Children suffering from prolonged, acute, convulsive seizures may not always receive timely rescue medication in schools and other community settings as intended by their specialist physician, according to the first findings of the PERFECT[1] Initiative. The results were presented as part of a symposium at the ILAE's 10th European Congress on Epileptology (ECE), in London. The Steering Committee for The PERFECTTM Initiative, which comprises a group of leading clinical epilepsy specialists from six countries across Europe, also highlight discrepancies in comprehensive European guidelines and legal frameworks that ensure children with prolonged, acute, convulsive seizures are treated quickly whether in hospital or in the community, and recommend specific training on rescue medication for all those responsible for the child.[i]

Prolonged, acute, convulsive seizures can pose a significant health threat in children with epilepsy, a neurological disorder affecting nearly one million children and adolescents in Europe.[ii] Evidence suggests that treatment should be given immediately if a seizure persists longer than 5 minutes after onset.[iii] However, in the case of schools, despite the fact that many children are prescribed rescue medication by their doctors, teachers often opt not to administer seizure rescue medication unless specific training or provision has been made, typically via the school nurse. Instead an ambulance may be called, causing possible delays in seizure treatment.[iv]

"The PERFECT Initiative is the first to investigate the discrepancies that often exist in European countries between policy and practice in the treatment of prolonged, acute, convulsive seizures in children," said Prof J. Helen Cross, UCL Institute of Child Health, Great Ormond Street Hospital for Children and Young Epilepsy. "We found that the differences in clear guidance, awareness and education around the use of rescue medication for treating seizures in children living with epilepsy, ultimately create a shortfall in care that we, as clinicians, intend that they receive, whether in hospital or away from it."

This first phase of the PERFECT Initiative was designed to examine existing treatment guidelines and legal frameworks and policies for treating prolonged, acute, convulsive seizures in the community, in six European countries (France, Germany, Italy, Spain, Sweden and the UK). The authors found that, while guidelines were effective for in-hospital treatment of prolonged, acute, convulsive seizures, the picture was often different in the community. In many cases, rescue medication consists of intra-rectal diazepam, which can be considered socially inappropriate to administer in the community setting. Whether a child receives rescue medication at school depends primarily on the availability of staff willing to accept responsibility for administering the treatment.1 Key recommendations from the PERFECT Initiative Steering Committee include:1
Establishing clear links between the treating physician, families and the child's day-to-day community environment (e.g. schools), allowing for better provision of information on epilepsy and training on seizure intervention for all those individuals responsible for the child

New and revised comprehensive guidelines to ensure children with prolonged, acute, convulsive seizures are treated according to the treatment plan set by their physician, wherever the seizure occurs

Individualised treatment plans for every child are established between the treating physician and the family/carers concerned, to help ensure the best possible standards of care for the child away from the hospital setting.
ViroPharma Incorporated (Nasdaq: VPHM), as part of its commitment to help create better care for children with prolonged, acute, convulsive seizures, has organised and funded the PERFECT Initiative in collaboration with a group of leading clinical epilepsy specialists. Vanessa Newman, Associate Director Medical Affairs, Europe, at ViroPharma said: "The PERFECT Initiative was designed to investigate any possible shortfalls in the current approach in Europe to the management of prolonged, acute, convulsive, seizures in children treated in the community with rescue medication. We believe that we can help improve care for children at risk of seizures by supporting collaboration between key stakeholders, identifying opportunities for social integration, and facilitating better education at all levels. We are proud to have initiated PERFECT and look forward to helping support the improvement in care for children with epilepsy that The Steering Committee recommends."

The second two phases of the PERFECT Initiative include a survey of physicians and nurses who treat children with prolonged, acute, convulsive seizures, followed by a survey of children and their parents regarding their treatment, care, guidance and quality of life. Results of these phases are due to be published in 2013.

About the PERFECT Initiative

ViroPharma, as part of its commitment to help create better care for children with prolonged, acute, convulsive seizures, has organised and funded the PERFECT (Practices in Emergency and Rescue medication for Epilepsy managed with Community administered Therapy) Initiative in collaboration with a Steering Committee group of leading clinical epilepsy specialists. The Initiative aims to document and communicate first of its kind data on the impact of conflict of policy and practice in the treatment of prolonged, acute, convulsive seizures.

The PERFECT Initiative is designed to facilitate collaboration between key stakeholders, identifying opportunities for social integration around children experiencing breakthrough seizures, and supporting means of better education of the condition at the community level. It consists of three phases, a review and comparison of policy and real-world practice, a survey of physicians and nurses who treat children with prolonged, acute, convulsive seizures, and a survey of children and their carers relating to their experiences of breakthrough seizures.

 

References:
[1] Practices in Emergency and Rescue medication For Epilepsy managed with Community administered Therapy

[i] Wait S, et al. The administration of rescue medication to children with prolonged acute convulsive seizures in the community: what happens in practice? Eur J Paediatr Neurol. 2012. doi:10.1016/j.ejpn.2012.07.002. Published early online.

[ii] Epilepsy in the WHO European Region: Fostering Epilepsy Care in Europe. 2010. Available at: http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf. Last accessed July 2012.

[iii] Lagae L. The treatment of acute convulsive seizures in children. Eur J Pediatr 2011;170:413-8. [iv] Kriel RL, et al. Home use of rectal diazepam for cluster and acute prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol 1991;7:13-17.

