Full Answer
What is the duration of acyclovir treatment for herpes simplex virus (HSV) relapse?
Three patients received a second course of acyclovir for a clinically suspected relapse five days, 12 days, and six weeks after initial treatment was stopped; the polymerase chain reaction assay was not repeated in these cases. A fourth patient had received acyclovir for 26 days, but HSV DNA was still detectable in the CSF at the end of treatment.
Can acyclovir be used to diagnose herpes simplex encephalitis (HSV)?
Methods: Patients were included if they were treated with acyclovir and the diagnosis of herpes simplex encephalitis was confirmed by culture of herpes simplex virus (HSV) from the brain, an increase in the CSF HSV antibody titre, or detection of HSV deoxyribonucleic acid in the CSF.
How long does acyclovir stay in your CSF?
A fourth patient had received acyclovir for 26 days, but HSV DNA was still detectable in the CSF at the end of treatment. Four months later neurological symptoms and a CSF pleocytosis recurred; HSV DNA was present in the CSF, but disappeared five days after restarting acyclovir.
What is the dosage of acyclovir for herpes simplex encephalitis (HSE)?
Intravenous (IV) acyclovir needs to be started in all adults with suspected or confirmed cases of HSE in the dose of 10 mg per Kg body weight every 8 hours. Children up to 11 years and neonates are treated with higher doses (15-20 mg per Kg body weight).
How long should I take acyclovir for encephalitis?
For the patient with confirmed HSV encephalitis the correct dose was given for two weeks. Most authorities now consider that aciclovir should be given for 14 to 21 days because of the risk of relapse.
How long does it take for acyclovir to suppress?
Response and effectiveness. Valacyclovir is a prodrug that is rapidly converted to acyclovir after oral dosing. Peak concentrations of acyclovir are reached within one to three hours. It may take up to three days before a reduction in symptoms occurs.
How long does HSV PCR stay positive?
PCR is highly sensitive (94-98%) and specific (98-100%). Results become positive within 24 hours of the onset of symptoms and remain positive for at least 5-7 days after the start of antiviral therapy.
Does acyclovir affect IgG levels?
Daily acyclovir chemosuppression for 1 year reduced mean IgG antibody concentration by 10% from baseline values (P less than 0.01), whereas in patients receiving intermittent therapy no significant decline was observed.
Does acyclovir affect fertility?
Effect While Trying to Conceive There are no known effects of valacyclovir treatment on fertility or conception rate. If you plan on attempting to conceive in the near future and you're taking valacyclovir for genital herpes, talk with your physician before attempting to get pregnant.
What are the long term effects of acyclovir?
Low red blood cells and platelets: This drug may cause thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). These conditions cause dangerously low levels of red blood cells and platelets in your body. This may be fatal (cause death). Symptoms can include fatigue and low energy.
How long does HSV IgG stay positive?
The time required for the development of IgG antibodies following HSV infection varies from 21 to over 42 days with most individuals having detectable IgG 21–28 days after exposure to the infection and probably lasting for life.7–,9 IgM antibodies are usually detectable 9–10 days after exposure and last 7–14 days, ...
How accurate is HSV PCR blood test?
PCR assays or other NAATs are the most sensitive test currently available to detect HSV in clinical samples. The detection rates of the PCR assays were shown to be 11–71% superior to virus culture [26,41-44].
Can HSV antibodies go away?
It may take between six and eight weeks to detect antibodies in a herpes blood test after first becoming infected with HSV. Also, antibodies may disappear with time, especially if the person has infrequent recurrences of herpes.
Does acyclovir prevent antibodies?
Oral acyclovir is thus effective and well tolerated in patients with herpes genitalis. Treatment with acyclovir also diminishes the humoral antibody response to HSV, but it does not prevent recurrence.
Does acyclovir create antibodies?
However, both oral and intravenous acyclovir were associated with later development of antibodies to two glycoproteins (of 80,000 and 60,000 mol wt [IIg80 and gD, respectively]) and one nonglycosylated polypeptide of 66,000 mol wt (vp66).
Do antivirals lower immune system?
Antivirals can: Block receptors so viruses can't bind to and enter healthy cells. Boost the immune system, helping it fight off a viral infection. Lower the viral load (amount of active virus) in the body.
How does HSV-1 enter the brain?
