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Journal of Experimental Biology and Agricultural Sciences, April - 2014; Volume – 2(2)

Journal of Experimental Biology and Agricultural Sciences

http://www.jebas.org

ISSN No. 2320 – 8694

RABIES – ITS PREVIOUS AND CURRENT TREND AS AN ENDEMIC DISEASE OF HUMANS AND IN NIGERIA

Ajoke Modupeoluwa Ehimiyein1,* and Ikhide Oluwatoni Ehimiyein2

1Department of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria. 2Gimaf Veterinary Consult, Kaduna, Nigeria

Received – March 18, 2014; Revision – April 05, 2014, Accepted – April 18, 2014 Available Online - April 30, 2014

KEYWORDS ABSTRACT

Rabies The review examines rabies as an acute progressive and fatal disease of the in Transmission , , humans and . Emphasis is laid on the current findings in the genotypes of the rabies and its molecular composition. in different parts of the world with emphasis on Pathogenesis Nigeria is highlighted. The transmission, pathogenesis, clinical signs and neurological phases of rabies are reported. Special attention is paid to recovery from rabies and unvaccinated survivor of Humans rabies. It is concluded that prompt and state of the art diagnostic tests that are field-based and introduction of efficient national programmes are crucial for the successful control and eradication of Dogs rabies. Adequate and appropriate strategies which are based on „‟ approach are necessary in order to implement efficient control and eradication measures against rabies-endemic, especially in developing countries. A better understanding of the relationship between humans and dogs is a prerequisite for the implementation of more effective strategies for rabies control programmes in Nigeria.

* Corresponding author E-mail: [email protected] (Ajoke Modupeoluwa Ehimiyein)

Peer review under responsibility of Journal of Experimental Biology and Agricultural Sciences.

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138 Ehimiyein and Ehimiyein

1 Introduction assumed that the virus is viable in the medium over six months (Elsa & Ogunkoya, 1996). Rabies comes from the word rabere, which means to rage or rave. Rabid dogs sometimes appear to be angry or in a 2 The rage. About 3000 BC, this Latin word rabere may have roots in a Sanskrit word rabhas meaning “violence” (where the Rabies virus belongs to the Family (Mallewa et victim becomes violent (Nottidge, 2005)). The Greeks called al., 2007), of the (Madhusudana et al., rabies lyssa or lytta, which means frenzy or madness. It has 2010), Order (Nel, 2005). It has seven many synonyms worldwide. Democritus in the 15th BC used genotypes (Genotypes 1 to 7) mammals are the reservoir host, the term “nerve fire” for this disease and Hippocrates later mainly carnivores especially dogs and bats (Rupprecht et al., described it as hydrophobia (Wilkinson, 1988; Nottidge, 2005). 2002). Genotypes 1 comprise the classical RABV isolates in The Egyptian god, sirus was depicted as a furious because dogs and are reported from almost every countries of the dog rabies was very common at that time (Nottidge, 2005). In world (Wu et al., 2009). It is endemic in all continents, but few (30th BC), the god of death had a dog as his companion European countries, some islands of peninsulas and Antarctica and messenger. Rabies was also mentioned with respect and are free of the disease. Genotypes 2 to 7 include the rabies- concern in the legal documents of Mesopotamia in the 23rd BC, related (RRV), more specifically, the Lagos virus and ancient Chinese writings indicate that it was recognized in (LBV; Genotype 2) (Picard-Meyer et al., 2007), the Mokola dog‟s centuries before the birth of Christ (Wilkinson, 1988). (MOK) virus (MOK; Genotype 3), the Duvenhage (Gt 4) The disease is found in almost all parts of the world and the (Markotter et al., 2006; Adedeji et al., 2010), the European bat first documented fatality in man bitten by a dog was in the 23rd 1 and 2 (EBLV-1 and 2) (Genotypes 5 and 6), and BC (Nottidge, 2005). In , the first major outbreak of the Australian bat lyssavirus (ABLV; Genotype 7), (Fauquet et rabies in dogs was in Ethiopia in 1884 and in South Africa in al., 2004; Markotter et al., 2006; Paweska et al., 2006). Rabies 1893. In Nigeria, the first documented case in humans was in is the first of seven genotypes (Hambolu et al., 2013) which 1912 and in dogs was in 1925 (Boulger & Hardy, 1960). represents the classical rabies viruses; whereas the remaining groups (Genotypes 2 through 7) correspond to rabies–related Rabies is a viral that causes encephalomyelitis viruses (Badrane et al., 2001), five of which have caused fatal (Dacheux et al., 2012). It affects all warm-blooded animals infection (Warrell & Warrell, 1988). The LBV is classified as (Warrell & Warrell, 2004; Adedeji et al., 2010), and having Genotype 2. Two genotypes 3 and 4: Mokola virus, were about 100% case-fatality rate (WHO, 2000). Human mortality originally isolated from shrews found in Ibadan, Nigeria due to rabies is estimated to be 50,000 deaths per year (Adedeji et al., 2010), and Duvenhage virus in bats was first worldwide, mostly reported from and Africa (Dacheux et found in South Africa, and occasionally found only in Africa al., 2012; Yousaf et al., 2012) but it has worldwide public (Paweska et al., 2006). Genotypes 5 and 6, EBLV1 and health importance (Streicker et al., 2012). Still the disease is EBLV2 are found in insectivorous bats across Europe. In endemic in Nigeria (Ogunkoya, 2007; Ehimiyein et al., 2010; addition, a lyssavirus recently isolated from a fruit bat known Okpe et al., 2011). In Nigeria, first human rabies case was as flying ( alecto) in 1996 was found to be diagnosed in 1912 (Boulger & Hardy, 1960), while canine responsible for one human death in Australia (Hopper et al., rabies was first diagnosed in 1925 at Yaba Rabies Laboratory, 1998). Lagos, Nigeria and officially reported in 1927 (Boulger & Hardy, 1960). Other rabies-related viruses include Obodhiang isolated from mosquito in Sudan (Kuzmin et al., 2006), Kotonkan from Dogs were confirmed as the reservoirs and vectors of human midges in Nigeria (Smith, 1996) and Oulo-fato from dogs and rabies, accounting for 94% of the cases (Nel & Rupprecht, ground in West Africa (Bouffard, 1912; McMillian & 2007). At least, 10,000 persons have been estimated to be Boulger 1960). The lyssavirus group consists of viruses that exposed to rabies annually in Nigeria, apparently are morphologically, morphogenetically and pathogenetically underestimated (Ehizibolo et al., 2011) because there is no similar, sharing cross-reacting antigens (Shope et al., 1970). efficient monitoring and reporting system of the disease. In The genus was divided into two phylogroups as a result of Nigeria and many other developing countries in the tropics, at serological and genetic analyses (Badrane et al., 2001). least 10% of samples received at laboratories for rabies Phylogroup I comprises all the viruses; except MOK virus, diagnosis are decomposed because of inadequacy of which belongs to phylogroup II with LBV (Vazquez-Moron et transportation and storage facilities (Barrat, 1996; Elsa & al., 2006). Based on this division, all the viruses of Ogunkoya, 1996; Durr et al., 2008), leading to the phylogroup I genotypes have caused fatal rabies such as misdiagnosis of most of the cases. For efficient transportation, in man, whereas MOK virus has probably only various methods of preservation and transportation have been caused three known human , one of which was fatal experimented (Elsa & Ogunkoya, 1996; Durr et al., 2008). encephalitis (Mallewa et al., 2007). Experimentally, The use of 50% glycerol/phosphate-buffered sulphate for phylogroup II viruses are less pathogenic, and there is little, if preservation is commonly practiced in Nigeria, and it is any, cross-neutralisation with the phylogroup I lyssaviruses (Markotter et al., 2006). Intramuscular and intracerebral

