herpes simplex virus encephalitis ( hse ) is an acute infection accompanied by significant morbidity and mortality with the diagnosis often made by cerebrospinal fluid ( csf ) polymerase chain reaction ( pcr ) testing .
we report a case of a healthy 35-year - old woman presenting with altered mental status . due to suspicion of herpes encephalitis
, a csf pcr for herpes virus was sent for examination and acyclovir was started .
the patient had an immediate response to acyclovir ; however , when the pcr returned negative she was discharged without therapy .
the altered mental status returned and she was started on acyclovir therapy and a second csf pcr sample was sent and was again negative .
mri performed at initial hospitalization was negative , but a repeat mri demonstrated bilateral temporal lobe involvement suggestive of herpes encephalitis .
csf pcr for herpes virus is highly sensitive and specific and remains the standard for diagnosing herpes encephalitis .
clinicians should be aware of the pitfalls of csf pcr testing , specifically false - negative results .
herpes simplex virus encephalitis ( hse ) is an acute infection accompanied by significant morbidity and mortality .
clinically , hse has a prodrome of fever , headache , seizure , focal neurologic signs , and altered consciousness ; however , mild or atypical presentations have been reported [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ] .
the diagnosis of hse is generally clinical with confirmatory tests including lumbar puncture and cerebrospinal fluid ( csf ) polymerase chain reaction ( pcr ) testing .
auxiliary tests to aid diagnosis include electroencephalogram ( eeg ) , computed tomography ( ct ) , and especially magnetic resonance imaging ( mri ) .
we present a patient initially suspected to have hse although with a negative mri and csf examination including pcr for herpes simplex virus ( hsv ) .
the patient was started on acyclovir with an initial response but was discharged after the pcr was negative .
the patient returned with worsening symptoms , this time with mri and eeg both suggestive of hse ; however , repeat csf pcr for hsv was again negative . the high sensitivity and specificity of pcr for hsv leads physicians to rely on this test for making or excluding the diagnosis of hse , although false - negative results may occur .
cases with a high pre - test probability for hse and suggestive mri and/or eeg examinations , although with two false - negative pcr tests , are seldom encountered or reported in the literature .
a 35-year - old hispanic female without a significant past medical history arrived at the emergency department complaining of headache , dizziness , nausea , and vomiting for 2 days prior to admission .
the headache was localized to the frontal region and accompanied by photophobia and phonophobia and six episodes of vomitus . immediately prior to admission ,
the patient had had a witnessed generalized seizure of 30 - 45 s duration without bowel or bladder incontinence and developed postictal confusion without postictal lateralized neurological deficits . at the time of admission , she was disoriented to person , place , and time with a gcs of 9 .
lumbar puncture revealed clear fluid with glucose 69 mg / dl , protein 31 mg / dl , 2 wbc , 3 rbc , no monocytes or lymphocytes , and without xanthochromia .
urine analysis , toxicology , culture of blood , csf , and urine were all negative .
acyclovir ( 10 mg / kg i.v . , 3 times per day ) was started as empiric treatment in addition to levetiracetam for seizure prevention .
eeg showed generalized slowing suggestive of encephalopathy although it was extremely limited due to patient movement and inability to cooperate .
twenty - four hours after initiation of acyclovir the patient was lethargic but not confused .
forty - eight hours following admission , the patient 's mental status was reported to be at baseline , gcs 15 , and she was eager to return home .
acyclovir was switched to oral preparation and after one dose , the csf hsv - pcr returned negative , and the patient was discharged without further need to continue antiviral medication . within 24 h , she returned to the emergency department complaining of severe headaches , vomiting , and an episode of unresponsiveness , slurred speech , and blank starring as reported by family members . at the time of admission
, she had intermittent episodes of confusion ; however , the remainder of the physical examination was normal .
acyclovir ( 10 mg / kg i.v . , 3 times per day ) was restarted .
repeat lumbar puncture was performed with glucose 79 mg / dl , protein 24 mg / dl , 50 wbc , 17 rbc , and negative for xanthochromia , cryptococcal antigen , vdrl , rpr , bacterial antigens , lyme , west nile antigen , and cmv antigen .
after careful consideration of the differential diagnosis of our patient , attempts were made to exclude limbic encephalitis with nmda receptor antibody test , which was ultimately negative .
overnight , the patient became increasingly confused , delirious , and extremely agitated followed by a witnessed tonic - clonic seizure .
respiratory distress ensued , and due to the inability to protect her airway , intubation and mechanical ventilation was initiated and a loading dose of valproic acid was started for seizure control .
she became febrile to a maximum of 101.3f ( 38.5c ) and developed thick endobronchial secretions identified as gram - positive cocci and gram - negative rods .
she remained febrile with a chest x - ray finding suggestive of developing infiltrate at the right lung base .
repeat eeg demonstrated absence of normal background activity with generalized slowing and presence of periodic lateralized epileptiform discharges .
repeat mri had increased signal intensity in the medial aspect of the temporal lobes , more marked on the left than on the right , and was felt to be compatible with an acute phase of herpes encephalitis ( fig . 1 , fig .
the patient remained encephalopathic for 1 week with minimal improvement during which time her pneumonia resolved .
