VHF Encephalitis

1
VHF Encephalitis

• Prof. Dr. Mehmet BAKIR

2
Definition of Viral Hemorrhagic Fever

• Fever
• Myalgia
• Bleeding including dermal, intradermal,
  gastrointestinal system,and vaginal or another
  organ/system

3
The etiology of VHF

• Filoviridae (Marburg virus ve Ebola virus)
• Arenaviridae (Lassa virus, Junin, Machupo,
  Sabia, and Guanarito virus)
• Lassa ,and Junin virus can cause encephalitis,and
  menengitis
• Bunyaviridae (Crimean-Congo hemorrhagic fever
  virus CCHFV, Rift Valley fever virus RVFV
  ,Hantavirus)
• RVF and Toscana virus can cause encephalitis, and
  menengitis
• Flaviviridae
• Yellow fever virus and Dengue virus, West Nile
  virus
• DENV and WNF can cause encephalitis, and
  menengitis

4
West Nile Virus

• From Flaviviridae family and the Flavivirus genus
• WNV is a positive sense single stranded RNA virus
• and an important pathogen for humans,
  horses, dogs, birds and reptiles
• Birds are considered to be the main reservoir
  hosts of WNV,
• Migratory birds play an important role in its
  spreading
• The natural cycle of WNV typically involves
  ornithophilic Culex
• mosquitoes feeding on avian hosts
• From human to human can be transported by
  transfusion or transplantation of organs

Monath and Heinz 1996, Rappole et al. 2000,
Apperson et al. 2004, Iwamoto 2003, Pealer LN
2003,
5

• Horses are highly susceptible
• The latest outbreaks of WNV include an increased
  proportion of neurological disease in both humans
  and horses
• Mortality rates among clinically affected horses
  have been estimated around 38, 28, 44 and 42
  during outbreaks in the USA, France (2000),
  Morrocco and Italy (1998), respectively
• West Nile virus has a wide geographical
  distrubution that includes countries of Europe,
  Asia, Africa, Australia, and America
• WNND were confirmed by European countries such
  as Greece (197 cases) , Romania (54 cases),
  Italy (3 cases), Hungary (15 cases), Portugal (1
  case) and Spain (1 case) 5 in 2010

Castillo- Olivares and Wood 2004, Petersen and
Roehrig 2001, Tber Abdelhaq 1996, Cantile et al.
2001, Murgue et al. 2001, Ostlund et al. 2001,
Hubalek and Halouzka 1999, Savage et al. 1999,
Hayes et al. 2005
6
West Nile Virus

• The first acute human WNV infection cases were
  documented and reported from Manisa province in
  Turkey.
• From July to November in 2010, 47 cases of WNV
  infection were detected (35 were probable, 12
  were confirmed)
• The central nervous system manifestations were
  found in 40 patients

7
WNV

• An other study was performed at Hacettepe
  University Hospital. Paired serum and
  cerebrospinal fluid (CSF) samples from 87 adult
  patients with the preliminary diagnosis of
  aseptic meningitis/encephalitis of unknown
  etiology were evaluated retrospectively to
  identify WNV-related syndromes.
• WNV IgM and IgG antibodies were detected in 9.2
  (8/87) and 3.4 (3/87) of the serum samples,
  respectively.

Ergünay K, et al, 2010
8

• In this study, 371 sample from 234 individuals
  were collected from Ankara and Izmir
• Two cases of WNV CNS infections and 14 cases of
  TOSV infections were identified via serological
  testing

9
Surveillance and outbreak reportsEmergence of
West Nile virus infections in humans inTurkey,
2010 to 2011H Kalaycioglu (h.kalaycioglu_at_hotmail.
com)1, G Korukluoglu1, A Ozkul2, O Oncul1, S
Tosun3, O Karabay4, A Gozalan1, Y Uyar1,D Y
Caglayik1, G Atasoylu5, A B Altas1, S Yolbakan1,
T N Ozden5, F Bayrakdar1, N Sezak3, T S Pelitli6,
Z O Kurtcebe6, E Aydin6,M Ertek11. Refik Saydam
National Public Health Agency, Ankara, Turkey2.
Ankara University, Faculty of Veterinary
Medicine, Department of Virology, Ankara, Turkey
3. State Hospital, Manisa, Turkey 4. Training and
Research Hospital, Sakarya, Turkey 5. Provincial
Health Directorate, Manisa, Turkey6. Ministry of
Health, General Directorate of Primary Health
Care, Ankara, Turkey
Age group (years) Number of cases Incidence (per 100,000 population)
lt20 8 0.10
20-29 3 0.07
30-39 1 0.03
40-49 6 0.19
50-59 8 0.33
60-69 4 0.28
70-79 12 1.29
gt80 5 1.63