[v] Ekinci O, et al. Depression and anxiety in children and adolescents with epilepsy: Prevalence, risk factors, and treatment. Epilepsy Behav 2009;14:8-18.

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The EFNS-ENS consensus recommendations for the usage of PCR technology for the diagnosis of infections of the nervous system have been published. A summary of the guideline is given below.

Polymerase chain reaction (PCR) is a simple and rapid, easy- to- use approach to diagnose infections by amplifying nucleic acids. The reliability of PCR technology for the diagnosis of neurological infections is dependant on the type of pathogen

The PCR involves the in vitro enzymatic synthesis of millions of copies of a specific DNA segment. 
1. The reaction is based on the annealing and extension of two oligonucleotide primers that flank the target region in duplex DNA
2. After denaturation of the DNA, each primer hybridizes to one of the two separated strands such that extension from each 3′ hydroxyl end is directed toward the other. 
3. The annealed primers are then extended on the template strand with a DNA polymerase. 

These three steps (denaturation, primer binding, and DNA synthesis) represent a single PCR cycle. Consequently, repeated cycles of denaturation, primer annealing, and primer extension result in the exponential accumulation of a discrete fragment whose termini are defined by the 5′ ends of the primers. 

The length of the products generated during the PCR is equal to the sum of the lengths of the two primers plus the distance in the target DNA between the primers. PCR can amplify double or single-stranded DNA, and with the reverse transcription of RNA into a cDNA copy, RNA can also serve as a target.

Quantitative PCR, uses precision optics and DNA-binding fluorescent dyes or fluorescent labels to monitor amplification in real-time.

Viruses

PCR not only allows a specific diagnosis in an individual patient but can also define the spectrum of disease caused by a particular virus and when applied to large numbers of clinical samples can help understand the epidemiology of neurological infections. 

Several viruses can be looked for in the same CSF or other sample using the technique of multiplex PCR in which several pairs of primers specific for particular viral sequences are used. Where more than one virus is detected in a CSF sample, the significance of the virus detected has to be carefully evaluated, especially if such a dual viral infection is made more likely by immunosuppression as occurs during Human Immunodeficiency virus (HIV) infection 

While evaluating PCR results the sensitivity and specificity of the particular assay are important factors to take into consideration ie. the possibility of false negative and false positive results. The timing of the CSF sample and the physical conditions such as specimen storage can be important

Using quantitative PCR real-time PCR allows the determination of the viral load in a patients' blood or CSF. Although this is not carried out routinely in most laboratories, it has been used in some cases to assess the severity of the viral disease burden and/or the prognosis, examples being Cytomegalovirus (CMV) and JC virus infections

Besides CSF Viral PCR can also be carried out on other tissues such as peripheral blood, brain, or other tissue biopsy specimens.

Herpes simplex virus

1. The sensitivity of CSF PCR in HSE is 96% and the specificity is 99% . Hence CSF PCR can be recommended as a highly reliable method of diagnosing HSE without the need for brain biopsy (Level A).
2. It is important to carry out CSF PCR for both HSV-1 and HSV-2 since HSV-2 is also associated with mild or atypical of cases of HSE, particularly in immunosuppressed patients such as those with HIV infection as well as neonatal HSE caused by HSV-2.
3. Timing of PCR: The CSF PCR for HSE can be negative during the early stage of the infection. Re-examination of the same negative CSF a few days later may yield a positive PCR result . The CSF PCR may also be negative if the sample is taken too late during the infection since the yield of virus is highest during the first week of the infection following which it falls .The guidelines recommend the optimum timing of CSF PCR at 2–3 days to 10 days after symptom onset (Level C). 
4. If HSE is strongly suspected even if CSF PCR obtained within the first 72 h of the onset of symptoms is negative it should be repeated few days later to obtain a definitive diagnosis (Level B).
5. Treatment with acyclovir does not reduce the chances of PCR detecting HSV during the first week of infection so such treatment should not influence the decision to carry out a PCR test (Level A). Once acyclovir has been started in a case of suspected HSE with a negative PCR, we recommend that it is continued for 14 days unless an alternative diagnosis has been established (Level C). 
6. Currently it is not recommended to repeat the CSF PCR in all patients after 14 days of acyclovir treatment. There is an on going US NIH anti-viral study group trial which also addresses this issue.
7. Quantitative PCR: Routine Quantitattive PCR to assess the viral load has not been shown to be a useful prognostic marker in an individual patient with HSE and hence is not recommended.