There are presumably 3 routes by which the HSV-1 is thought to enter the brain from the initial peripheral site of infection. The first path is from the site of primary oro-pharyngeal infection to the brain via trigeminal or olfactory nerves. The second mechanism involves the same neuronal pathways from the reactivation of an initial infection at the periphery. The last mechanism is purely due to the reactivation of the latent in-situ HSV -1 in the brain. Viremia is well documented in neonates and immunocompromised patients. Primary infection causes encephalitis in most children. Neonatal encephalitis could be either due to primary infection or secondary infection due to viremia and multisystem involvement. In neonates, primary infection is almost always acquired due to perinatal exposure during labor or post-delivery.
How much mortality is associated with herpes simplex?
Herpes simplex encephalitis in adults is associated with significant morbidity and mortality. The mortality is estimated to be between 20% to 30%, even with prompt diagnosis and treatment. [33][34][35] One large retrospective study found an APACHE Score of more than 27, and more than 48 hours delay in starting acyclovir after hospital admission as key factors in predicting poor outcomes.[27] Severe disability was seen by about 20% of patients in this study. Morbidity and mortality are significant in neonates and children, whether treated or untreated. [2]
What is the most common cause of encephalitis?
The annual incidence of herpes simplex encephalitis is approximately 2 to 4 per 1000,000 population worldwide.[8] HSV-1 encephalitis constitutes 10% to 20% of the 20,000 annual viral encephalitis patients in the USA. A multicenter population-based study identified herpes simplex as the most common cause of infectious encephalitis in the UK.[9] HSV is again the most common pathogen identified in hospitalized encephalitis patients in Australia.[10] The incidence of HSV-1 encephalitis appears to be almost similar in Sweden and the United States of America, as shown by studies in these countries. [8][11]
What is the cause of herpes simplex?
Herpes simplex encephalitis is caused by Herpes Simplex Virus type 1(HSV-1) or type 2 (HSV-2). HSV-1 causes encephalitis in children beyond the neonatal period as well as in adults, and it is the most common etiology for sporadic non-seasonal encephalitis across the world. HSV-2 commonly causes encephalitis in neonates and the immunocompromised. Herpes simplex encephalitis is associated with significant morbidity and mortality in adults and children despite antiviral treatment. This activity reviews the evaluation and management of herpes simplex encephalitis, also stressing the need for close coordination and communication between various health care professional teams to ensure the best outcome in individual patients.
What are the long term morbidities of Klüver Busy Syndrome?
Significant long term morbidity, including cognitive and behavioral abnormalities, anterograde amnesia, and features of Klüver Busy Syndrome, have been well documented. Even though the standard mental status examination is within normal limits, many suffer from dysnomia and difficulty for new learning, especially via visual and verbal media. A Swedish study showed rehospitalization in 87% of patients for various indications, including seizure episodes, neuropsychiatric symptoms, and thromboembolic events.[8] Autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor for glutamate has been reported in children and young adults. Recurrent neurologic symptoms occurring in a patient with a recent history of HSE should prompt a CSF evaluation for HSV DNA and anti-NMDAR antibodies.
What are the different types of encephalitis?
The differential diagnoses of viral encephalitis must include arboviral infections, including West Nile, and St Louis encephalitides, Eastern & Western equine encephalitides, as well as California and Japanese en cephalitides . Other etiologies include herpes viruses (EBV, CMV, VZV, HHV 6 & 7), and also miscellaneous causes like mumps, enterovirus, dengue, adenovirus, lymphocytic choriomeningitis, subacute sclerosing panencephalitis due to hypermutated measles virus & progressive multifocal leukoencephalopathy caused by JC virus.
What are some examples of non-infectious causes of encephalitis?
Non-infectious causes for encephalitis (for example, autoimmune or paraneoplastic encephalitis, acute disseminated encephalomyelitis)
Why does HSV persist despite aciclovir?
Very rarely this may be because a resistance to Aciclovir, meaning the drug is no longer effective at being able to inhibit replication of the virus. In this situation, the HSV remains detectable in the CSF and therefore additional or alternative antiviral medications are given.
How to test for herpes virus?
The key diagnostic procedure is a lumbar puncture (LP) (spinal tap) to take some of the fluid bathing the brain and spinal cord (cerebrospinal fluid, abbreviated to CSF) for laboratory analysis. One of the tests called the polymerase chain reaction (PCR) is very sensitive at detecting low levels of viruses’ genetic fingerprints. In general, the test is useful for up to 10 to 20 days after the onset of neurological disease and then usually becomes negative. At this time, a further procedure for the detection of herpes virus antibody in the CSF can be used. This also provides an accurate diagnosis. This latter test is often used as a follow up test if the initial PCR test (s) is negative.