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Rabies – Its Previous and Current Trend as an endemic disease of Humans and Mammals in Nigeria 139 inoculation of mice with phylogroup I is highly pathogenic, 2.1 Characteristics of the Rabies Virus whereas intracerebral inoculation of phylogroup II is pathogenic in mice (Adedeji et al., 2010). Additional four new Rabies virus is very sensitive to environmental factors. It is rabies-related lyssaviruses, have been isolated from bats in highly sensitive to sunlight, ultraviolet irradiation and heat at Eurasia: Irkut, Aravan, Khujand and West Caucasian Bat 60oC (for five minutes), lipid solvents (70% alcohol and ether), Viruses (Botvinkin et al., 2003; Kuzmin et al., 2003; Liu et al., sodium deoxycholate, trypsin, and common detergents. 2013). However, it is preserved at sub-zero temperature and in glycerin (Awoyomi et al., 2007; Adedeji et al., 2010). Lyssaviruses are a group of negative single-stranded non- segmented RNA viruses (Drew, 2004; Yousaf et al., 2012). 3 World Prevalence of Rabies The viral particle is bullet-shaped and measures about 180 µm in length and 75 µm in width. The viruses are made up of a Rabies still remains a fatal infection in man and animals. It is helical ribonucleoprotein core (RNA) surrounded by an found all over the world, except in some countries where there envelope of a helical structure which is extremely labile is strict system, rigorous eradication programme or (Lingappa et al., 2013). Rabies virus also possesses a negative- natural barriers like mountains and rivers. Recently, the United stranded RNA genome of about 12 Kb, and encodes five major States of America has been declared free of canine rabies proteins (Dacheux et al., 2008). The five major polypeptide (Rupprecht & Tumphey, 2007). By 1995, the world estimate components are of different molecular sizes, forming the deaths were about 70,000 humans per year, which are about protein moiety of the virus. These are the (N- 200 humans each day worldwide. However, there are only protein), phosphoprotein (P-protein), matrix protein (M- about 35,000 notifications per year (CDC, 2004). Animal protein), glycoprotein (G-protein), and polymerase (L) rabies ranked 12th in the WHO list of infectious and parasitic (Nottidge, 2005; Yousaf et al., 2012; Xinjun et al., 2012). The diseases that constitute the major causes of death (WHO, surface shows a honey-comb arrangement with surface 1994). It was also rated the 11th cause of human death due to projections, having a knob-like structure at the distal end. Each infectious diseases in 2000 (Finnegan et al., 2002). It has been projection is made up of a bi-layer membranous lipoprotein reported that 98% of human rabies cases occurred in the envelope, penetrated by a single G-protein (Dietzcshold et al., developing countries of Asia, Africa and Latin America 1987). (Dacheux et al., 2012). Many developed countries of the world have accurate reports on the outbreaks of rabies. In Nigeria, the The N-protein and L-proteins together with the genomic RNA status of rabies is unknown as reported by WHO (2006), form a nucleocapsid which is enveloped by a membrane therefore and humans are grossly under- containing the transmembrane. The G-protein, which consist of reported (Fagbami et al., 1981). spikes are mainly responsible for the antigenicity of the virus. The M-protein forms the inner core of the membrane, 3.1 Rabies in Asia providing a connection between the nucleocapsid and the cytoplasmic domain of the glycoprotein (Grahams et al., 2008). Most of the Asian countries like Pakistan, Sri Lanka, Many variants of the rabies virus have been identified Afganistan, India, Nepal, Bangladesh, Myanmar, Thailand, (Nottidge, 2005; Smith, 1989). Previous antigenic studies Laos, Cambodia, , parts of Indonesia, Philippines and performed on both the N and G has demonstrated the antigenic most former Soviet Republics are still canine rabies endemic diversity of Lyssaviruses (Smith, 1989; Rupprecht et al., 1991; (Wilde et al., 2005; Meng et al., 2011; Hossain et al., 2012). Kissi et al., 1995; Xinjun et al., 2012), in an attempt to Rabies endemicity in China and India has been well compare the intrinsic and extrinsic genetic diversities of the documented, but its mode of transmission from country to Lyssavirus genotypes, partially sequenced 69 rabies virus country in Asia is largely unclear (Meng et al., 2011). isolates from various parts of the world and compared them to Currently, India and China have highest human rabies cases in 13 representative isolates of the Lyssavirus genotype. the world (WHO, 2005).