Varicella-Zoster virus

1. The sensitivity and specificity of VZV PCR in cases of VZV-associated neurological disease has been estimated at 80% and 98%, respectively.
2. CSF PCR for VZV should be considered in all cases of encephalitis of unknown cause . 
3. PCR is also helpful in proving the etiology in a spectrum of neurological conditions caused by VZV without reactivation including VZV vasculopathy, zoster sine herpete, and myelopathy, meningoencephalitis, and polyneuritis cranialis. It is important to think of this possibility in differential diagnosis. In such cases in addition to CSF PCR for VZV DNA other tests for eg detection of anti-VZV IgG in the CSF should also be carried out.
4. CSF anti-VZV IgG more sensitive than PCR in VZV vasculopathy

Cytomegalovirus

1. CSF PCR has a very high sensitivity and specificity for detecting CMV infection and is recommended in patients with suspected CMV associated neurological disease.
2. Quantitative CMV PCR may also be useful to correlate disease severity and monitor the efficacy of anti-viral therapy 

Epstein–Barr virus

1. EBV PCR on the CSF (Level C) is recommended in patients presenting with symptoms suggestive of the range of neurological conditions associated with EBV including encephalitis, aseptic neuritis, cerebellar ataxia, myelitis, and several peripheral nerve disorders including various types of acute radicultis, radiculoplexopathy, acute autonomic neuropathy, Guillain–Barre syndrome, and cranial neuropathies .
2. The sensitivity of CSF EBV PCR in AIDS patients with a suspected CNS lymphoma is very high, at 97% -100%
3. Quantitative PCR can also be used in such patients to predict the risk of developing non-Hodgkin CNS lymphoma and for monitoring the effects of chemotherapy 

Enteroviruses

1. Enteroviruses (EV) disease spectrum includes a non-specific febrile illness, aseptic meningitis, and encephalitis. A chronic meningoencephalitis may also occur in immunocompromised patients.
2. CSF Enterovirus PCR is highly sensitive and specific in patients suspected of having an EV infection and recommended for both accurate diagnosis and improved patient management.
3. Reverse transcription (RT)-PCR for EV provides a rapid and very accurate diagnosis of an infection in <24 h and much more quickly than is possible with standard viral culture (Class II). 
4. The CSF PCR for EV results should however be interpreted carefully in case of false negative results since some studies have shown that EV PCR of specimens from the respiratory and gastro-intestinal tracts yielded higher results than did CSF
5. Obtaining a specific diagnosis is particularly important since patients may be potentially treated with the antiviral agent pleconaril. 

JC Virus

1. JC Virus (JCV) is a polyoma virus that is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of the CNS that occurs mainly in immunocompromised individuals, primarily those with AIDS and recently also associated with natalizumab therapy in multiple sclerosis patients.
2. The specificity of CSF PCR progressive multifocal leukoencephalopathy is excellent at 98.5–100% though the sensitivity is lower in the region of 50–82% (Class II).
3. CSF PCR to detect JCV DNA is now the established and routine method of diagnosis in PML and has superseded brain biopsy 
4. In cases where the PCR is negative in a brain biopsy should be seriously considered to obtain a definitive diagnosis. 
5. Quantitative PCR is also helpful since higher CSF JC virus loads have been found to be associated with shorter survival times and viceversa. JC virus loads have also been used to monitor the effects of antiviral therapy in PML patients

Human immunodeficiency virus

1. Diagnosis will already have been made on the blood
2. Quantitative PCR to measure the CSF viral load has been a valuable tool in assessing neurological involvement in HIV infection such as HIV-associated dementia and encephalitis and also to monitor therapy as the CSF viral load decreases markedly following highly active antiretroviral therapy (HAART).

Human T-cell lymphotropic virus-1

1. Human T-cell lymphotropic virus-1 (HTLV-1) is strongly associated with tropical spastic paraparesis and HTLV-1-associated myelopathy
2. Use of PCR is recommended (Level C) in the diagnosis of tropical spastic paraparesis and HTLV-1-associated myelopathy. 
3. The sensitivity and specificity of CSF PCR for tropical spastic paraparesis and HTLV-1-associated myelopathy has been reported as 75% and 98.5%, respectively. Combination of CSF PCR and anti-HTLV-1 antibody index useful in diagnosis (Class III Level C)

Bacteria

The PCR results are usually available well within 24–36 h for common bacterial infections and utilize low volume of CSF (≥1 ml) for analysis. 

PCR methods may employ one of the several available techniques:

1. Nested or semi-nested PCR with hybridization and sequencing, or use of universal primers and restriction endonuclease enzyme digestion. Nested approach is considered better in detecting meningeal infections with Borreila, Listeria, or Mycoplasma because of the low numbers of bacterial DNA and relatively few copies of 16S rRNA gene in the CSF
2. Probe-based real-time PCR is often preferred when using a multiplex PCR for simultaneous detection of different specific target sequences. Real-time quantitative multiplex PCR is considered a highly sensitive technique for fast identification of a causative pathogen of bacterial meningitis and can detect as few as two copies of Neisseria meningitidis, Streptococcus pneumoniae, and Escherichia coli, 16 copies ofListeria monocytogenes, and 28 copies of group B streptococcus whereas the sensitivity for broad-range 16S rRNA-based PCR was about 10–200 organisms per ml of CSF
3. Broad-range bacterial PCR is based on use of primers that recognize conserved regions of the genes encoding for eubacterial 16S ribosomal RNA (rRNA). The broad-range bacterial PCR combined with sequencing may be of particular advantage in rapid diagnosis and identification of the etiologic agent in community acquired bacterial meningitis .