What is herpes simplex virus encephalitis (HSE)?
HSE is a type of infectious encephalitis which happens when herpes simplex virus (HSV) enters the brain. HSV can be of two types: HSV1 and HSV2. HSV1 is mainly associated with infections of mouth and throat early in life often without symptoms, but lately, it has also been associated with genital herpes. HSV2 is associated with genital herpes predominantly in adolescents and adults as it is transmitted through sexual activity.
How does HSV1 affect the body?
Around 90% of adults become infected with HSV1 during their life. The virus attaches to, and enters sensory nerves in the throat and moves to nerve cells called ‘ganglia’ (e.g. the trigeminal ganglia). Here the virus establishes a latent (hidden) and life-long infection. In some people, from time to time, the virus may reactivate to produce recognisable lesions such as cold sores around the lips and nose.
What are the symptoms of HSE?
HSE usually develops over a period of days but, like any other viral infection, depending, for example, upon the immunity of the patient, the disease may take a variable course. Typically, it begins with very generalised ‘flu-like’ symptoms followed by neurological deterioration. The most common symptoms including: 1 Headache. 2 Confusion. 3 Nausea 4 Fever. 5 Seizures 6 Drowsiness.
How long does it take for HSE to develop?
Symptoms of HSE. HSE usually develops over a period of days but, like any other viral infection, depending, for example, upon the immunity of the patient, the disease may take a variable course. Typically, it begins with very generalised ‘flu-like’ symptoms followed by neurological deterioration.
What is the mortality rate after aciclovir?
After Aciclovir was introduced, the mortality rate has reduced to 10-20%. This being said, it is of utmost importance that Aciclovir is started immediately, otherwise, the risk of complications post-infection such as cognitive impairments, epilepsy and other issues increase.
How does HSV get into the body?
HSV initially gains access to host tissues through mucous membranes or damaged skin. After primary infection of the mucosal or skin epithelium, the virus infects sensory neurons via interactions with cell-surface glycosaminoglycans such as heparan sulfate [7], and cell adhesion molecules such as nectin-1 [8, 9], and travels to the neuronal cell body in the dorsal root ganglion via fast retrograde axonal transport [10, 11].
How common is HSV-1?
HSV-1 infection is common, with seropositivity among older adults estimated to be 60–90 % worldwide [39]. A survey from 2005 to 2010 including Americans between 14 and 49 years of age in the USA estimated HSV-1 seropositivity at ~54 % and HSV-2 seropositivity at ~16 % [40]. While HSV-2 is also capable of causing encephalitis (particularly in the immunocompromised host), HSV-1 is responsible for ~90 % of HSV encephalitis in adults and children, and is the focus of this review [41]. Despite only rarely manifesting as encephalitis in infected individuals, HSV-1 is consistently the single most common cause of sporadic encephalitis worldwide [42–52]. The incidence of HSVE worldwide is estimated to be between 2 and 4 cases/1,000,000 [44], and the incidence in the USA is similar [53]. There is a bimodal distribution with peak incidence in the very young (up to 3 years of age), and again in adults aged > 50 years, but the majority of cases occur in those over 50, with both sexes equally affected [44, 54–56].
What are the symptoms of HSVE?
Many patients present with prodromal symptoms, suggesting upper respiratory tract or other systemic infection. Signs and symptoms of encephalitis then progress over the course of several days in most cases of HSVE [57, 58]. The most common manifestations include encephalopathy, fever, seizures, headaches, and focal neurological deficits [57–62]. Although clinical features of HSVE have been well described in multiple large epidemiological studies, the clinical manifestations lack specificity. In a series of 106 cases of HSVE, the primary reasons for hospital presentation were seizures (32 %), abnormal behavior (23 %), loss of consciousness (13 %), and confusion or disorientation (13 %) [60].
What is the term for herpes?
Herpetic infections have been recognized since the time of ancient Greece. The word herpes translates as “creeping” or “crawling”, and is a reference to herpetic skin lesions. Goodpasture [3] and others demonstrated that material from herpetic lip and genital lesions produced encephalitis when introduced into the scarified cornea or skin of rabbits. In the 1920s, the Mathewson commission was among the earliest reports to suggest HSV caused encephalitis in humans [4]. The first pediatric case report of HSVE was published in 1941 [5]. The first adult case, a 25-year-old man who presented with headache, fever, aphasia, and left pupillary dilatation, was reported in 1944 [6]. On postmortem pathological examination, there were numerous petechiae and ecchymoses with perivascular lymphocytic cuffing in the left temporal lobe, midbrain, and pons. Intranuclear inclusions were identified and virus was isolated from the patient’s brain. Significant progress in the pathobiology, diagnosis, and treatment of HSVE has been made since these early reports.