• Province of residence

Ankara 1 0.02
Adana 1 0.05
Antalya 1 0.05
Kocaeli 1 0.06
Afyon 1 0.14
Konya 3 0.15
Manisa 2 0.15
Izmir 8 0.21
Isparta 1 0.24
Balikesir 3 0.26
Diyarbakir 4 0.26
Aydin 4 0.41
Karaman 1 0.43
Mugla 4 0.50
Sakarya 12 1.39
Total 47 0.19
The overall incidence of WNV infections was
deteced in 0.19 cases per 100,000 population in
humans in a sureveillance study in Turkey, 2010
to 2011
10
United States, 2011
MMWR / July 13, 2012 / Vol. 61 / No. 27
11

• WNV recognized in North America in 1999 and is
  the most frequent cause of epidemic
  meningoencephalitis in North America.
• Between 1999 and 2009, over 12,000 cases of WNND
  were reported in the United States.

Debiasi RL, 2011
12
In WNV infection

• Pathological changes within the central nervous
  system develop as a direct result of viral
  proliferation within neuronal
• and glial cells, cytotoxic immune response
  to infected
• cells, diffuse perivascular inflammation,
  and microglial nodule formation

Smith RD, Hum Pathol 2004 Agamanolis DP, Ann
Neurol 2003 Gyure KA. J Neuropathol Exp Neurol
2009
13
West Nile Virus

• Incubation period is 2-15 days.
• Asymptomatic infection, West Nile Fever, and West
  Nile neuroinvasive disease (WNND) follow this
  incubation period.
• Of all cases, 80 is asymptomatic and 20 is
  symptomatic.
• Less than 1 of symptomatic cases have a
  neuroinvasive disease.
• Most of illnesses is seen as West Nile fever
  and observed as clinical symptoms and findings as
  followsSelf-limited dengue-like illness
• Fever, headache, retro-orbital pain, back pain,
  fatigue, arthralgia, and myalgia, anorexia,
  nausea, vomiting, diarrhea, maculopapular rash,
  lymphadenopathy

Hayes et al. 2005, Petersen and Marfin 2002,
Solomon and Vaughn 2002
14
West Nile neuroinvasive disease (WNND)

• WNND includes severe neurologic illness
  categories
• Clinical and laboratory findings seen in the WNV
  meningitis include fever, nuchal rigidity, CSF
  pleocytosis.
• Encephalitis includes 60 of WNND cases and
  there is ususally altered mental status in these
  cases consisting
• of people less than 55 years old or
  immunocompromised patients
• The other neuroinvassive disorders of WNV include
  
• meningoencephalitis,
• acute flaccid paralysis,
• tremor, myoclonus or both tremor and myoclonus,
• and parkinsonism

15
Diagnosis of WNND

• Many patients with WNND have normal neuroimaging
  status
• but abnormalities may be present in areas
  including the basal ganglia, thalamus,
  cerebellum, and brainstem
• CSF protein is elevated
• Cerebrospinal fluid invariably shows a
  pleocytosis, with a predominance of neutrophils
  in up to half the patients.
• With demonstration of WNV-specific IgM antibodies
  in cerebrospinal fluid or serum approximatelly
  half of all cases will be positive in the first
  7 days whereas Ig G Antibodies will be positive
  in 7-21 days
• RNA in serum and/or CSF can be detected by PCR
  method.

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Therapy and prevention

• Therapy

• Prevention

• there is no proven therapy for WNND,
• several vaccines and antiviral therapy with
  antibodies, antisense oligonucleotides, and
  interferon preparations are currently undergoing
  human clinical trials.
• Supportive therapy has to be carried out.

• Repellents and body protective clothing can use
  to avoid the bite of the mosquito
• It can use insecticides for mosquitoes
• There are studies for vaccine but not available
  for general use

17
Dengue Haemorrhagic Fever virus

• Virus is from Flaviviridae family and Flavivirus
  genus
• Dengue is an RNA virus that is grouped into four
  serotypes (DENV-1 through DENV-4).
• This virus is
• non-enveloped,
• spherical with a diameter of 50nm
• and a positive-sense,single-stranded RNA
  genome.

