventilator, underwent tracheostomy/PEG, and was discharged to a skilled nursing facility after a two-month hospitalization.
TAKE-AWAYS
While patients will classically present with seizures and altered mental status, seizures are not a necessary diagnostic criteria for herpes encephalitis.
Immunocompromised patients may also present atypically.
CT scan may not identify early disease.
Acyclovir is the cornerstone of treatment, and recurrence is low when treated with an appropriate antiviral course.
FACULTY REVIEWER
Dr. Libby Nestor
RESOURCES
Brandsaw MJ, Venkatesan A. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management. Neurotherapeutics. 2016 Jul;13(3):493-508.
Gnann John W, Whitley Richard J. Herpes Simplex Encephalitis: an Update. Curr Infect Dis Rep (2017) 19: 13.
Jouan Youenn, Grammatico-Guillon Leslie, Espitalier Fabien, Cazals Xavier, Francois Patric, and Guillon Antoine. Long-term outcome of severe herpes simplex encephalitis: a population-based observational study. Critical Care (2015): 19: 345.
Oud Lavi. Herpes Simplex Virus Encephalitis: Patterns of Epidemiology and Outcomes of Patients Admitted to the Intensive Care Unit in Texas, 2008 - 2016. J Clin Med Res. 2019 Dec; 11(12): 773–779.