Acute meningitis

1. Currently available PCR methods detect Hemophilus influenzae, N. meningitidis, S. pneumoniae, L. monocytogenes in CSF and have a sensitivity of 87–100% and specificity of 98–100%
2. Quantitative multiplex RT-PCR is commonly preferred for the detection of common pathogens of acute bacterial meningitis. 
3. PCR-based detection of bacterial pathogens is also considered more sensitive than culture in patients with ventricular catheters and suspicion of nosocomial meningitis or conventional cultures withprior antibiotic treatment
4. The positive predictive value of broad-range PCR is 98%, and the negative predictive value is 100%; ie a negative bacterial PCR assay virtually excludes the diagnosis of acute bacterial meningitis.
5. It is recommended that in house nucleic acid amplification methods for diagnosis of bacterial infections in CSF are deemed unreliable and should not be used in clinical practice (Class IV Grade C) owing to high inter-assay variability and low specificity
6. The advantage of uniplex vs multiplex quantitative RT-PCR is currently unclear (Class IV Grade C).
7. PCR-based diagnostic tools should be used only as an adjunct rather than a substitute for current methods of bacteriological diagnosis by conventional staining and culture.
8. In Future: it might be possible to rapidly diagnose bacterial infections by Gram stain-specific probe-based real-time PCR using 16S rRNA which will enable simultaneous detection and discrimination of clinically relevant Gram-positive and Gram-negative bacteria directly from blood samples 

Chronic meningitis

1. Tuberculous Meningitis:
   1. Quantitative RT-PCR has been shown to substantially increase diagnostic yield in TBM.
   2. A wide range of sensitivities have been reported for PCR-based tests forMycobacterium tuberculosis in CSF samples . 
   3. Using CSF filtrate than CSF sediment has been reported to give higher yield of positive result qualitative RT-PCR. 
   4. Since PCR-based methods are also prone to cross-contamination like conventional cultures, and the diagnostic specificity of PCR-based diagnosis of TBM may be compromised in endemic areas . 
   5. A negative CSF PCR result does not exclude the diagnosis of neurotuberculosis when CSF and imaging data suggests otherwise and one must be aware of false positives as well.
   6. In acute bacterial meningitis , CSF rapidly becomes sterile after antibiotic therapy and bacterial DNA may not be detectable beyond 8 h of treatment . However Mycobacterial DNA may persist for up to a month in CSF after starting therapy .Hence even if initial PCR result is negative, repeating quantitative RT-PCR test in successive CSF samples for M. tuberculosis may aid to diagnosis even if initial PCR result is negative
   7. The current consensus is that repeating CSF PCR within first 3 weeks may aid diagnosis in tuberculous meningitis if the initial result is negative (Class IV, Grade C).
2. Lyme neuroborreliosis: 
   1. In Lyme neuroborreliosis CSF PCR for Borrelia is probably useful as a diagnostic test only in very early stages and is not recommended as a diagnostic test for chronic Lyme disease or measure treatment response as a follow-up.
   2. However in patients with atypical forms of erythema migrans PCR on skin biopsies may become useful in the diagnosis of early Lyme borreliosis. 
   3. CSF- PCR is not presently a validated diagnostic test for Lyme neuroborreliosis (Class IV, Grade C).
   4. Direct microscopy and culture remain the gold standard of microbiological diagnosis of bacterial infections of central nervous system where feasible and current range of diagnostic bacterial PCR tests do not replace them (Class II Grade A).
   5. Commercially available and standardized quantitative RT-PCR is recommended for routine use in CSF samples (Class II, Grade A) of patients with suspected bacterial meningitis. 

Parasites

1. The diagnosis of a parasitic infection of the CNS rests upon clinical signs and symptoms, clinical history, travel history including geographic exposure and, finally, on laboratory techniques.
2. In resource poor areas light microscopy remains the diagnostic mainstay. 
3. Indirect methods like serology do not distinguish between past, latent, reactivated, or acute infection and is not useful in assessing response to therapy or prognosis. 
4. In immuno-compromised patients, indirect diagnostic methods (serology for antibody detection, etc.) have a very low sensitivity. 
5. Highly specific tests to detect antigen, for example, rapid antigen detection system (RDTS) luciferase immune precipitation system (LIPS), molecular-based approaches, in particular PCR , loop-mediated isothermal amplification (LAMP) , real-time (RT) PCR , and luminex technology have shown a high potential for use in diagnosing parasitic infestations with increased sensitivity and specificity .

Molecular-based diagnostic tests in protozoal infections of the CNS

Table below lists the protozoa that have the capacity to invade the CNS, causing neurological disease and details the molecular-based techniques used in their detection. Except cerebral toxoplasmosis the other molecular-based assays are still experimental diagnostic techniques and have not yet replaced serology or direct proof by light microscopy.

 

