case51单疱脑炎.doc

Case of the Month Patient #51HistoryPresent Illness: A 40 year old homemaker, previously in good health, experienced a transient episode of left-sided face, arm, and leg numbness lasting about 10 minutes. The following day, she developed recurrent left-sided numbness, with speech disturbance described as difficulty with articulating words. She was taken to a nearby hospital, but on arrival, her symptoms of numbness and dysarthria had spontaneously resolved. A computed tomographic scan of the head was reported as normal, and the patient was admitted for observation. The following morning at 2 a.m., she developed a seizure described by a nurse as grand mal, lasting about 30 seconds with tongue biting and bladder incontinence, and followed by transient confusion and aphasia. Electrolytes and a complete blood count were within normal limits. A lumbar puncture was performed, revealing clear, colorless cerebrospinal fluid with glucose 72 mg/dl, protein 55 mg/dl, 0 white blood cells, and 0 red blood cells). An MRI study of the head with diffusion-weighted and FLAIR sequences was read as normal, and an electroencephalogram likewise showed no abnormalities. Phenytoin was initiated, and the patient returned to her baseline mental status. On the third hospital day, the patient developed a low-grade fever (temperature to 102 F) and delirium with psychotic features. She was able to follow commands. A chest x-ray revealed patchy infiltrates in the left lower lobe. She was treated with ceftriaxone and clindamycin for a presumed aspiration pneumonia, and with olanzapine for management of psychotic symptoms. Her fever persisted, and she became aphasic, with diminished responsiveness. Blood and urine cultures showed no growth. Doxycycline, acyclovir and methylprednisolone were added to her medical regimen, and the patient was intubated for airway protection. A second lumbar puncture was performed, revealing clear, colorless cerebrospinal fluid with an opening pressure of 26 cm H2O, with glucose 81 mg/dl, protein 80 mg/dl, 0 white blood cells, and 0 red blood cells. A repeat EEG showed diffuse slowing with the development of a burst-suppression pattern. On the sixth day of her hospitalization, the patient was transferred to the Ben Taub General Hospital for further evaluation and management. On initial examination in the ICU, the patient exhibited intermittent forced eye deviation to the right, with subtle, rhythmic twitching of the right arm. The serum phenytoin level was 9.7 g/ml, and the patient was loaded with additional phenytoin, with transient improvement in the level of consciousness and disappearance of spontaneous motor manifestations. The Neurology Service was consulted for further evaluation, and noted that the patients level of consciousness had again declined, without evident seizure activity. Past Medical History: Previously healthy. The patients mother reported an apparent insect bite on the neck about five days prior to her hospital admission. No history of surgeries or blood transfusions. Allergies: No known drug allergies. Medications: (at home): Ibuprofen as needed for occasional headache. (in hospital): Aspirin 325 mg q.d., fosphenytoin 100mg q8h, amlodipine 5 mg q.d., famotidine 20 mg q12h, acyclovir 600 mg q8h, digoxin 0.25 mg q.d., methylprednisolone 250 mg q6h, clonidine 0.1 mg q6h. Family History: Diabetes mellitus in a paternal aunt and maternal grandmother. Her father had hypertension, and died of congestive heart failure at age of 78. A second cousin died at age 30 of breast cancer. Social History: The patient was born in India. She spent 12 years in Saudi Arabia before becoming a Texan (12 years in Dallas and 3 years in Houston). She is married with three healthy teenage children. There is no history of smoking, alcohol or illicit drug use. There was no history of recent travel to foreign countries or outside the Houston area. There was no history of swimming in freshwater lakes. Peak temperatures in Houston in October ranged from 80-85 F (27-29 C), and the weather had been unusually dry. Physical ExamGeneral: Well-developed, well-nourished appearing lady lying in supine position, orotracheally intubated and with nasogastric tubing. Vital Signs: Temperature: 102 F (39 C). Blood Pressure: 154/70 mmHg. Pulse: 120/min, regular. Respiration: 12/min (ventilator in assist control