The N gene consists of 1353 nucleotides and encodes 450 Rabies in Asia has never been controlled except for a few amino acids which is well conserved among lyssaviruses island countries or regions. Domestic dogs play a major role in (Conzelmann, 1998) and are synthesized in large amounts (Meng et al., 2011), and are responsible for during cell infection. During morphogenesis, N-protein binds more than 95% of human rabies cases in China and India tightly to genomic RNA, protecting it from the ribonuclease (Meng et al., 2011; Nadin-Davis et al., 2012). There are certain action (Poisson et al., 2001). In the mature virion, the N- factors that limit the control of rabies in Asia some of them are protein constitutes the major component of the internal helical lack of motivation by the government, funding and social- nucleocapsid. In rhabdoviruses, it is involved in the regulation cultural differences (Wilde et al., 2005). A major problem in of transcription and replication (Ivanov et al., 2010). It also most of the developing countries is how to control domestic plays an important role in the T-helper response, when dogs (Meng et al., 2011). In recent decades, emphasis has been challenged with Lyssaviruses are antigenically different from on post-exposure treatment. Rabies is still endemic in Asia, the vaccinal strains (Dietzcshold et al., 1987; Ertl et al., 1991). despite of all the measures that are in place (Meng et al., 2011).

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140 Ehimiyein and Ehimiyein

3.2 Rabies in Europe and America Direct immunofluorescence staining was performed on brain Most of the European countries have already eliminated canine samples of suspected animals in Kaduna State, northern rabies, but are still struggling with rabies in wildlife like Nigeria, (Ezeokoli & Umoh, 1989). It was discovered that , foxes and bats. In Chile, canine rabies has been there were more dogs and, consequently, more rabies controlled but insectivorus bats have been identified as the outbreaks in the southern than northern part of the State. main rabies vector (Yung et al., 2012). Rabies in Seventy percent of the dogs were older than one year and 75% of America is still a threat to people and animals. Post- were not vaccinated against rabies. It was also observed that exposure prophylaxis is given to approximately 40,000 persons most of the dogs involved in bites had identifiable owners each year for rabies prevention (CDC, 2012). Wildlife rabies (Okpe et al., 2011). The seasonal and age-specific rates of constitutes about 90% of the rabid animals reported to Centers infection of rabies follow classical trends. Cases seemed to for Disease Control and Prevention (CDC, 2012). Enforcement cluster around April and September primarily, corresponding of policy might have in the control of rabies in to the breeding seasons for dogs in Zaria, Nigeria (Ezeokoli & these regions (Yousaf et al., 2012). Umoh, 1989), and associated with intense communal activities (including dog fights), conducive to the spread of infectious 3.3 Rabies in Africa diseases, particularly bite-transmitted rabies.