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DENV epidemiology

• This infection is the most destructive arboviral
  disease
• The number of countries reporting outbreaks has
  increased 10-fold since the last 30 years.
• Dengue is a worldwide condition spread throughout
  the tropical and subtropical zones between 30 N
  and 40 S.
• These countries are
• Pacific-Asian region, Americas, Middle East, and
  Africa.
• Approximately 50-100 million infections occur
  each year resulting in approximately 25,000
  deaths.
• Vectors are the mosquitoes Aedes aegypti and
  Aedes albopictus
• Dengue represents the second leading cause of
  acute fever in travellers

19

• The incidence of neurological symptoms among
  dengue patients varies from 1 to 25 in all
  dengue admissions
• In Indonesia, 70 of virologically confirmed
  fatal dengue infections (n30) presented with one
  or more neurological signs, and 7 of those
  admitted for viral encephalitis turned out to be
  dengue-infected.
• In another study , 4.2 of patients with
  neurological symptoms tested positive for dengue.

Thakare J, . et al1996, Kankirawatana P, et al.
2000, Solomon T, et all,2000, Puccioni-Sohler et
al., 2000,. Jackson et al., 2008, Garcia-Rivera
EJ, et all, 2002
20
In this study, the authors reviewed the etiology
of viral menengitis and encephalitis in a dengue
endemic region, in Brazil. Dengue viral
encephalitis brought about 47 of all
encephalitis cases. Journal of the Neurological
Sciences 303 (2011) 7579
21
In the same study mentioned above, Dengue viral
menengitis is 10 of all menegitis cases.
Journal of the Neurological Sciences 303 (2011)
7579
22
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öööööööööööööööööcbzvnbnb.önbn
In this study, the authors included 265 cases of
AFE and 39 patients were evaluated as dengue
encephalopathy
23
Neurological Manifestations of Dengue

• From the pathogenesis point of view, neurological
  manifestations of dengue can be grouped into
  three categories
• (1) Related to neurotropic effect of virus
  (encephalitis)
• (2) Related to systemic complication of dengue
  infection (encephalopathy)
• (3) Post infectious like acute disseminated
  encephalomyelitis, myelitis, Guillain-Barre
  syndrome, optic neuritis.

Murthy JMK. Neurological complication of dengue
infection. Neurol India. 2010 58 581-84.
24
Clinical manifestations

• Patients with Symptomatic Dengue Fever have

• Patients with Dengue Hemorrhagic Fever and Shock
  Syndrome (the most severe form) have

• malaise, headache, myalgias, retro-orbital pain,
  bone pain, arthralgias, nausea, vomiting
• petechiae, and a diffuse erythematous
  maculopapular rash

• Hepatomegaly
• Hemorrhage (including epistaxis, gingival
  hemorrhage, and gastrointestinal hemorrhage)
• Disseminated intravascular coagulation, plasma
  leak, and shock may be fatal during this phase.

Neurological complications are uncommon
manifestations of dengue fever, Neurological
dengue is classified as a form of Severe Dengue
(WHO 1997, 2009).
25
Neurlogical complications

• Encephalitis is the most common clinical status
  (from 4.2 to as much as 51) and has following
  characteristics
• Fever, headaches, altered consciousness or
  personality, seizures, or focal neurological
  signs
• myalgias, diarrhea, joint or abdominal pain,
  rash, and bleedings are reported in only 50 of
  encephalitis cases
• The other clinical statues include meningitis and
  myelitis
• Acute disseminated encephalomyelitis (ADEM) is
  rarely described in association with dengue
  infection

26
Laboratory findings

• CT and MRI findings
• hemorrhages, diffuse cerebral edema,
• focal abnormalities involving the globus
  pallidus, the hippocampus, the thalamus, and the
  internal capsule
• Analysis of CSFlymphomononuclear pleocytosis and
  normal glucose levels
• However, normal CSF cellularity has been shown in
  more than half of patients with dengue
  encephalitis.

27
Diagnosis

• Cell culture for DENV
• RT-PCR for detecting of viral RNA in serum,
  plasma, or CSF
• ELISA for identifying dengue virus specific IgM
  and or immunoglobulin G in serum obtained during
  the acute and convalescent phases of infection

28
Management of Dengue Fever

• There is no specific anti viral treatment and
• The management is essentially supportive and
  symptomatic (Bedrest)
• The key to success is frequent monitoring and
  changing strategies depending on clinical and
  laboratory evaluations
• (Fluid, electrolyte, blood and blood products)

29
Prognosis

• Mortality rates vary from 5 to 22
• Causes of death include multi-organ failure,
  hemorrhagic complications, and circulatory
  collapse.
• Most patients completely recover by the time of
  hospital discharge
• Neurological sequelae include
• spastic paresis,
• static myelopathy following transverse myelitis,
• residual spasticity,
• prolonged drowsiness,
• residual paralysis and Parkinsonian syndrome.