mode). Pulse oximetry showed 99-100% saturation. HEENT: Normocephalic, no evidence of trauma; anicteric sclerae; conjunctival injection is evident. No oropharyngeal lesions noted. Neck:Signs of meningismus are present. No lymphadenopathy evident; normal jugular venous pulsations present. Chest: Clear to auscultation bilaterally. Cardiovascular: Tachycardia; no murmurs, gallops, or rubs detected. Abdomen: Soft, not distended; no organomegaly. Normally active bowel sounds. Extremities: No clubbing, cyanosis or edema. Skin examination disclosed no rashes or other lesions. Neurological ExaminationMental Status: Eyes opened to sternal rub and roamed preferentially toward the left side, but the patient did not regard objects or persons. There was no forced eye deviation. There was no response to visual threat. Cranial Nerves: Both pupils responded to light, constricting from 2 mm to 1 mm. Consensual responses were present. The oculocephalic response to passive head movement was present and symmetric. There was no apparent facial asymmetry. There was no response to auditory stimuli. Sensorimotor: Painful stimuli applied to the extremities elicited withdrawal equally in all four limbs, but no localization of stimuli or facial grimacing was observed. No spontaneous movements of the trunk or extremities were evident. Reflexes: Symmetrically very brisk, with distal spread throughout. CSF-Antibodies/Antigen TestReference RangePatient ResultCryptococcal antigenNegativeNegativeCSF-Chem/Cells/VDRL .Reference Range Day 2Day 5Day 7AppearanceClear, ColorlessClear, ColorlessClear, ColorlessClear, ColorlessGlucose40-70 mg/dL72 mg/dL81 mg/dL53 mg/dLProtein10-40 mg/dL55 mg/dL80 mg/dL68 mg/dLRBC0/cu mm000WBC0-5/cu mm 0017PMN.1%Lymphs.97%Monocytes.1%VDRLNonreactiveNonreactiveNonreactiveNonreactiveCSF Culture-AFB No growth detectedCSF Culture-Fungus No growth detected.CSF Culture-Routine Gram stain negative. No growth at 7 daysCSF Culture-Viral NegativeEEG 10 second sweepElectrodes referenced to the ipsilateral ear; odd numbers = left side; even numbers = right side. Lead designations: FP = frontal polar; C = central; O = occipital; T = temporal; A1 = reference electrode, left ear; A2 = reference electrode, right ear. 窗体顶端窗体底端EEGDiffuse slowing of background activity is apparent, with FIRDA (frontal intermittent rhythmical delta activity). There is clear asymmetry, with waveform amplitude and frequency being depressed in the left temporal region compared to the right. MRI: Brain The MRI study performed at the transferring hospital (Day 2) was obtained and reviewed. No significant abnormalities were noted on multiple sequences, including T1 weighting with/without gadolinium, T2 weighting, FLAIR and diffusion-weighted sequences.CBC with Diff/PlateletsBLOOD CELL PROFILE:Reference RangePatient Result WBC4.5-11.00 K/ul 11.1 KRBC4.2-5.5 M/ul 5.2 MPLT150-400 K/ul284 KHgb12.0-16.0 g/dL11.8Hct37-47%35.3MCV82.0-100.0 fl83.6MCH27-34 pg28.1MCHC31.0-37.0 g/dL33.5WBC differential count: NormalBlood Chemistries Test PerformedReference Range Patient Result Sodium135-148 meq/L143Potassium3.5-5.0 meq/L3.4Chloride101-111 meq/L113Bicarb22-29 mEq/L20Glucose70-110 mg/dL92Calcium8.6-10.6 mg/d9.1Albumin3.5-5.0 g/dl4.0Alkaline phosphatase50-136 U/L72Phosphorus2.5-4.9 mg/dL-LDH313-618 U/L403Total protein6.4-8.2 g/dL7.3Total bilirubin0-1 mg/dL0.8SGOT (AST)15-37 U/L21SGPT (ALT)30-65 U/L34Uric acid2.6-7.2 mg/dL-HSV Studies .Day 2Day5Day 7HSV by PCR of CSFNegativeNegativePositiveHSV-1 by PCR.DetectedSummary and Discussion Patient #51 Case of the Month HomeHistory and PhysicalTest ResultsWrite Your DiagnosisCheck Your DiagnosisTest YourselfYvonne Kew, M.D., Ph.D.R. Glenn Smith, M.D., Ph.D. Dennis R. Mosier, M.D., Ph.D.DiagnosisHerpes Simplex Encephalitis (HSV Type 1) Clinical SummaryThis case illustrates many of the diagnostic challenges that may be encountered in patients presenting with herpes simplex infection of the brain. The patient had presented with transient focal sensory symptoms, followed by a witnessed seizure, and only on the third day of her illness began to exhibit fever and progressive decline in mental status. At this point, treatment was empirically initiated with antibacterials and with acyclovir, although EEG studies and a high quality MRI study were unrevealing. Two successive CSF examinations, on days 2 and 5, showed no evidence of a leukocytic