Protozoal pathogen	CNS manifestation	Molecular-based diagnostic technique
Free living amebae  Acanthamoeba spp.  Balamuthia mandrillaris  Naegleria fowleri	Granulomatous amebic encephalitis Acute primary amebic meningoencephalitis	PCR Nested PCR Real-time PCR PCR Real-time PCR Multiplex real-time PCR
Entamoeba histolytica	Brain abscess	Real-time PCR Multiplex tandem real-time PCR High through put multiplex PCR Probe-based detection with luminex beads
Babesia microti	Anemia, hypoxic encephalopathy	PCR
Plasmodium falciparum	Cerebral malaria, multi-organ malaria	Real-time PCR PCR multiplex real-time PCR   quantitative nucleic acid sequence-based amplification Real-time quantitative nucleic acid sequence-based amplification  Loop-mediated isothermal amplification Polymerase chain reaction/ligase detection reaction fluorescent microsphere-based assay PCR ELISA Nested PCR Reverse transcription loop- mediated isothermal amplification (RT-LAMP)
Plasmodium knowlesi	Usually severe anemia Rarely: cerebral malaria	Nested PCR
Toxoplasma gondii	Cerebral toxoplasmosis (granulomata, acute encephalitis; very rare in immuno-competent, usually in immuno-compromised patients) Congenital toxoplasmosis	Quantitative polymerase chain reaction  Rapid-PCR (B1-gene)   Loop-mediated isothermal amplification
Trypanosoma cruzi	Acute meningoencephalitis, myocarditis, in chronic Chagas disease: cardio embolic stroke	PCR Loop-mediated isothermal amplification
Trypanosoma brucei gambiense and Trypanosoma bruceirhodesiense	Chronic (T. b. gambiense) or sub-acute (T. b. rhodesiense) meningoencephalitis  Sleeping sickness	PCR Real-time PCR Nucleic acid sequence-based amplification and PCR coupled to oligo-chromatography  Loop-mediated isothermal amplification (LAMP)

 

Molecular-based diagnostic tests in helminthic infestations of the central nervous system

1. Conventional PCR has been supplemented by nested and multiplex PCR as well as real-time PCR for the detection of several parasitic infestations and infections, respectively.
2. More advanced techniques as loop-mediated isothermal amplification (LAMP) and luminex-based assays have also been proposed as possible diagnostic techniques in parasitic diseases of the nervous system. 
3. Direct visualization or detection of the helminths, either the adult worm, the larval stage, or the eggs, be it in body fluids or biopsied material, still represents the golden standard of diagnosis

 

Helminth	CNS manifestation	Molecular-based diagnostic technique
Angiostrongylus cantonensis	Eosinophilic meningitis	Multiplex PCR Loop-mediated isothermal amplification assay
Echinococcus granulosus	Cystic echinococcosis (space-occupying intracranial cyst)	Direct-PCR
Filarial species Wuchereria brancofti, Brugia malayi	Lymphatic filariosis, rarely: neurofilariasis (cerebral larva migrans)	Real-time PCR
Paragonimus westermani	Space-occupying intracranial cyst	Multiplex PCR Loop-mediated isothermal amplification
Schistosoma spp.	Space-occupying granuloma intracerebral and spinal space- occupying granuloma	PCR Real-time PCR Polymerase chain reaction – oligochromatic dipstick
Strongyloides stercoralis	Strongyloides stercoralis hyperinfection syndrome (in the immune-compromised) with fulminant meningitis and sepsis syndrome (accompanying gram negatives)	PCR Real-time PCR Pentaplex-real-time PCR High throughput multiplex PCR and probe-based detection with luminex beads Duplex-real-time PCR
Taenia solium – larval stage:Cysticercus cellulosae	Neurocysti-cercosis (Space-occupying, cystic intracranial lesions, epilepsy)	PCR Nested PCR Semi-nested PCR PCR amplified DNA sequences targeting T. soliummitochondrial cox1 gene and cob gene Loop-mediated isothermal amplification
Toxocara canis(cati)	Larva migrans visceralis (cerebralis, intracranial granuloma, vasculitis)	PCR

 

Fungi

The gold standard of diagnosis is positive cultures together with microscopy, antigen/antibody testing in serum, and CSF. However the slow growth of fungi in culture, cross-reactivity in case of antigen detection, and dependence on the demonstration of an antibody response or even by the failure to mount an adequate immune response are drawbacks. There is not enough data to recommend the routine use of PCR in fungal infections.

Histoplasmosis (Histoplasma capsulatum) :

1. Most common endemic mycosis in Europe
2. Chronic meningitis is the most frequent CNS manifestation of histoplamosis
3. Cerebral or spinal masses and encephalitis are less common. 
4. Fungal culture is the gold standard diagnostic test in non-CNS manifestations, but it may take up to 6 weeks 
5. CSF cultures usually do not yield growth.
6. Histoplasma capsulatum antigen and antibodies can be determined by different methods in CSF and are used to establish diagnosis. However, cross-reactivity with other dimorphic fungi and Cryptococcus species is seen in upto 50% of cases.
7. There is no commercial kit available for routine use for PCR in CNS histoplasmosis

Coccidioidomycosis (Coccidioides immitis)

1. Chronic basal meningitis is the most common coccidioidal CNS manifestation.
2. Occasionally, CNS coccidioidomycosis presents as meningoencephalitis or intracranial mass lesion.
3. Coccidioides sp. grows in culture within 2–5 days 
4. Coccidioides sp. is isolated from CSF only in a third of patients with CNS manifestations 
5. CSF antibodies can be detected in up to 70% of patients with meningitis during the initial analysis, and in the majority of cases later. 
6. Currently, there are no standardized CSF antigen detection methods
7. No PCR is available for commercial use.

Blastomycosis (Blastomyces dermatitidis)

1. CNS manifestations of blastomycosis are rare, mostly cranial/spinal epidural abscess, meningitis, and brain abscess in AIDS patients.
2. Definitive diagnosis of blastomycosis requires growth of the organisms in culture. 
3. CSF culture is rarely positive, and only stereotactic brain biopsy may be diagnostic.
4. cytological examination of CSF may sometimes reveal Yeast forms.
5. CNS blastomycosis may be diagnosed by presence of antibodies in serum and CSF, cross-reactivity with other fungi is possible. 
6. Chemiluminescent DNA probes have been developed but not standardised or commercially available.

