the prognosis mainly depends on the viral pathogenicity , the host immune status , and the availability of virostatic therapy . herpes simplex virus type i ( hsv-1 ) is the most commonly recognized virus of such an acute , sporadic encephalitis worldwide . the lethality without virostatic therapy was about 70% and could be lowered to 14 - 20% with the aid of a treatment regimen like acyclovir signs and symptoms of this rapidly progressive disease include headache for a few days , followed by acute confusion , focal deficits , seizures or hemiparesis , hallucinations , and altered levels of consciousness . our intention by presenting three cases is to alert for atypical manifestations of herpes simplex encephalitis ( hse ) . we recommend a high index of suspicion , and repeated clinical and laboratory test when facing an encephalitic syndrome . a 48-year - old man with known symptomatic epilepsy reported diarrhea and fever for some days . thus the emergency physician administered 7.5 mg midazolam intravenously and admitted the patient to the neurological department . on admission , the patient was sedated and presented residual aphasia . a meningeal irritation was not noted . there were no visible injuries , therefore a series of seizures due to afebrile infection was presumed . the next 2 days the patient 's condition improved , he was afebrile and no focal neurological deficits were present . electroencephalography showed slightly slowed focal activity on the left temporal side on the background of normal alpha wave activity . the day before the planned discharge from inpatient care , the patient suffered with sudden onset of a series of epileptic seizures progressing to a convulsive status with high fever of 40c . as anticonvulsive agents phenytoin , levetiracetam , midazolam , and propofol were applied , the cranial computed tomography ( cct ) scan at this time revealed hyodensities in the right temporal lobe and the right insular cortex [ figure 1a ] . the following cerebrospinal fluid ( csf ) analysis showed elevated lymphocytic cell count ( 27/l ; normal < 4 ) with normal glucose but elevated protein ( 699 mg / dl ( normal < 450 ) ) , indicating an inflammatory csf syndrome . polymerase chain reaction ( pcr ) assay for hsv-1 was tested positive . a treatment regimen was implemented with acyclovir ( 10 mg / kg body weight ) three times daily for 21 days . cranial magnetic resonance imaging ( mri ) on day 10 showed extended encephalitic changes in the right frontal and temporal lobe [ figure 1b ] . after a rehabilitation program , follow - ups took place as an outpatient . yet due to neuropsychological impairments he can not work in his profession as a carpenter anymore . under the current antiepileptic therapy ( levetiracetam 1500 mg daily ) , the patient is seizure - free . ( b ) 10 days later , axial t2-weighted mr image shows increased signal intensity in the right temporal and frontal lobe an 84-year - old woman was found on the floor with altered mental status and myoclonic jerks . some days earlier , levofloxacin was prescribed by her physician due to cystitis . on admission , the working diagnosis in the emergency room was quinolone associated delirium . in order to exclude other etiologies , a cct was performed , revealing a hypodense lesion in the right temporal lobe [ figure 2a ] . the following csf analysis showed elevated lymphocytic cell count ( 36/l ; normal < 4 ) and protein ( 961 mg / dl ( normal < 450 ) ) ; lactate and glucose were normal [ figure 2b ] . a therapy with acyclovir ( 10 mg / kg every 8 h for 14 days ) was initiated . gradually the patient recovered and took part in a rehabilitation program . a year later , the patient was admitted due to a symptomatic seizure . at this time ( b ) 4 days later axial t2-weighted mr image shows increased signal intensity in the right temporal lobe and additional movement artefacts a 51-year - old diabetic woman was admitted to hospital with fever and acute confusion . in the emergency department a cct was unremarkable [ figure 3 ] and lumbar puncture showed 1 cell/l ( normal < 4 ) and slightly elevated protein 646 mg / dl ( normal < 450 ) with normal glucose . as blood glucose was high ( 351 mg / dl ) , an infection triggered diabetic disorder was suspected . however , as fever continued and confusional symptoms predominated , a second lumbar puncture was performed . the result , this time , showed elevated cell count ( 31 cells/l , normal < 4 ) and elevated protein 1157 mg / dl ( normal < 450 ) . hsv was tested positive in the first and second csf sample by pcr . despite virostatic therapy with intravenous acyclovir ( 10 mg / kg every 8 h for 21 days ) furthermore neuroradiologically severe left - hemispheric encephalitic changes could be observed [ figure 3c ] . after a prolonged rehabilitation