pleocytosis or of red cells, although CSF protein was noted to be elevated. Of perhaps greatest relevance, two successive PCR studies for herpes simplex virus in the CSF were reported as negative. Immediately following transfer to the Ben Taub General Hospital (day 7), a third lumbar puncture was performed, documenting for the first time a mild lymphocytic pleocytosis of the CSF. At this time, a positive PCR assay of the CSF for HSV type 1 was documented. An EEG performed shortly after transfer (see the Test Results menu) suggested the presence of a focal temporal lobe process. A follow-up MRI scan of the head demonstrated more characteristic findings of herpes simplex encephalitis affecting the temporal and frontal lobes: T1 post-contrastFLAIRBased on the persistence of fever, and continued clinical and radiological progression despite early administration of acyclovir, the possibility of an acyclovir-resistant strain of herpes simplex virus was considered. Foscarnet was empirically added to the patients regimen of acyclovir, with subsequent improvement in her fever and regaining of consciousness. The patient, however, sustained considerable neurologic injury from her infection, and at about six months from her initial presentation still exhibits disabling residual cognitive and motor impairment. She has been able to participate in rehabilitation and gait training, and continues to slowly improve. DiscussionThe term herpes is derived from a Greek word meaning to creep. The classically recognized presentation of HSV encephalitis involves the relatively abrupt onset of fever, focal signs, seizures, and/or deteriorating level of consciousness, and in such patients, the diagnosis is usually entertained early in the clinical course. However, many patients present with an initial prodromal phase of creeping progression, during which the disease may appear to smolder for a time before entering into a phase of rapid decline. In some of these patients, behavioral or psychiatric manifestations, amnestic symptoms, or language disturbance may be the presenting signs of illness, and the diagnosis of an early herpetic infection may be difficult to distinguish from other, more common, causes of psychiatric or neurologic dysfunction. Early in the course of herpetic infection of the CNS, the patient may not appear seriously ill. With the advent of PCR detection of viral DNA isolated from nucleated cells of the CSF, mild cases of HSV encephalitis and atypical presentations of HSV infections of the brain, have been documented (e.g., Fodor et al., 1998). Atypical presentations of HSV encephalitis has been associated with HSV type 2 infection, with immunosuppression (e.g., steroids or HIV disease), and with predominant involvement of the nondominant temporal lobe (Fodor et al., 1998; Jacobs, 1999). The CSF examination in herpes simplex encephalitis is nearly always abnormal on the initial lumbar puncture, but may be minimally so. In one series, 4% of patients with confirmed HSV encephalitis had an initially normal cell count on the first LP, while 13% had an initially normal CSF protein (Kennedy, 1988). Other series have reported similar percentages of normal or near-normal initial CSF studies (reviewed in Fishman, 1992). PCR of CSF for HSV DNA is generally reported to have a high degree of sensitivity (95-97%) and specificity (99-100%) for active HSV infection of the CNS. However, in one recent series (Studahl et al., 1998), 2 of 10 patients with confirmed HSV encephalitis had initially negative PCR for HSV, with repeat studies becoming positive at times as late as 7 days. Both of these patients had a short duration of disease ( 2 days) at the time of the initial LP. Both EEG and MRI studies have been reported to be highly sensitive for detection of focal encephalitis; however, early in the course of illness (as was observed in this patient), these studies can also be negative. Given the documented efficacy and relatively modest toxicity of acyclovir, empiric treatment with antiviral therapy should be initiated on suspicion of HSV encephalitis, instead of waiting for confirmation of the diagnosis. We believe that continued empiric antiviral therapy should be strongly considered in patients with clinically suspected HSV encephalitis even if the initial PCR studies of CSF are negative, particularly in those patients studied