30
Prevention

• Tissue culture-based vaccines for dengue virus
  types are immunogenic but not available for
  general use
• Repellents and body protective clothing can use
  to avoid the bite of the mosquito
• It can use insecticides for mosquitoes

31
Arenaviridae

• At least eight arenaviruses are known to cause
  human disease
• New World viruses,
• Junin virus (JUNV), Machupo virus (MACV),
  Guanarito virus (GTOV), and Sabia virus (SABV)
  (all members of lineage B) are etiologic agents
  of hemorrhagic fever syndromes in South America,
• Whitewater Arroyo virus (WWAV) (lineage A) has
  been linked to two fatalities in North America .
• Old World viruses
• Lassa virus (LASV), Lujo virus, and lymphocytic
  choriomeningitis virus (LCMV

32
Arenaviridae

• Arenaviridae is a spherical or pleomorphic
  virion ( with a diameter of 50300 nm) with
  envelope and has single-stranded RNA
• Virus is inactivated by
• heating to 56oF,
• pHlt5.5 or gt8.5, and
• UV/gamma irradiation
• Chemical agents like 0.5 sodium hypocorite, 0.5
  phenol and 10 formalin are sufficiently good
  inactivants against the virus.

33
Lassa virus

• Lassa virus and Lujo virus can cause hemorrhagic
  fevers
• and Lassa fever accounts for 10 to 15 of
  adult medical admissions in West Africa
• Rodent-to-human transmission (the multimammate
  rat, Mastomys species-complex)
• Infected rodents remain as carriers throughout
  their life (no clinical symptoms)
• Infected rodents excrete the virus through the
  urine, saliva, respiratory secretion

34
Lassa virus

• Human infections can occur
• when individuals are exposed to aerosol forms
  of the virus
• or after direct contact between infectious
  materials and abraded skin.
• Ingestion of food or materials contaminated by
  infected rodent excreta
• The virus can be isolated in the blood, faeces,
  urine, throat swab, vomit, semen and saliva of
  infected persons ( during 30 days or more )
• Infected persons present serious threat to the
  environment
• Health care workers are at risk if proper barrier
  nursing and infection control are not maintained.
  

35
Pathogensis

• The ilness is developed by
• endothelial cell damage/capillary leak,
• platelet dysfunction,
• suppressed cardiac function,
• cytokines and other soluble mediators of shock
  and inflammation

36
Clinical aspects

• Incubation period is approximately 5-21 days
• Typical symptoms include
• gradual onset of fever, headache, malaise,
• pharyngitis, myalgias, retro-sternal pain, cough,
  vomiting arthralgia, weakness, sizziness,
  abdominal pain, diarrhea
• A minority group present with classic symptoms of
  bleeding, neck/facial swelling and shock.

37
Lassa virus

• Neurological signs include confusion,
  disorientation, locomotor dysfunction, tremors,
  convulsions and coma.
• The clinical picture can vary.
• Encephalopathy was the most prominent syndrome.
• Severely ill patients may die and the mortality
  rate is particularly high among pregnant women.
• Convalescence can be prolonged in patients who
  recover.
• Transient or permanent deafness often occurs.

38
Diagnosis

• Virus isolation
• ELISA for antigen of virus and IgM or IgG for
  virus
• Immunohistochemistry (for post-mortem diagnosis)
• RT-PCR for detecting RNA of virus

39
Treatment

• It includes supportive measures and ribavirin.
• Ribavirin is most effective when started within
  the first 6 days of illness
• Its major toxicity is mild hemolysis and
  suppression of erythropoesis. Both is reversible.
• Presently, it contraindicates in pregnancy,
  although it may be warranted if mothers life is
  at risk

40
Poor prognosis

• Poor prognosis can be due to
• high viremia,
• high serum AST levels as more than150 IU/L
• bleeding
• encephalitis
• edema
• third trimester of pregnancy

41
Prevention and control

• Programs for rodent control and avoidance
• Health education strategies for preventing
  infections
• in people living in endemic area
• Hospital training programs to avoid nosocomial
  spread
• Diagnostic technology transfer
• Specific antiviral chemotherapy (ribavirin)
• There are studies for vaccine but not available
  for general use