Dogs have been the major reservoir of rabies to humans in In Nigeria, dogs are kept for various reasons including hunting Africa (Fitzpatrick et al., 2012). Approximately 24,000 deaths in the hinterland, where men still take up hunting as a occur per year in Africa, although most of the incidents are profession; dogs are less commonly used as partners; and the under-reported. The sites of exposures are usually in the rural middle-class families in the cities keep dogs as or for areas where prompt diagnosis and post exposure prophylaxis security reasons (Eze & Eze, 2002). Dogs are commonly used are not readily available thereby leading to increase in human for sacrifice to Ogun, the god of iron, and also presented to in- deaths (Yousaf et al., 2012). Some factors militate against the laws during traditional weddings. is considered a control and elimination of rabies in Africa; socio-cultural delicacy in various parts of Nigeria; Cross-River, Akwa-Ibom, beliefs, lack of prompt field-based diagnostic tests, funding, Ondo, Plateau, Taraba, Kaduna, Gombe, and in some parts of illiteracy etc. Imo, Enugu, Abia, Ebonyi and Anambra States. Dog meat sellers consider the business very lucrative because there is a 3.4 Prevalence of Rabies in Nigeria continuous rise in the demand for dog meat in Nigeria. The meat is popularly known as „404‟which was named after the Rabies is a major disease of public health importance and is French-built Peugeot pick-up van, very commonly used for widespread in Nigeria (Ehimiyein et al., 2010; Abubakar & transportation in Nigeria, a tribute to dog‟s ability to run fast. Bakari, 2012). In Nigeria, rabies was recognized by local Majority of the dogs killed are either stolen or sold by their people prior to 1912 in various dialectic names such as owners to meet financial needs (Sudarshan et al., 2007). On digbolugi (Yoruba), ciwon haukan kare (Hausa), ginnaji arrival, the dogs are kept without food and water in a confined (Fulani), ebua idat (Efik/Ibibio) and ara nkita (Igbo) and dirty environment for an average of 4-7 days before being (Nottidge, 2005). Official disease reporting system in Nigeria displayed in the market for sale; this further explains why a is rudimentary, hence information is lacking on the precise disease like rabies can easily be spread among the dogs and to prevalence and distribution of rabies. No wildlife host has humans (Elsa and Ogunkoya, 1996). been clearly identified, although sporadic cases in wildlife reservoir have been reported (Adedeji et al., 2010). The 4 Transmission of Rabies domestic dog seems to be the major source of human exposure to rabies and perhaps also the reservoir host in Nigeria Rabies is transmitted through the bite of a rabid animal (Ezeokoli & Umoh, 1989). (Yousaf et al., 2012). Transmission is usually from saliva of an infected animal which comes in the contact by the bite from Ehizibolo et al. (2011) reported that records from the National animal to animal or animal to man. Dogs are the primary Veterinary Research Institute, Vom, Nigeria also show that, source of infection to humans and other domestic animals over a 10-year period of 1990-2000, 95% of suspected rabies (Sudarshan et al., 2007). Though the dog is moderately cases submitted for diagnosis were dogs and only one was a susceptible, it acts as a reservoir for urban rabies virus in bat. The relative roles of stray and owned dogs in the developing countries (Qasim et al., 2013). Transmission epidemiology of rabies in Nigeria follow the classical pattern through aerosol has been done experimentally in animals, but in which the stray dog seems to be the disseminator among none has been documented occurring naturally in humans dogs (bringing the virus from one community to the other, (Davis et al., 2007), contamination of mucous membrane of the while the owned dog is the more important source of human mouth or corneal transplant (Takayama, 2008) and bruised exposure (Awoyomi et al., 2007; Okpe et al., 2011). Most skin, or by aerosolized particles or a fresh wound, licked by a owned dogs in Nigeria are free-roaming, providing ample rabid animal (CDC, 2011). Other possible routes of infection opportunity for contact with rabid strays (Awoyomi et al., are through ingestion, transplacental and transmammary 2007). (Okonko et al., 2010).

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Rabies – Its Previous and Current Trend as an endemic disease of Humans and Mammals in Nigeria 141

Figure 1 A view of the processing of a slaughtered dog. Note the head which is also being prepared with bare hands for consumption

Dog markets may play an important role in the spread of rabies probably associated with brain stem infection (Venugopal et and other zoonotic diseases in Nigeria and other developing al., 2013). Retrograde from the brain, via nations, where slaughtering and processing of dog meat are somatic and autonomic efferent nerves, deposit virus in many done without the right equipment and protective gears. Thus, tissues (Jackson et al., 2003); including skeletal and cardiac butchers work with bare hands and are usually at risk during muscles, adrenal medulla (where infection may be clinically the processing and the sale of the dog meat. Both healthy and, significant), kidneys, taste buds, respiratory tract, cornea, and apparently, sick dogs are brought to the dog market for sale; a nerve twiglets in the hair follicles. At this stage, productive situation which makes more contact between dog to dog and occurs, with budding from outer cell dog to humans likely (Ehimiyein et al., 2010; Mshelbwala et membranes in the salivary, lacrimal and other glands, which al., 2013). permits the further transmission of rabies by bites to other mammals. Uncontrolled replication leads to disease and 5 Pathogenesis of Rabies ultimately death (Jackson et al., 2003. There is no evidence of viraemia, but rabies virus is shed in saliva, lacrimal and Rabies virus is highly neurotropic (Madhusudana et al., 2010) respiratory tract secretions, but rarely in urine and in milk and causes fatal encephalitis (Dimaano et al., 2011), when the (Anderson et al., 1984). virus gains access to the CNS. Transmission of Lyssavirus infections is mostly through the contamination of bite wounds 6 Clinical Signs of Rabies with the saliva of an infected animal (Frymus et al., 2009). Subsequently, the virus infects local sensory and motor Warm-blooded animals are susceptible to rabies virus infection neurons (Warrell & Warrell, 2004) and replicate locally in (Yousaf et al., 2012), and although clinical rabies usually ends skeletal muscle cells or attach directly to nerve endings, in in death, many infections are aborted and the hosts are particular to nicotinic receptors at motor-end asymptomatic (Fekadu et al., 1983). The differences in rabies plates. Attachment also occurs to several other neuronal infection in reservoir host species, which include foxes, receptors (Lafon, 2005). It rapidly ascends the nervous system , dogs, cats and „dead end‟ host species (, horse, to the brain by entering the presynaptic nerve ending through man) have more to do with behavioural patterns of each endocytosis, and may be associated with synaptic vesicles. species, when rabid than with the nature of the infection Inside peripheral nerves, the virus is carried in a retrograde (Ogunkoya, 2007). Precise and consistent topographic direction by fast axonal transport, centripetally to the CNS. locations of rabies virus in the brain have been identified for The virus remains intra-neural throughout its passage and is the specific at various stages of clinical inaccessible to extra-neural . On reaching the CNS, illness in affected humans and animals (Healy et al., 2013). there is massive viral replication on membranes within neurons Dogs and cats are major hosts of rabies worldwide, and are of and trans-synaptic transmission of virus occurs from cell to epidemiological zoonotic importance while humans represent cell. Involvement of the limbic system and amygdaloid nuclei „dead end‟ hosts (Nadin-Davis et al., 2012). Dogs have causes aggressive behaviour in animals. Hydrophobia in man is remained the major hosts and are intermediate in susceptibility