early in the course of illness. Differential DiagnosisThe differential diagnosis for HSV encephalitis is broad, and includes most CNS processes capable of producing fever, encephalopathy and focal neurological deficits. Of note in this case, titers for St. Louis encephalitis were reported as a borderline positive result, a finding that we consider to be of marginal specificity. Few cases of St. Louis encephalitis were reported in the Greater Houston area during the year of the patients presentation, and the unusually dry weather at this time had kept mosquito populations low. In this patient, the focal abnormalities noted on the EEG and MRI following transfer, and the presence of an alternative diagnosis, rendered an arboviral encephalitis unlikely. The patient was not believed to be clinically immunosuppressed, and screens for HIV infection as well as specific assays for several opportunistic infections were negative, rendering these diagnoses unlikely. Likewise, screens for active inflammatory conditions such as systemic lupus were unremarkable. Normal clinical cardiovascular examination and echocardiography, together with negative blood cultures, were felt to exclude bacterial endocarditis, which can also mimic the fever, focal deficits, and alteration of mental status seen in patients with HSV encephalitis. A blood smear for malaria was negative, and the patient had no reported history of this condition. Finally, no evidence for septic cerebral venous thrombosis was found on either the initial or follow-up MRI studies. Apparent Failure of Acyclovir TreatmentNucleoside analogs, such as acyclovir, have long been the mainstay of treatment in cases of suspected HSV encephalitis. Acyclovir is initially monophosphorylated by viral thymidine kinase (for which it has particular affinity), and subsequently converted into di- and triphosphate forms by cellular guanylate kinase and other cellular enzymes. The resultant acyclovir triphosphate, at least in vitro, competes with and also inactivates the viral DNA polymerase, and may also incorporate into the viral DNA itself. Acyclovir is given intravenously, typically 10-15 mg/kg every 8 hours in the case of suspected HSV encephalitis, and continued for at least 14 days (e.g., Keating, 1999). Adverse effects include hypersensitivity, and renal tubular dysfunction, especially in the setting of dehydration or excessive dosage. Acyclovir has documented efficacy in the treatment of HSV encephalitis, reducing mortality and increasing the percentage of patients with little or no residual impairment (e.g., Skoldenberg et al., 1984; Whitley et al., 1986). However, even with early acyclovir treatment, persistent neurologic deficits frequently occur (McGrath et al., 1997), and disease may clinically progress even with early initiation of therapy.Apparent failure of acyclovir treatment can occur following delay of therapy, early termination of therapy, or in the situation of catastrophically progressing disease. However, in this patient, acyclovir was initiated early in the course of disease, and fever and clinical progression continued despite maintenance of this regimen.Apparent failure of treatment can also occur as a result of evolving mass effect from edema or hemorrhage, seizure activity precipitated by persisting irritation, or an adverse immune-inflammatory response to the initial herpesvirus infection. In this patient, steroid treatment had been initiated early in the course of therapy, and breakthrough seizures were clinically and electrographically controlled with anticonvulsant medications. These observations suggested the possibilities of viral resistance to acyclovir, or of unfavorable drug pharmacokinetics, as causes of poor clinical response to therapy, and another antiviral agent, foscarnet, was empirically added to the patients regimen. Resistance of HSV to acyclovir has typically been documented in immunocompromised patients on viral suppression regimens, or in patients receiving extended therapy for ocular or chronic mucosal infections (e.g., Chakrabarti et al., 2000). Its incidence in the community of non-immunocompromised and previously untreated hosts is likely to be low but has not been convincingly documented. Resistance may result from mutations in the viral thymidine kinase that affect its expression, affinity for acyclovir, or phosphorylation functi