Cryptococcosis (Cryptococcus neoformans/gattii)

1. Chronic basal meningitis is the most frequent CNS manifestation of cryptococcal disease causing subacute dementia or visual symptoms.
2. Culture alone is generally not the method of choice. 
3. The diagnostic mainstay is antigen detection with >90% sensitivity and specificity. This test in CSF can be positive early in infection. 
4. Microscopic examination of CSF using India ink stain is diagnostic in up to 80% of AIDS patients and about 50% in non-immunocompromized.
5. The usage of CSF PCR for the diagnosis of suspected CNS cryptococcosis is likely to be of value

Candidiasis (Candida albicans and other C. species)

1. Candida species are the fourth leading cause of fungal bloodstream infections and associated with a mortality rate of up to 50%.
2. CNS Candidiasis can develop in the setting of disseminated candidiasis with microabscesses of the brain parenchyma or as candida meningitis in association with a foreign body (e.g. catheter, ventricular shunt) or other CNS invasive procedures (e.g. surgery).
3. Blood cultures are considered the gold standard for routine diagnosis of invasive candidiasis but are time-consuming.
4. CSF, stains and routine cultures have a low yield in identifying the pathogen in chronic Candida meningitis. 
5. Serological diagnosis of CNS candida infection, either by antigen detection (mannan) or by antibody determination, has not been validated. 
6. PCR protocols for detection of candidal infection have been described and require probes for different subspecies. PCR may also assess mutations associated with resistance to antifungal medication.

Aspergillosis (Aspergillus fumigates and other species)

1. There are numerous species of aspergillosis recognized, but most cases of CNS infection are attributed to A. fumigates, A. flavus,A. terreus, and A. versicolor. Major CNS manifestations include hemorrhagic infarction, abscess, and meningitis; less frequent are mycotic cerebral aneurysm and granuloma.
2. Culture is insensitive and diagnosis requires non-culture-based methods. 
3. Two antigen assays, the [1,3]-beta-D-Glucan assay (sensitivity 87%), a relatively non-specific assay and the galactomannan assay (>95% sensitivity and specificity), an Aspergillus-specific antigen, are commercially available and used in clinical routine for blood specimen and sometimes in CSF samples.
4. A combination of the galactomannan (antigen) assay and PCR may improve diagnosis.
5. The sensitivity of PCR testing for Aspergillus is limited during antifungal treatment.
6. The usage of CSF PCR for the diagnosis of suspected CNS aspergillosis is likely to be of value

Mucormycosis/zygomycosis (Mucor, Rhizpous, Rhizomucor, Absidia, Cunninghamella, Apophysomyces, Saksenaea)

1. Mucormycosis is an acute and aggressive fungal infection, which can develop as isolated cerebral mucormycosis (16%), extension to the brain from rhinocerebral mucormycosis (69%) or via the hematogenous route (15%).
2. Diagnostic techniques include histology, culture, and PCR. The diagnosis is mostly made by a combination of histology and culture.

Conclusion

1. The main use of PCR technology is to the diagnosis of infections caused by viruses followed by bacterial infections of the CNS with the notable exception of tuberculous meningitis.
2. The efficacy of PCR for the diagnosis of both protozoal infections and helminthic infestations has also been established but far from becoming routine in resource-poor countries where such infections are prevalent.
3. There are class IV evidence studies reporting the feasibility of CSF PCR for evaluating CNS manifestations by Histoplasma, Coccidioides, and Candida, and of tissue for CNS mucormycosis. There is not enough evidence at present to recommend the use of PCR as a routine diagnostic tool in these cases.

Original citation:

Steiner, I., Schmutzhard, E., Sellner, J., Chaudhuri, A. and Kennedy, P. G. E. (2012), EFNS-ENS guidelines for the use of PCR technology for the diagnosis of infections of the nervous system. European Journal of Neurology, 19: 1278–1291. doi: 10.1111/j.1468-1331.2012.03808.x [ Abstract]

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12th conference of the Baltic Child Neurology Association
30 May - 1 June, 2013, Kaunas, Lithuania

On behalf of the Organizing Committee it is our great pleasure to invite you to attend the 12th Conference of Baltic Child Neurology Association (BCNA) in Kaunas, Lithuania, on 30 May - 1 June, 2013. This major scientific event is being held every two years since 1991 and provides a wonderful opportunity for child neurologists to share their professional experience with colleagues from different countries, also to get new ideas and impulses for scientific research and for the improvement of clinical care for neurologically affected children. Also, it provides the possibility to experience the warm atmosphere in the circle of old and new friends, the "professional siblings".

The scientific program will cover the most relevant topics, like epilepsy, development disorders and cerebral palsy, autism, autoimmune and demyelinating disorders, also rare diseases that require special attention due to the risk of severe complications and new treatment / management possibilities.

We are happy to note that among other outstanding speakers, the Board members of International Child Neurology Association (ICNA) are ready to join the conference program by providing presentations on different topics. We would also encourage our colleagues from the Baltic and other neighbour countries to share their experience in different fields of child neurology.

We look forward to welcoming you in Kaunas!