program , ( a ) unenhanced axial ct scan shows no significant changes in the left temporal lobe . ( c ) 14 days later , unenhanced axial ct scan shows marked hypodensity in the left temporal lobe a 48-year - old man with known symptomatic epilepsy reported diarrhea and fever for some days . thus the emergency physician administered 7.5 mg midazolam intravenously and admitted the patient to the neurological department . on admission , the patient was sedated and presented residual aphasia . a meningeal irritation was not noted . there were no visible injuries , therefore a series of seizures due to afebrile infection was presumed . the next 2 days the patient 's condition improved , he was afebrile and no focal neurological deficits were present . electroencephalography showed slightly slowed focal activity on the left temporal side on the background of normal alpha wave activity . the day before the planned discharge from inpatient care , the patient suffered with sudden onset of a series of epileptic seizures progressing to a convulsive status with high fever of 40c . as anticonvulsive agents phenytoin , levetiracetam , midazolam , and propofol were applied , the cranial computed tomography ( cct ) scan at this time revealed hyodensities in the right temporal lobe and the right insular cortex [ figure 1a ] . the following cerebrospinal fluid ( csf ) analysis showed elevated lymphocytic cell count ( 27/l ; normal < 4 ) with normal glucose but elevated protein ( 699 mg / dl ( normal < 450 ) ) , indicating an inflammatory csf syndrome . polymerase chain reaction ( pcr ) assay for hsv-1 was tested positive . a treatment regimen was implemented with acyclovir ( 10 mg / kg body weight ) three times daily for 21 days . cranial magnetic resonance imaging ( mri ) on day 10 showed extended encephalitic changes in the right frontal and temporal lobe [ figure 1b ] . after a rehabilitation program , follow - ups took place as an outpatient . yet due to neuropsychological impairments he can not work in his profession as a carpenter anymore . under the current antiepileptic therapy ( levetiracetam 1500 mg daily ) , the patient is seizure - free . ( b ) 10 days later , axial t2-weighted mr image shows increased signal intensity in the right temporal and frontal lobe an 84-year - old woman was found on the floor with altered mental status and myoclonic jerks . some days earlier , the patient was somnolent and disorientated , but without meningeal irritation . on both arms , the working diagnosis in the emergency room was quinolone associated delirium . in order to exclude other etiologies , a cct was performed , revealing a hypodense lesion in the right temporal lobe [ figure 2a ] . the following csf analysis showed elevated lymphocytic cell count ( 36/l ; normal < 4 ) and protein ( 961 mg / dl ( normal < 450 ) ) ; lactate and glucose were normal [ figure 2b ] . a therapy with acyclovir ( 10 mg / kg every 8 h for 14 days ) was initiated . a year later , the patient was admitted due to a symptomatic seizure . at this time , she still showed marked neurocognitive impairment , needing moderate home care . ( b ) 4 days later axial t2-weighted mr image shows increased signal intensity in the right temporal lobe and additional movement artefacts a 51-year - old diabetic woman was admitted to hospital with fever and acute confusion . in the emergency department , no signs of meningeal irritation and focal neurological signs were detected . a cct was unremarkable [ figure 3 ] and lumbar puncture showed 1 cell/l ( normal < 4 ) and slightly elevated protein 646 mg / dl ( normal < 450 ) with normal glucose . as blood glucose was high ( 351 mg / dl ) , an infection triggered diabetic disorder was suspected . however , as fever continued and confusional symptoms predominated , a second lumbar puncture was performed . the result , this time , showed elevated cell count ( 31 cells/l , normal < 4 ) and elevated protein 1157 mg / dl ( normal < 450 ) . hsv was tested positive in the first and second csf sample by pcr . despite virostatic therapy with intravenous acyclovir ( 10 mg / kg every 8 h for 21 days ) furthermore neuroradiologically severe left - hemispheric encephalitic changes could be observed [ figure 3c ] . after a prolonged rehabilitation program , ( a ) unenhanced axial ct scan shows no significant changes in the left temporal lobe . ( c ) 14 days later , unenhanced axial ct scan shows marked hypodensity in the left temporal lobe the characteristic clinical presentation of a viral encephalitis usually consists of fever , headache , clouding of consciousness , seizures , and often focal neurological deficits such as hemiparesis , ataxia , or dysphasia . besides hsv-1 and -2 , a number of differential diagnoses had to be considered , such as vascular , metabolic , and other noninfective