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142 Ehimiyein and Ehimiyein to the infection in developing countries (Dacheux et al., 2012). signs, evident of the disease. In dog rabies, there are classically This means that dogs in comparison with many other animals distinct or overlapping stages of the disease, which include: are moderately susceptible to the disease. Johnson (1971), (a) Prodromal (change in mental attitude), observed that no other virus is so adapted to selective neuronal (b) Furious, populations that can drive the host in fury to transmit the virus (c) Dumb, and to another host animal or human than the rabies virus. In other (d) Atypical forms. words, biting desire reaches its peak at a time the titre of the virus becomes high in the saliva. Virus may appear in the 6.2 The Prodromal Stage saliva up to 7 days before symptoms appear. The prodromal or melancholy stage may or may not develop or Cats, skunks, bats, raccoons and cattle are highly susceptible to it passes quickly enough that it may not even be noticed by the rabies (White et al., 2007) and about 75% of rabid cats show a owners of the dogs and inexperienced . Signs pronounced furious phase before progressive sets in peculiar to this stage include change in affection; normally (Fekadu et al., 1983). Most cats in developing countries are not friendly dogs may become withdrawn, seeking one place of kept under confinement, so the status of rabies might be seclusion after another (usually dark places) and normally difficult to be established within the species. The average independent dogs may become highly affectionate and lick incubation of rabies in cats varies between two weeks to their owners‟ hands or faces. Dogs which are not confined may several months and years and the disease manifests in two wonder long distances from their home premises. Other signs forms; dumb and the furious forms. Deaths occur 1-10 days characteristic of this stage of the disease include: after the onset of clinical signs (Frymus et al., 2009). In (a) Disappearance from home longer than usual, endemic areas where dogs are the maintaining reservoirs, the (b) (fly-biting), virus tends to spill over to cats. However, when the (c) Changes in voice, transmission cycle is broken in dogs by means of mass (d) Springing at moving objects (broom-attacking), vaccination, the disease disappears in cats as well (Nadin- (e) Claustrophobia, Davis et al., 2012). On the other hand, where both dog and (f) Chewing at the site of infection (hyperesthesia of wildlife transmissions are occurring, control of the the bite site), transmission cycle in dogs may expose a previously (g) which at this time may be moderate and unrecognized host. For example, wildlife- transmission usually disappears as symptoms progress. This stage cycle was observed in the USA and Europe (Nadin-Davis et lasts a few hours to 36 hours. The animals then go al., 2012). Cats, especially young males because of their into either dumb or furious rabies stages or may just nocturnal outdoor habit, are frequently exposed to rabid drop dead (Ogunkoya, 2007). animals. A change in the normal behaviour of a cat should be suspected. Two forms of rabies can be identified in cats: the 6.3 Furious Rabies furious and the paralytic. There is no distinction among the three clinical stages of the furious form of rabies in cats. This is the stage of rabies described as aggressively mad dog, Common clinical signs of rabies in cats are fever, anorexia, in which the affected animal constitutes a serious community diarrhea and vomiting ( Tierkel, 1959; Shimshony, 2009). hazard. The clinical period may vary from so short, therefore likely to be unnoticed, to a period of extreme excitation, 6.1 exaggerated responses to stimulation and aggressive behaviours, lasting from 1 to 7 days (Rosatte, 1988). A dog According to (Tierkel, 1959), the incubation period is usually affected with this stage of the disease become violent, irritable between 3 to 8 weeks, rarely exceeding 4 months, but within a and may attack anything that it comes across. If let loose, such range of 10 days to 6 months. This was confirmed among 26 a dog may wander, often going in a straight line as if being dogs that died of laboratory-confirmed rabies in England chased by something. It may stop only to attack a moving or during or after a 6-month quarantine period. The incubation non-moving inanimate object that gets within range of sight, period has been said to depend on the size of the viral sound or smell and then move on. During attacks, the dog inoculums, the proximity of the wound to large nerves, and the apparently, feels no pain, may lacerate the mouth or knocks out length of the neural path from the wound to the brain (Yang et the teeth in such frenzy (Fekadu et al., 1983). A frenzied dog al., 2013). Thus, it may be shorter following bites on the face can inflict bites on many animals and humans before death. For and head and longer when the bites occur in the legs or the example, a furious dog in frenzy left 41 people and 9 other extremities. It may also be shorter in small breeds of dogs as dogs bitten during a 4-hour period before it was killed compared with large breeds (Beran, 1979). Studies on the (Bernard, 1984). The usual characteristic snarls and barks are pathogenesis of rabies in the CNS have shown that clinical absent during these attacks. A rabid dog is usually silent when signs were not observed until after several growth cycles of the attacking. During this furious period, the dog may show virus had occurred, and the virus had spread through the entire increased thirst and may drink, or try to drink before the CNS with the involvement of numerous neurons. The clinical muscles of deglutition are paralyzed. There is usually no sign signs may be variable in dogs at the onset but by the time the of hydrophobia. Some dogs, both male and female, show animal dies, there usually have been enough characteristic sexual arousal. In spite of these behavioural aberrations, most

