As effective therapies for the treatment of herpes simplex encephalitis (HSE) have become available, the virology laboratory has acquired a role of primary importance in the early diagnosis and clinical management of this condition. Several studies have shown that the polymerase chain reaction (PCR) of CSF for the detection of herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) DNA provides a reliable method for determx ining an aetiological diagnosis of HSE. The use of PCR in combination with the detection of a specific intrathecal antibody response to HSV currently represents the most reliable strategy for the diagnosis and monitoring of the treatment of adult patients with HSE. The use of these techniques has also led to the identification of atypical presentations of HSV infections of the nervous system and permits the investigation ofpatients who develop a relapse of encephalitic illness after an initial episode of HSE. A strategy for the optimal use of the investigative laboratory in the diagnosis of HSE and subsequent management decisions is described. (7 Neurol Neurosurg Psychiatry 1996;61:339-345 centres in the brainstem. In the most severe cases death occurs after seven to 14 days. In a double blind placebo controlled study of treatment of HSE, the mortality in patients treated with placebo was 70% and moderate to severe neurological sequelae affected the great majority of the survivors. 16 A range of clinical presentations of HSV infection of the nervous system, including mild disease courses, relapsing and remitting encephalitis, or unusual neurological syndromes, sometimes related to specific anatomic locations, have now been described Unusual presentations ofHSV infections of the nervous system The role of laboratory investigation in the diagnosis and management ofpatients with suspected herpes encephalitis: a consensus reportThe specificity in this study was assessed on CSF samples from 60 patients with non-HSE encephalitis. None of these samples were found to be HSV PCR positive.22 The use of PCR in this context represents one of the most successful diagnostic test procedures ever described in clinical neurology. To date the limited data available suggest that the HSV PCR remains positive for at least five days after the initiation of acyclovir therapy. Data from PCR obtained from patients who are receiving acyclovir must therefore be interpreted with caution.It is still a matter of debate whether the HSV DNA detected in CSF is derived from intact virions or from viral DNA not associated with mature virions.57 Detection of HSV DNA is, however considered to be associated with viral replication and HSV infection of the CNS.60Demonstration of a humoral immune response within the CNS The intrathecal synthesis of antibody against HSV during the course of HSE can be demonstrated by testing CSF and serum samples collected at the same time. An increased CSF:serum quotient for the HSV antibody titre, adjusted for CSF-blood barrier integrity, indicates a specific intrathecal antibody response....
This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.
In normal conditions, albumin and immunoglobulin (Ig)G in the cerebrospinal fluid (CSF) originate from the blood, and there is no antibody production within the central nervous system. Up to 20% of CSF proteins are intrathecally synthesized, but the major fraction is blood-derived. The CSF/serum albumin quotient (QAlb) is the best marker of the blood-CSF barrier function. The corresponding immunoglobulin quotients (QIGG, QIGA, QIGM) are not linearly related to QAlb and their correlations are defined by an hyperbolic equation. This equation is used to discriminate between a blood-derived and a locally produced fraction of immunoglobulins in case of an intrathecal humoral immune response. The detection of CSF-specific oligoclonal IgG is more sensitive than the quantitative comparison between QIGG and QAlb. A further step is the determination of antibody indices and the detection of specific oligoclonal antibodies by antigen-driven immunoblots. CSF analysis remains a cornerstone for the diagnosis of various neurological disorders, including multiple sclerosis and infectious diseases of the central nervous system.
A group of neurologists and clinical neurochemists representing twelve countries worked towards a consensus on laboratory techniques to improve the quality of analysis and interpretation of cerebrospinal fluid (CSF) proteins. Consensus was approached via a virtual Lotus Notes-based TeamRoom. This new approach respecting multicultural differences, common views, and minority opinions, is available in http://www.teamspace.net/ CSF, presenting the implicit, complementary version of this explicit, printed consensus. Three key recommendations were made: CSF and (appropriately diluted) serum samples should be analyzed together in one analytical run, i.e., with reference to the same calibration curve. Results are evaluated as CSF/serum quotients, taking into account the non-linear, hyperbolic relation between immunoglobulin (Ig)- and albumin-quotients rather than using the linear IgG index or IgG synthesis rate. Controls should include materials with values within the reference ranges (IgM: 0.5-1.5 mg/l; IgA: 1-3 mg/l; IgG: 10-30 mg/l and albumin: 100-300 mg/l). The physiological, methodological and clinical significance of CSF/serum quotients is reviewed. We confirmed the previous consensus on oligoclonal IgG, in particular the usefulness of the five typical interpretation patterns. The group compared current external and internal quality assurance schemes and encouraged all members to maintain national or local traditions. Values for acceptable imprecision in the CSF quality assurance are proposed.
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