three weeks after the second admission , the patient had returned to baseline and was able to leave the medical center . written informed consent
was obtained from the patient for use of medical information and images for publication of this case report .
a copy of the written informed consent is available for review by the editor - in - chief of this journal .
with the discovery of pcr , diagnosis of central nervous system infections has become more sensitive and specific , particularly with infections caused by the herpes virus .
pcr is considered the standard for the diagnosis of hse , although specific csf serologic testing can be employed in cases where suspicion remains high in the setting of a negative pcr test .
retrospective diagnosis can be made with the presence of anti - hsv igg in the csf .
pcr allows for the detection of minute quantities of viral dna or rna present in fluids and tissues by nucleic acid amplification over a short time period   and has nearly replaced brain biopsy for diagnosis of hse in regions where the test can be performed .
negative pcr tests are associated with low csf protein and leukocyte counts , and in such cases , clinical suspicion should dictate the treatment course . the sensitivity and specificity of csf pcr for hsv exceeds 95% , allowing exclusion of hse in patients with high pre - test probability should the result return negative . in the study by lakeman and whitley ,
pcr sensitivity and specificity were reported as 98 and 94% , respectively , with positive and negative predictive values of 95 and 98% , respectively , when compared with brain biopsy .
however , in patients with high clinical probability of hse , a negative pcr result , while decreasing the likelihood of hse , does not entirely exclude the possibility of infection .
few reports exist identifying hse in patients with negative pcr [ 13 , 14 , 15 ] .
reported a series of 3 cases of hse confirmed by csf antibody testing in the setting of negative pcr tests .
possible explanations for negative pcr results have been suggested and include : pcr sent very early in the disease development ( days 1 - 4 with neurological symptoms ) and viral load too low for detection , although this is unlikely as the pcr technique by virtue of the amplification process allows for the detection of minute amounts of viral copies , as low as 10 copies of viral inhibitors , and a small - volume csf sample [ 11 , 14 , 16 ] .
in addition , low csf cell counts , variation in primers used during pcr processing , sample dilution , and location of infection in the central nervous system have all been suggested as the cause for false - negatives results [ 1 , 14 , 17 ] .
recommend repeating the pcr 4 days after development of symptoms and before deciding the patient does not have hse and prematurely concluding acyclovir treatment .
patients with normal diagnostic tests and mild clinical symptoms are more likely to have negative pcr tests . in our case ,
the patient had a repeat pcr sent 6 days after the development of symptoms , and despite suggestive mri and eeg and worsening clinical symptoms , the result was negative .
attempts were made to uncover an alternative diagnosis according to the experiences highlighted by chataway et al . .
radiographically , the most common areas of involvement are the medial temporal lobes , which are best observed with mri .
sensitivity of mri is reported to be best 48 h after onset of symptoms and approaches 85% , although it can be falsely negative in very early stages on infection .
eeg may serve as an occasional adjunct in the diagnosis of hse , demonstrating periodic lateralized epileptiform discharges as characteristic findings .
specificity of eeg remains low in the diagnosis of hse when used as a single diagnostic exam but can be helpful when pcr is negative in patients with high clinical probability . in our case , the mri on initial presentation failed to demonstrate any significant areas of disease , although repeat mri , 6 days following onset of symptoms , revealed florid changes suggestive of hsv infection .
treatment course is weight based in adults , roughly 10 mg / kg every 8 h intravenously for 10 - 21 days .
suspicion of hse should remain high in all cases of acute encephalitis , especially in the absence of alternative diagnoses , even in cases when pcr examination is negative . in such cases , repeating lumbar puncture should be entertained with repeat hsv - pcr testing and possible serologic testing of the csf . in our case , the patient had clinical symptoms , mri and eeg suggestive of hse , although with two negative pcr tests separated in time . in patients with high clinical suspicion and negative hsv - pcr ,
repeat lumbar puncture should be considered and empirical acyclovir treatment should be considered . in our case ,
continuation of acyclovir was warranted and proved efficacious as the patient achieved near - complete resolution . in all such cases ,
the authors report that there are no conflicts of interest . no monetary compensation or grants
 introductionherpes simplex virus encephalitis ( hse ) is an acute infection accompanied by significant morbidity and mortality with the diagnosis often made by cerebrospinal fluid ( csf ) polymerase chain reaction ( pcr ) testing.case presentationwe report a case of a healthy 35-year - old woman presenting with altered mental status . due to suspicion of herpes encephalitis 
 , a csf pcr for herpes virus was sent for examination and acyclovir was started . 
 the patient had an immediate response to acyclovir ; however , when the pcr returned negative she was discharged without therapy . 
 the altered mental status returned and she was started on acyclovir therapy and a second csf pcr sample was sent and was again negative . 
 mri performed at initial hospitalization was negative , but a repeat mri demonstrated bilateral temporal lobe involvement suggestive of herpes encephalitis . 
 the patient was successfully treated for 21 days with acyclovir.conclusioncsf pcr for herpes virus is highly sensitive and specific and remains the standard for diagnosing herpes encephalitis . 
 clinicians should be aware of the pitfalls of csf pcr testing , specifically false - negative results . 
 although rare , these false negatives can result in premature termination of treatment . 
Introduction
Case Presentation
Conclusion
Introduction
Case Report
Discussion
Conclusion
Disclosure Statement