encephalopathies . in all the three patients , it was difficult to make the diagnosis of viral encephalitis . in the first patient with known symptomatic posttraumatic epilepsy , who reported diarrhea , initially , fever was missing . since admission , he had been improved clinically , hence the working diagnosis was a series of seizures , triggered by a gastrointestinal infection . not before the acute onset of high fever and an epileptic status , a concurrent etiology , in particular encephalitis was considered . in the second patient , the working diagnosis was a delirium in the elderly due to the intake of quinolone . primarily encephalitis was not considered . hence , the suspicion was drawn to hse , which was finally proved by csf analysis . in the third patient , normal focal neurological status , normal cct , normal cell count in csf , and missing neck stiffness made an encephalitic cause of the signs and symptoms at the time of admission improbable . initially a disorder associated with known long lasting diabetes was assumed , as current glucose level was elevated . however , as clinical signs and symptoms progressed , a second csf analysis was conducted , leading to correct diagnosis . from our patients first , hse does not always have an abrupt onset with rapid progression , but can show a biphasic course of disease with a period of clinical improvement after a first phase of illness . additionally , in a patient with known epilepsy , a concurrent etiology , such as hse in patient 1 , has to be considered as the trigger of an epileptic status . additionally , the fact that the nondominant lobe of the brain had been affected , might had been initially masking the signs of encephalitis . second , in a delirium in an elderly with cognitive impairment , hse should be included as a potential differential diagnosis . despite hse having a bimodal age distribution ( patients below 20 years of age or above 50 with the peak between 60 and 64 years ) , only few data have been reported about hse in older adults . in a series of 12 elderly hse patients , major symptoms observed in this series had been behavioral changes and disorientation as in patient 2 . these symptoms are common in various disorders in older patients and can easily be misdiagnosed . thus if hse is considered early imaging , preferably a mri , due to its higher sensitivity in the evaluation of patients with encephalitis , csf studies should be performed . third , regarding hse , early csf analysis can show a normal cell count as in patient 3 . such a constellation has been reported lately in patients with a recent history of whole - brain - irritation , suggesting an anergic course of hse . furthermore , it could be demonstrated in 2 - 3% of patients with hse that a positive pcr of csf for hsv could be confirmed , but no other pathological csf parameters . even these patients were all immunocompromised , as most other single patients reported earlier . in all patient despite normal csf cell count , test on hsv-1 by pcr assay was positive as reported by jakob , et al . , however , even pcr assay can be negative , leading to premature termination of antiviral treatment . in conclusion , diagnosis of hse is challenging , needing a high grade of suspicion and a high willingness to reconsider the initial working diagnosis . csf analysis and brain imaging are mandatory for identifying cns symptoms . moreover , as a first line of treatment , acyclovir is to be considered early , even before any proven diagnosis .
herpes simplex encephalitis ( hse ) still remains a serious illness with high morbidity and mortality . 
 the characteristic presentation of hse usually consists of fever , headache , and altered mental function . 
 we present three patients with atypical features of hse . 
 first , a 48-year - old man with symptomatic posttraumatic epilepsy , who developed a gastrointestinal infection , seizures , and fever . 
 after significant clinical improvement , the patient had fever again and developed a status epilepticus , which led to the diagnosis of hse . 
 second , an 84-year - old woman with hyperactive delirium after levofloxacin intake . 
 cranial computed tomography ( cct ) revealed hypodense temporal changes , prompting lumbar puncture and diagnosis of hse . 
 third , a 51-year - old diabetic woman presented with fever and acute confusion . as cct and cell count of cerebrospinal fluid ( csf ) were normal , infection and hyperglycemia as initial diagnoses were postulated . due to aphasic symptoms , the differential diagnosis of a stroke was taken into account . 
 thus a second lumbar puncture led to the correct diagnosis of hse . 
 these atypical presentations need a high grade of suspicion and a high willingness to reconsider the initial working diagnosis , in order to prevent a diagnostic delay .