Milda Endzinienė
Conference President
Chair of the Lithuanian Child Neurology Association

Nerija Vaičienė-Magistris
Conference Vice-President

http://www.bcna2013.com/

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EPNS Research Meeting 2012
14. / 15. Dec 2012
Beuggen – Rheinfelden Germany, near Basel

Main topics for talks:
Epilepsy
Ataxia
Research groups:
ADHD
Ataxia
Autoimmune-inflammatory diseases
Developmental Neurology
Epilepsy
Neonatal Neurology, Neurodegeneration and Neuroprotection 
Neurometabolic diseases 
Neuromuscular diseasesDear Colleagues

We are very happy to invite you to the 3rd Research Conference of the EPNS in joined organization with the Statuskonferenz der Gesellschaft für Neuropädiatrie. We will meet from 14/15th of 
December 2012 in Beuggen, a nice cloister close to Rheinfelden/Basel. We hope that this  environment will stimulate international collaborations and research in Paediatric Neurology. 

There will be again eight different working groups: 

1. Ataxia
2. Autoimmun-inflammatory diseases 
3. ADHD (new)
4. Developmental Neurology
5. Epilepsy
6. Neonatal Neurology, Neurodegeneration and Neuroprotection
7. Neurometabolic diseases
8. Neuromuscular diseases

The leaders of these working groups have put together a short description of their respective themes and goals, which you can find in the latter part of this invitation. If you would like to participate actively in the preparation of a specific working group, feel free to contact your chair person!. We also hope that it will be possible for you to encourage young colleagues to join us for this meeting. It would be a unique opportunity for them to join a research group or to start their own project within the field with some support from an experienced researcher in the field. As usual there are also three plenary sessions, which this year will be organised from the group of 
ataxia and epilepsy. In these talks we try to give you an insight into hot research topics in the field.  At the final discussion each group will present their working group summary. There will again be an award of the EPNS research prize for the group with the most outstanding and innovative ideas for future research.

Concerning housing we have the possibility to accommodate 62 persons for sleeping in the cloister and additional rooms in a nearby hotel. This will be in one bed-, two bed- and some multi-bed rooms at a reduced rate. Please indicate your preferred type of accommodation (and room sharing) on the registration form. Room reservation will work on a first come-first serve basis. 

We hope that we succeeded in putting together an interesting and stimulating program for all of us and that we will see many young as well as advanced researchers over these two days in Beuggen. 

We are looking forward to meeting you again.
Sincerely yours,

Prof. Dr. med. Barbara Plecko-Startinig 
Prof. Dr. med. Bernhard Schmitt Prof. 
Dr.med. Maja Steinlin

 

PROGRAM

PROGRAM PAEDIATRIC NEUROLOGY RESEARCH CONFERENCE
Beuggen, Germany, December 14-15, 2012
Friday, December 14, 2012
12.00-13.00 Arrival Registration Lunch
13.00-13.15 Welcome
13.15-13.45
Plenary Lecture Ataxia
Cerebellar and brainstem malformations: news form the Italian Registry
Enza Maria Valente, Rom (I) 
13.45-14.15 Genetics of ataxia in children: update from recent research
Andrea Nemeth, Oxford (GB) 
14.15-15.30 Working groups 1-8
15.30-16.00 Coffee Break
16.00-19.00 Working groups 1-8
19.30 Get together and Dinner
Followed by
Informal discussions over a glass of wine
Saturday, December 15, 2012
08.30-09.30 Working groups
09.30-10.00 
Plenary Lecture Epilepsy
Sleep, Epilepsy and Cognitive Function 
Reto Huber, Zürich (CH)
10.00-10.30 Neuromics Research Project
Volker Straub, Newcastle upon Tyn (GB)
10.30-11.00 Coffee Break
11.00-13.00 Presentations and Discussions of working groups 1-8
13.00-13.30 Final discussion 
Award of the EPNS Research Prize
13.30 Lunch/Farewell

Working groups and their topics - see also special flyers of different working groups!

Neonatal Neurology, Neurodegeneration and Neuroprotection 
Chair: Regina Trollmann (This email address is being protected from spambots. You need JavaScript enabled to view it.)
The discussion will cover newest research data on models of perinatal brain hypoxia and ischemia, their effects and their contribution to clarify the pathophysiology of hypoxic ischemic brain injury.You are welcome to bring your own ideas, to inform about your own model, to get help in choosing an appropriate model for your own research questions. Information on neuroprotective strategies will be shared and possible joint research on neuroprotectives in asphyxia will be discussed.

Metabolics
Chairs: Linda De Meirleir (This email address is being protected from spambots. You need JavaScript enabled to view it.)
Barbara Plecko (This email address is being protected from spambots. You need JavaScript enabled to view it.)

This year the metabolic group will focus on basal ganglia diseases. Following two invited lectures on  neuroimaging as well as Leigh Disease, the group will try to work on guidelines for pattern recognition and a standardized metabolic and genetic work-up. Participants are kindly invited to present unsolved cases and to found a collaborative network for unclear basal ganglia disease of probable genetic background.

Ataxia
Chair: Peter Baxter (This email address is being protected from spambots. You need JavaScript enabled to view it.)
Results of the validation of the SARA scale by Deborah Sival will be presented. Instructions on SARA scale will be given, followed by discussion on how to proceed for validation within different countries (cultures) and also interrater viability. Update on the Eurataxia database – and information on how to join the database from different centres. 