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Rabies – Its Previous and Current Trend as an endemic disease of Humans and Mammals in Nigeria 143 dogs continue to recognize their owners depending on the stage than in the furious form. The animal lasts a little longer from and respond in a quiet way to their master‟s voices and onset to death than in furious rabies. This is the stage that command (Fekadu et al., 1983). This may be the reason why most affected dogs are presented with to the Small Animal some owners unknowingly could handle their mad dogs and Clinic of the Ahmadu Bello University Veterinary Teaching bring them to clinics without receiving bites. Although affected Hospital (ABUVTH) (Ogunkoya, 2007). In cats, the prodromal dogs may snap at those whom they know if threatened, they do phase usually lasts less than 1 day and is characterized by low- not commonly attack their masters. Rabid dogs generally grade fever and pronounced change in behaviour. Affectionate recognize their homes and know the way back home. cats may suddenly become apprehensive, withdrawn or Hallucinations may continue and depraved appetite such as temperamental. Independent active cats may become unusually pica and self-mutilation from chewing inanimate objects may solicitous. The furious or excitatory phase lasts between 1 and become evident. Extreme claustrophobia may be exhibited. 4 days, but may persist up to 7 days. Rabid cats may retreat The eyes of affected dogs, when examined, may show into hiding places from which they spring out and attack, when development of strabismus “-like squint” which may be approached or when sought out by their owners. The attacks by unilateral or bilateral; convergent or divergent. Profuse rabid cats are particularly vicious because feline species seek salivation also occurs, with the head characteristically held at a out the victim‟s jugular vein when attacking, and they are downward angle, causing or frothing of tenacious particularly dangerous. When not attacking, affected cats show saliva. Drooling in the mouth and the holding of the tail tightly muscular twitching or tremor, papillary dilatation and flashing between the rear limbs have been described as characteristics eyes, the mouth may be foaming with saliva, their backs of canine rabies through the ages. As the clinical signs arched and the claws protruded out making a frightening sight. progress, the change in voice also progresses due to paralysis Unlike dogs, rabid cats appear not to recognize or respond to of laryngeal muscles, causing a “deep bay voice”. Towards familiar persons (Tierkel, 1959). The paralytic phase of the death, the rabies howls disappear. There is progressive disease lasts about 1-4 days and the affected cat shows in- paralysis of muscles of coordination (Ogunkoya et al., 2007). coordination, most marked in the rear legs, and subsequently developing into ascending paralysis. Paralysis of the muscles 6.4 Dumb or Paralytic Rabies of the head and neck leads to hoarseness of the voice and drooling or foaming of saliva. The paralytic or dumb form Some authors have described the and the lowest predominates in few cases and the affected cats may , part of the brain stem (medulla oblongata) as the areas mainly show unusual affection, or may hide until death ensues. Death affected in dumb rabies. Some other parts that are also affected usually occurs in a few hours, but may also come in 1-3 days include the spinal cord areas, transmitting motor impulses to after clinical onset. the muscles, and parts controlling sensory impulses of touch and temperature from the skin. Other authors have described Nearly all human rabies cases are known to occur following dumb rabies as the last stage of the furious form. Transmission exposure to the virus through the saliva of rabid animals. The of the disease can result in paralytic or violent form (Ghosh et victims get exposed either through direct bites or contact with al., 2009). Murphy (1985) associated the depression and freshly abraded skin or mucous membranes (Yousaf et al., with the infection and subsequent dysfunction of neurons of 2012). Five reported cases of human rabies have been the higher centers of the brain. In affected dogs, the affected considered to have resulted from aerosol exposure (Davis et animals appear as if poisoned, an observation that can be made al., 2007), three in bat caves and two through accidental following melancholy or furious stage signs. Rabid dogs may exposure from infected laboratory animals (Winkler et al., develop in-coordination, of the muscle resulting from 1973). In addition, rabies has occurred in four people who ascending paralysis due to the paralysis of the jaw, leading to received corneal transplants from persons who died from the jaw being hung open as a result of the paralysis of undiagnosed rabies encephalitis (Takayama, 2008). Clinical deglutition muscles. The paralysis progresses to the head and rabies in humans can be divided into five stages: incubation neck, and then involves one or both hind legs causing the period, prodromal stage, acute neurological phase, coma and animal to sway or fall. A thick mucus and stringy saliva may death. However, few cases of spontaneous recovery have been be drooping from the mouth of the affected dog as a result of reported (Bernard, 1984). the body‟s inability of the animal to swallow. The pupillary changes seen in furious rabies may also be observed. The body 6.6 Incubation Period in Humans temperature may be normal or sub-normal. There is coma and death ensues from paralysis of the respiratory muscles The average incubation period of between 31 and 90 days has resulting in respiratory failure. The clinical course in this form been reported, but it can be as short as 7 days, although it could of rabies in dogs lasts 1 to 3 days (Ogunkoya, 2007). be as long as 25 years (Shanker et al., 2012). Less than 1% of well documented cases had incubation periods of between 1 6.5 Atypical or Rabies and 5 years following exposure (Takayama, 2008). The incubation period is usually between 20 and 90 days and it is This is a mixture of furious and dumb rabies. The animal shorter if the site of bites is on the head (25-40 days), shows intermittent aggression, which is usually followed by a compared to when it is on an extremity (46-78 days) (Held et temporary calmness. The degree of aggressiveness is lower al., 1967). The incubation periods are usually shorter in