What is the most common cause of sporadic encephalitis worldwide?
Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.
What is the innate immune response to HSV?
Infection with HSV triggers a robust response from the innate immune system until adaptive immunity is able to assist in clearing active infection. Early in the course of the immune response to HSV, pattern recognition receptors, called Toll-like receptors (TLRs), located on cells of the innate immune system, recognize and bind to conserved viral motifs known as pathogen associated molecular patterns [25]. This triggers dimerization of the TLRs, which subsequently activates signaling pathways that initiate the production of proinflammatory cytokines such as interferons (IFNs), tumor necrosis factor, and various interleukins [26]. IFNs contribute to host resistance to viral proliferation through activation of the Jak-Stat signaling pathway [27], and by triggering production of both RNAse enzymes that destroy cellular RNA (both host and viral) and double-stranded RNA-dependent protein kinase, which halts cellular translation [28]. Deficiencies in the immune response to HSV (e.g., defects in the TLR-3 pathway, including TLR3 itself, UNC93B1, TIR-domain-containing adapter-inducing IFN-β, tumor necrosis factor receptor-associated factor-3, TANK-binding kinase 1, or IFN regulatory factor-3) leave the host susceptible to HSVE [29–31].
What serum test is used for encephalitis?
Serum laboratory studies that should be obtained on all adults with encephalitis include complete blood count with differential, electrolytes, measures of renal and liver function, blood cultures, HIV testing (consider RNA), and treponemal testing. In children with encephalitis, Mycoplasma pneumoniaeIgM and IgG, as well as Epstein–Barr virus serologies (VCA IgG and IgM and EBNA IgG), should be obtained. Serum should also be reserved from the presentation, with convalescent serum collected 10–14 days later for paired antibody testing if needed (such as in idiopathic encephalitis). HSV serologies are generally not clinically helpful in the acute setting [66]. In patients at risk for tuberculosis, such as the immunocompromised and homeless individuals, skin or blood testing for Mycobacterium tuberculosisshould be considered.
What was the fever of a 71 year old HSE patient?
A 71 year-old HSE patient had a normal CT scan and a normal MRI. He presented with high fever (40°C) and a mild disease that improved quickly. He was discharged on day 17.
What is an acute encephalitis case?
The case definition of acute encephalitis was a patient aged ⩾28 days, hospitalized in mainland France in 2007 with (1) an acute onset of illness, (2) at least one abnormal result in the CSF (white blood cell count ⩾4 cells/mm 3 or protein level ⩾40 mg/dl), (3) fever or recent history of fever ⩾38°C, and (4) decreased consciousness or seizures or altered mental status or focal neurological signs. The protocol for laboratory investigation and aetiology of encephalitis in enrolled case-patients has been described previously
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- Reference Mailles and Stahl
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- 12 ].
What is the most common cause of acute infectious encephalitis?
Herpes simplex virus (HSV) is the most frequently identified cause of acute infectious encephalitis worldwide
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- Reference Whitley, Sheld, Whitley and Marra
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- 1 ]. Herpes simplex encephalitis (HSE) presents with a wide range of symptoms making clinical diagnosis difficult. The diagnosis relies on the detection of viral DNA in cerebrospinal fluid (CSF) by a highly sensitive (95–100%) and specific (94–100%) polymerase chain reaction (PCR) test
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- Reference Whitley, Sheld, Whitley and Marra
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- 1,
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- Reference Lakeman and Whitley
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- 2 ]. False-negative PCR results have been observed during the early course of HSE
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- Reference Weil
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- 3,
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- Reference Chaudhuri and Kennedy
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- 4 ], and after more than 10 days of disease evolution
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- Reference Chaudhuri and Kennedy
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- 4,
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- Reference Puchhammer-Stöckl
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- 5 ].
How many HSE patients have an abnormal CT scan?
Altogether, 24 (48%) HSE patients had an abnormal CT scan and 38 (95%) had an abnormal MRI. Thirty-six HSE patients had both a MRI and a CT scan, 15 (42%) of which were concordant. MRI revealed lesions in 21 HSE patients with normal CT scan results. Lesions were most frequently temporal ( n =48, 87%) or frontal ( n =16, 29%) ( Table 2 ). Fifteen (27%) HSE patients had lesions involving several lobes of the brain, 14 of which had a temporal lesion.