42
Bunyaviridae family, Phlebovirus genus (10
sercomplex)

• Sandfly fever serocomplex
• Sandfly fever Naples group
• Granada virus
• Massila virus
• Punique virus
• Sandfly fever Naples virus
• Toscana virus
• Sandfly fever Sicilian group
• Belterra virus
• Chagres virus
• Corfu virus
• Rift Valley fever virus
• Sandfly fever Cyprus virus
• Sandfly fever Sicilian virus
• Sandfly fever Turkey virus

• Virus has a single-stranded RNA genome with
  lipid-enveloped
• The genome consists of three segments the
  large(L), the medium (M),the small (S)

43
Phlebovirus (RVFV)

• RVFV is a highly pathogenic virus that can cause
  lethal disease in both humans and ruminant
  animals
• RVFV is transmitted primarily by Aedes mcintoshi
  mosquitoes,
• The virus has been detected in 23 species of
  mosquitoes
• RVF outbreaks in human populations vary in size,
  intensity and location with these parameters
  dependent upon rainfall and mosquito abundance
• Humans is infected by direct contact or aerosol.
• Tissue or body fluids of animals (aborted
  fetuses, slaughter, necropsy) are contagious

44
Chronology of Phlebovirus (RVFV) epidemia

• 1987 Senegal
• 1997-98 Kenya Largest outbreak reported (89,000
  humans cases - 478 deaths)
• 2000-01 Saudi Arabia and Yemen (First outbreak
  outside of Africa)
• 2003 Egypt (45 cases 17 deaths)
• 2006-7 Kenya ( Spread to surrounding areas,
  1000 human cases, 300 deaths)
• The largest recorded outbreak of RVF was in Egypt
  in 1977 with 10,000 to 20,000 human cases 8,9.
• 2010 South Africa (over 250 laboratory confirmed
  cases with an approximate case fatality rate of
  11)

45
Phlebovirus (Sandfly and Toscona virus)

• Virus transmitted to humans by insects of
  Phlebotomus genus (P. perniciosus and Phlebotomus
  perfiliewi )
• The virus has been detected in Italy and Spain
• Virus recently spread to many other Mediterranean
  and Europe countries such as
• Turkey, Cyprus, Greece, France, Portugal, Germany
• Most cases of the disease have been reported in
  residents in or travellers to the Mediterranean
  area.
• (Amaro et al., 2011 Brisbarre et al., 2011
  Depaquit et al., 2010, Di Nicuolo et al,2005 ,
  Ergünay et all. 2012,F.de Ory et al, 2013,
  Colomba et al 2011,

46
Phlebovirus (Sandfly and Toscona virus)

• Incubation period ranges from a few days to 2
  weeks,
• Clinical symptoms are
• headache (100, ),
• fever (7697),
• nausea and vomiting (6788)
• myalgias (18).
• Physical examination findings are
• neck rigidity (5395), Kernig signs (87),
• poor levels of consciousness (12),
• Tremors (2.6),
• paresis (1.7), and nystagmus (5.2) (L.
• Laboratory findings of CSF include cells more
  than 510 with normoglycorachia and
  normoproteinorachia.
• Blood samples may show leukocytosis (29) or
  leukopenia (6).

Charrel et al, 2005
47
Phlebovirus (Rift Valley fever virus)

• Incubation period is 2 to 6 days and it occurs
  often asymptomatic and with Influenza-like
  illness (Fever, headache, myalgia, vomiting). The
  patients recover between 2 to 7 days.
• A small percentage (1) of patients has
• Encephalitis,
• Retinal vasculitis,
• Hemorrhagic fever with melena, hematemesis,
  petechia, jaundice, shock, coma and
• case-fatality is about 50

48
Diagnosis

• Diagnosis is based on
• virus isolation
• antigen detection
• RT-PCR
• serology
• Treatment includes
• Symptomatic and supportive therapy
• Replacement of coagulation factors
• Ribavirin may also be helpful

49
Prevention and control for RVFV

• There are attenuated and inactivated vaccine for
  animal
• But there is a limited use for humans
• Vector control
• Animal housing control
• Barrier precautions

50
Conclusion

• Different viruses in VHF group can be the cause
  of ilnesses such as encephalitis, mengitidis and
  other neuroinvassive diseaases in contaminated
  parts of the world and in travellers
• Our aim is mainly to diagnosis such illnesses
  ,and to make appropriate treatment in due time
  and to prevent
• For this purpose severel research works have to
  be carried out, in order to develope new
  treatment methods and medicine