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144 Ehimiyein and Ehimiyein affected children than in adults. Exposures through bites on The outstanding symptoms occur dramatically or are of richly innervated areas of the body like the face, neck, hand gradual onset involving painful and spasmodic contractions of and, especially, finger-tips lead more frequently to clinical the muscles of deglutition, characteristically precipitated by infection and a shorter incubation period. Bites that occur on contact with fluid by the patient‟s face in an attempt to drink. the trunk or proximal portions of the limbs may take longer This observation was reported to occur in 30-50% of rabies time, unless such exposures are in direct proximity to major cases (Bernard, 1984). Ejection of fluid may be explosive with nerve trunks (Yousaf et al., 2012). During the incubation spluttering, coughing and entrance of fluid into the nasal period, the patients appear clinically well, except for clinical passages or trachea. Such episodes are terrifying and building signs and symptoms limited to bite trauma. Apart from this, up a state of hydrophobia, which could be stimulated by the many patients experience varying degrees of , taste, smell, sound, or sight of liquids, and in many situations associated with the prospect of impending fatal clinical including the patient‟s own saliva (Fekadu et al., 1983). The disease. However, during the few days of the incubation contractions may progress to involve jerky spasms of the period, affected victims may experience some pain, tingling diaphragm and chest muscles. The arms may be thrown sensation, and mild pruritis or paraesthesia which usually upward, the head jerked backward, and the whole body arched begins at the site of bite. The sensations may involve the bite in episthotonus. Choking, resulting from the respiratory site or progressively ascend towards the CNS. Invariably, muscular spasms may become so severe that prolonged apnoea trembling or weakness may appear in such affected limbs with cyanosis and gasping may ensue. Some patients feel so (Dimaano et al., 2011). much pain and constriction of the throat that they clutch at their necks (Fekadu et al., 1983). Stimuli, in addition to 6.6.1 Prodromal Period liquids, which may triggers the spasms include foods of any type, drafts of air especially across the face (aerophobia), or In humans, the prodromal period usually lasts for 24 to 48 touching of the inside of mouth or throat, sudden noise, and hours, but rarely this may extend to one week or longer. exposure to light. Even though the patients may be able to During this time, patients present vague symptoms of a state of continue to swallow solid boluses of food, liquid would induce being unwell, often with considerable apprehension. Malaise, painful contractions in the throat. As times passes, the spasms anorexia, low-grade fever, fatigue, headache, restlessness and of the throat increase in intensity and frequency to a point tension are all possible symptoms (Dimaano et al., 2011). In where they may occur spontaneously or nearly continuously. approximately 50% of patients, pain and paraesthsia occur at At this time, patients may reach extremes of agitation and the site of exposure and, if present, are usually the first rabies- terror. They may struggle frantically and attack nearby specific symptoms. persons, although they do not bite, and generally convulsion may ensue. At more severe stage, some non-specific and common symptoms, occurring during the prodromal period include In a study of 1839 patients at San Lazaro Hospital, Manila, -like conditions such as sore throat, which occurs in Philippines, all the cases had hydrophobia, 95.5% had association with cough, gastritis, , vomiting or enteritis aerophobia; only 9.4% had fever, 9.2% were restless, 6.7% (Dupont and Tarle, 1965). None of these manifestations is showed . Neurologic signs like pain (4.1%), of rabies in children or adults, and in the numbness (2.6%) and itching (2.3%). There was no post- absence of a history of exposure to the disease, they may not exposure prophylaxis given (Dimaano et al., 2011). In Nigeria, lead many attending physicians to suspect rabies. available records were not available to allow classification of the events given above. However, (Warrel, 1977) reported that 6.6.2 Acute Neurologic Phase of six clinical patients, all (100%) had hydrophobia. Generally, more than 90% of patients have some neurologic symptoms at The onset of clinical rabies in most patients is marked by the time of admission. Between episodes of excitation, patients excitatory manifestations, including increasing sensitivity to may become calm and lucid, and able to communicate and tactile, visual or auditory stimuli, and obvious decrease realize what is happening to them (Fekadu et al., 1983). The reaction to local pain. Victims develop hyperactivity, variable involvement of other nerves and portions of the brain disorientation, hallucinations, seizures, bizarre behaviour and lead to a wide variety of symptoms. Damage to the cranial nuchal rigidity. Other clinical signs are increased muscular nerves may cause facial paralysis, squinting or drooping of tone, accelerated pulse, pupillary dilatation, increased eyelids, paralysis or swelling of may lead to lacrimation, perspiration and salivation (Dimaano et al., 2011). hoarseness of the voice, and cries from pain or fear may In most cases, marked hyperactivity develops, which lasts from become more like barks. Salivation and lacrimation may be hours to days. Hyperactivity occurs typically intermittent with continuous and excessive, leading to a frothy flow from the 1-5 minutes of agitation, thrashing, running, biting, or other open mouth and a tear-stained face. Urinary flow may bizarre behaviour alternating with a period of calm (Dimaano fluctuate as posterior pituitary function becomes impaired et al., 2011). Hyperactivity episodes may occur spontaneously (Ogunkoya, 2007) Increased libido in male patient could occur. or be precipitated by a variety of tactile, auditory, visual or Temperature regulation may become erratic leading to brain- other stimuli (Fekadu et al., 1983). damaging above 42oC or the affected person may develop hypothermia. Both respiration and heartbeat may

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Rabies – Its Previous and Current Trend as an endemic disease of Humans and Mammals in Nigeria 145 become irregular with cluster breathing alternating with period (Jackson et al., 2003). No specific course of treatment for of apnoea while the blood pressure may fluctuate. Pneumonia, humans has been demonstrated to be effective, but a due either to the rabies virus or to infection secondary to combination of treatments, which might include rabies , inspired fluids or saliva, may ensue in patients who survive rabies immune globulin, monoclonal antibodies, and several days longer. interferon-alpa, has been proposed (Jackson et al., 2003).