How old are HSE patients?
All HSE patients but one were adult (median age 58 years, range 1 month to 85 years), and 31 (56%) were male. Seventeen (31%) reported comorbidities: four had cancer, one systemic lupus erythematosus, one congestive cardiac failure, three bipolar disorders and one senile dementia.
Does ACV cause renal failure?
No renal failure occurred in the 31 encephalitis patients with a full course of ACV despite reliable negative results or in the seven encephalitis patients with an alternative diagnosis.
What is the WBC level of a 60 year old man with HSV encephalitis?
This was a case report of a 60-year-old man with HSV encephalitis and normal CSF analysis (WBC count of zero, protein level of 18 mg/dL). The diagnosis was made based upon a positive PCR result and temporal lobe enhancement on MRI. No known cause of immunocompromise was present.
How many PCR tests were positive for HSV in 2012?
When applied to the 2008-2012 data, both the Reller Criteria and the Bouza Criteria would have resulted in cancellation of three PCR tests which were positive for HSV. Of these three tests, only one was judged to represent a clinically significant infection.
How many CSF specimens were submitted for analysis?
During the study period, 466 CSF specimens were submitted for analysis. Seventy were identified which had been rejected on the basis of the Bouza Criteria, but would have been accepted for testing using Reller Criteria. These were tested for HSV PCR, and none of the samples was positive.
What is the risk of HSV infection?
A patient with average risk for HSV infection (~1.5% pre-test probability) and negative Reller Criteria has a risk of HSV infection of ~1/17,000. A patient with a low pre-test probability of HSV (~0.5%) and a negative Bouza Criteria has a risk of HSV infection of ~1/14,000. The risk of acyclovir-induced nephrotoxicity from a short course of treatment isn't exactly clear, but probably much higher (e.g. ~1/20; Yildiz 2013 ). Therefore, the risk/benefit ratio doesn't favor the use of acyclovir in these cases.
How many CSF specimens were rejected for HSV PCR?
A total of 1,659 CSF specimens were submitted over this time period. Of these, 347 were rejected for HSV PCR because they didn’t meet the above criteria. 222 of these rejected specimens were frozen for subsequent analysis. Zero of these 222 specimens were positive for HSV-1. Two specimens tested positive for HSV-2, but upon further investigation these specimens came from patients with HIV (which hadn’t initially been communicated with the laboratory).
How many CSF samples were tested for HSV?
This was a large study from three Harvard-affiliated hospitals which correlated CSF chemistries with HSV PCR. Between 1996-2001, 2759 CSF samples were tested for HSV. 55 tested positive, including 16 patients with clinical HSV encephalitis. All HSV-positive patients had an elevated CSF leukocyte count (>5 cells/mm3), elevated protein (>50 mg/dL), or both. One patient with HSV encephalitis had a leukocyte count of 2 cells/mm3, and three patients had a leukocyte count below 10 cells/mm3. Similar to the Tang's study above, this shows that a normal leukocyte count doesn’t exclude HSV.
How many patients with CSF are positive for HSV?
Among all patients with CSF sampled, only ~1.5% are positive for HSV. Therefore, the average likelihood of missing a case of HSV using these criteria is as follows:
How long does acyclovir help with HSV?
For the HSV-replication relapse, more acyclovir treatment may help. De Tiège et al. recommend that a minimum of 15 days of acyclovir (45 mg/kg/day) may prevent the viral-replication relapse, especially for the early relapse in a few days. However, most of their cases received 60 mg/kg/day for 3 weeks. For those late relapses that may relate to an innate HSV-specific immune deficiency or familial high HSV susceptibility, more efficient treatment may include a combination of multiple antiviral agents or long-term oral acyclovir administration. The varying doses and durations of acyclovir administration by De Tiège et al may clarify the case-by-case variations in HSE. Treatment for HSE is not complete until negative results of CSF on PCR are confirmed at least twice, rather than to blindly administer acyclovir for 2 or 3 weeks. [3] The necessity of subsequent oral acyclovir or valacyclovir for extended periods needs further evaluation.
What type of virus causes relapses?
In addition, there may by another type of virus causing relapse besides HSV, such as Coxsackievirus A9 reported by Ito et al [4].
Can acyclovir be used for parainfectious relapse?
Treating the parainfectious relapse with further acyclovir treatment is not reasonable. Corticosteroids, immunoglobulin, or immunosuppressants may help. Early use of those medications depends on the alertness of clinicians to detect the presentation of choreoathetosis as an initial sign of this type of HSE relapse. [2]