Developmental Neurology
Developmental Neurology comprises traditionally two focuses:
1.Systemic Neurology / Clinical Neurophysiology / Functional Imaging

Chair: Volker Mall 
(This email address is being protected from spambots. You need JavaScript enabled to view it.)
The focus of this group are techniques of advanced imaging, transcranial magnetic stimulation (and other techniques of clinical neurophysiology), evaluation of neuronal plasticity, early brain (re-)organisation and the context of brain structure and function. Further clinical issues of cerebral palsy are a focus of this group, especially quality of life evaluation, hip development as well as epidemiology.

2.The more classical Developmental Neurology (evaluation, outcome and intervention in 
Developmental Disorders)
Chair: Joachim Pietz (This email address is being protected from spambots. You need JavaScript enabled to view it.).
A key issue of infant and developmental neurology are the best methods to investigate infants and toddlers. It has been recognized that many classical and well-established parts of neurodevelopmental examinations unfortunately exhibit only low prognostic values. We will present some new developments and results in the area of infant assessment, and hope to share it with other groups working in this field. 

Neuromuscular group
Chair: Volker Straub (This email address is being protected from spambots. You need JavaScript enabled to view it.)
The Neuromuscular Working Group aims to discuss the latest research developments and plans relevant for the diagnosis, care and treatment of paediatric neuromuscular diseases. The discussion will focus on the application of new omics approaches, current and future clinical trials andinternational neuromuscular projects funded by the EU. The working group session will also provide an opportunity for scientists and clinicians to present own research ideas and results.

Autoimmune inflammatory diseases
Chair: Kevin Rostasy, Banu Anlar, Martin Häusler (This email address is being protected from spambots. You need JavaScript enabled to view it.)
"Participants of the autoimmune / inflammatory working group will have the opportunity to present 
own projects. The working group will also work on one specific scientific topic which remains to be 
defined. Proposals are still welcome."

Epilepsy
Chair: Alexis Arzimanoglou (This email address is being protected from spambots. You need JavaScript enabled to view it.) and Helen Cross (This email address is being protected from spambots. You need JavaScript enabled to view it.)
During the epilepsy working group meeting, new international research projects as well as the progress on previously presented projects can be discussed. There will also be an update on the EPNS epilepsy registry (a prospective database collecting clinical data in children presenting with epilepsy below the age of 1 year) , recently launched and involving already now more than 25 centers throughout Europe. More specifically, there will be a last review of the most important items in the database before a final European launch in January 2013. Two other European projects, coordinated by the Utrecht Group (Time to Stop Trial on discontinuation of AEDs following epilepsy surgery and a Randomized Controlled Clinical Trial on Treatment of Electrical Status Epilepticus in Sleep – ESES) will be presented and discussed.

Attention Deficit Disorder (new working group!)
Chair: Manuel Antonio Fernandez (This email address is being protected from spambots. You need JavaScript enabled to view it.)

In this new working group will try to bring together professionals from different areas to share experiences and work on developing unified programs of assistance, research and teaching in various 
aspects of interest in ADHD. Will address the main issues of interest including genetics, neuroimaging, new technologies in clinical care and seek to join forces to ensure better diagnosis and treatment of these patients. All stakeholders are invited to participate actively in this group with the intention of creating a network of experts to standardize the criteria for ADHD care in different countries

If you would like to participate actively in preparation of your workshop or if you would like to present something during your workshop please get into contact with the chair of your working group directly.On the homepage of the EPNS and GNP more detailed programs of some working groups will be updated on a regular base as the information is provided by the chairs of the working group.

http://www.epns.info/ http://www.neuropaediatrie.com

This information will be updated on a monthly base till November 2012.

Organization committee
Prof. Dr. med. Barbara Plecko-Startinig
Extraordinariat Neuropädiatrie
Kinderspital Zürich
Universität Zürich 
Steinwiesstrasse 75
8032 Zürich 
Tel.: +41 44 266 73 30
Fax: +41 44 266 71 63
This email address is being protected from spambots. You need JavaScript enabled to view it.

Prof. Dr. med. Bernhard Schmitt
Leitender Arzt 
EEG/Epilepsie Abteilung
Kinderspital Zürich
Universität Zürich
Steinwiesstrasse 75
8032 Zürich
Tel +41 44 266 75 92
Fax +41 44 266 71 65
bernhard.schmitt kispi.uzh.ch

Prof. Dr.med. Maja Steinlin
Abteilungsleiterin 
Abteilung Neuropädiatrie, Entwicklung und 
Rehabilitation
Universitätsklinik für Kinderheilkunde
Inselspital
3010 Bern
Tel +41 31 632 94 24
Fax +41 31 632 95 00
This email address is being protected from spambots. You need JavaScript enabled to view it.

Secretary
Marianne Probst
Abteilung Neuropädiatrie, Entwicklung und Rehabilitation
Universitätsklinik für Kinderheilkunde
Inselspital
3010 Bern
Tel +41 31 632 94 24
Fax +41 31 632 95 00
This email address is being protected from spambots. You need JavaScript enabled to view it.

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Published: 25 September 2012

Last Updated: 08 February 2020

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