Generally, unless the patient dies abruptly from respiratory or Conclusions cardiac arrest, paralysis develops and becomes the most prominent neurologic problem. In 15-20% of cases the period It is concluded that prompt and state of the art diagnostic tests of hyperactivity is either minimal or absent and paralysis that are field-based and introduction of efficient national dominates the entire clinical course (Chopra et al., 1980). The programmes are crucial for the successful control and paralysis may be diffused and symmetrical, maximal in the eradication of rabies. Adequate and appropriate strategies bitten extremity, or ascend as in Landry-Guillain Barre which are based on „One Health‟ approach are necessary in syndrome (Gardre et al., 2010). The acute neurologic phase order to implement efficient control and eradication measures lasts 2-7 days with longer duration in severe paralytic forms. It against rabies - endemic, especially in developing countries. ends either with sudden death or with the onset of coma. Throughout this period, the mental status of the patient References continues to fluctuate, with periods of severe obtundation alternating with those of relative normality. Depressive or Abubakar SA, Bakari AG (2012) Incidence of injuries paralytic symptoms may become predominant from onset or at and clinical rabies in a tertiary health care institution: A 10- a point in the course of the clinical disease, in about 20% or year retrospective study Annals of African Medicine. Annals less of patients (Knuti, 1929). In clinical rabies, characterized of African Medicine 11: 108 -111. from onset by paralytic manifestations, involvement of the spinal cord occurs principally rather than the brain (Fekadu et Adedeji AO, Okonko IO, Eyarefe DD, Adedeji OB, Babalola al., 1983). The onset of clinical disease is usually characterized ET, Ojezele MO, Nwanze JC, Amusan TA (2010) An by headache, high fever and sweating. Constipation, anuria, overview of rabies- History, epidemiology, control and drooling of saliva due to inability to swallow, and stiffness of possible elimination. African Journal of the neck suggestive of meningitis may be observed. Paralysis Research 4: 2327-2328. may develop progressively involving the legs, arms and trunks and may ascend as in Landry-Guillain Barre syndrome (Gardre Anderson LJ, Nicholson KG, Tanxe RV (1984) Human rabies et al., 2010). Finally, the muscles of swallowing and in the United States, 1960-1979, Epidemiology, treatment and respiration may become paralyzed. Patients usually remain diagnosis. Annals of Internal Medicine 100: 728-731. lucid during the progression of paralytic phase. Hydrophobia is only rarely observed during this phase, and it is probably Awoyomi O, Adeyemi IG, Awoyomi FS (2007) associated with terminal throat spasms. and coma Socioeconomic factors associated with Non-vaccination of precede death. Paralytic human rabies had been associated with dogs against rabies in Ibadan, Nigeria. Nigerian Veterinary bat-transmitted rabies (Pawan, 1939), and (Warrel, Journal 28: 59-63. 1977) reported that it may be common in Nigeria. Coma occurs 4-10 days after onset of symptoms and may last for hours or Badrane H, Bahloul C, Perrin P, Tordo N (2001) Evidence of months (Bernard, 1984). In untreated patients, respiratory two Lyssavirus phylogroups with distinct pathogenecity and arrest usually occurs shortly after onset of coma and the patient immunogenicity, Journal of 75: 3268-3276. dies. For those that received intensive support, the duration of illness average 25 days (Anderson et al., 1984). During the Barrat J (1996) Simple technique for the collection and coma phase a variety of fatal or potentially fatal complications shipment of brain specimens for rabies diagnosis. In: Meslin may occur (Houff et al., 1979). FX, Kaplan MM, Koprowski H (Eds.), Laboratory Techniques in Rabies, World Health Organisation, Geneva, Switzerland, 7 Recovery from Rabies Infection pp. 425-432.

Rabies is nearly always fatal without proper PEP (CDC, 1999). Beran GW (1979) Clinical Signs of rabies in dogs. Van So far, there are six known occurrence of human recovery after Houweling Laboratory, Dumaguete City, Philippines, rabies infection, five of which were either previously Unpublished data. vaccinated (CDC, 1977), or received some form of PEP before the onset of illness (Madhusudana et al., 2010). However, only Bernard KW (1984) Clinical rabies in humans. In: Winkler one of the five patients recovered without neurologic sequence GW (Ed.), Rabies Concept for Medical Professionals, Miami, (Hattwick et al., 1972). The sixth case was unique because the Merieux Institute 5: 45-50. patient received no rabies prophylaxis either before or after the onset of illness. Historically, the mortality rate among Botvinkin AD, Poleschuk EM, Kuzmin IV, Borisova TI, previously unvaccinated rabies patients has been 100% Gazaryan SV, Yager P, Rupprecht CE(2003) Novel

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