Scott B. Halstead Uniformed Services University of the Health Sciences, Bethesda, MD, United States
Chikungunya and Zika viruses belong to different viral families. Both viruses exact a heavy toll of human disability. Chikungunya produces a crippling postacute illness arthritis and may be the cause of deaths in the very young and in older individuals with predisposing conditions. Zika virus is the cause at high incidence of Guillain-Barre syndrome (GBS) that follows acute infection by a matter of weeks, but more critically by a severe Congenital Zika syndrome (CZS) that has followed Zika infection of pregnant women in many countries in the Americas. Zika virus, itself, in susceptible individuals produces a mild febrile exanthem, with modest acute illness disability. A notable feature of Zika virus, possibly linked to placenta and fetal infection, is the ability of the virus to replicate in mucosal and generative organs. The fact that Zika virus is present in saliva and reproductive tract secretions results in a significant risk of person-to-person transmission. Despite abundant in vitro and laboratory model evidence that dengue antibodies enhance ZIKV infections, recent studies find no evidence that dengue antibody enhancement contributes to GBS or CZS.
Flavivirus; Togavirus; Alphavirus; Arbovirus; Clinical features; Febrile exanthem; Viral arthritis; Guillain-Barre syndrome; Congenital Zika syndrome; Aedes aegypti; Mosquito; Vectors
Chikungunya virus (CHIKV) and Zika virus (ZIKV), members of the Flaviviridae and Togaviradae families, respectively, are transmitted in the Aedes aegypti urban cycle and cause diseases that vary from mild to life altering and potentially fatal.
Extensive descriptions of clinical illnesses are in the medical literature from the previrological era, many resulting from a major outbreak attributed to CHIKV that occurred in Caribbean, North and South American countries during 1827–28 (Carey, 1971). Access to this informative clinical literature is available from reviews by Carey (1971) and Halstead (2015). Another lightly referenced source of published descriptions of the clinical course of chikungunya comes from peninsular SE Asia where CHIKV was hyperendemic in the 1960s resulting in high disease attack rates in children (Halstead et al., 1969b,c). The clinical features of CHIKV infections were carefully studied in children admitted to Thai hospitals (Halstead et al., 1969a; Nimmannitya et al., 1969). More specific details of outbreaks in Asia are provided in Chapter 5. Of African origin, CHIKV transmitted by Aedes aegypti caused a major outbreak in India in 1963–64. Chikungunya disease was first recognized in Calcutta and then spread throughout India resulting in millions of cases in all age groups, many with severe clinical outcomes (Pavri et al., 1964; Ramakrishnan et al., 1964; Anderson et al., 1965; Ramachandra Rao, 1965; Sharma et al., 1965; Singh and Sarkar, 1965). While joint pains were a predominant complaint during and after the acute illness, there were also case reports in documented CHIKV illnesses with hemorrhagic and neurological manifestations, some fatal (Aikat et al., 1964; Sarkar et al., 1964; Chatterjee et al., 1965; Jadhav et al., 1965; Thiruvengadam et al., 1965; Carey et al., 1969; Shah and Gadkari, 1987). Finally, even more extensive clinical descriptions entered the literature during the globalization of CHIKV that followed its escape from East Africa in 2005 and from Asia to the American hemisphere in 2013 (Ritz et al., 2015).
In adolescents and adults, CHIK illness begins with the sudden onset of a high fever, often accompanied by severe pain in one or multiple joints and soon thereafter by a characteristic facial flush. Generally, joints are not swollen. Characteristically, due to pain, a recumbent patient lies sidewise with knees pulled up staying as motionless as possible (de Ranitz et al., 1965). The illness progresses with myalgia, headache, a macular rash, inappetance, nausea and vomiting, and growing prostration. The incubation period following infectious mosquito bite to onset of fever is short, 2–4 days. Fever usually ends abruptly on days 3 or 4, and in one-third of cases is accompanied by a whole body macular and in some instances a maculopapular dengue-like rash. Pain continues in the joints of the hands, ankles, shoulder, or knees.
The 2005–06 epidemic on Reunion may have resulted in clinical illnesses in ~ 40% of a total population of 800,000 (Renault et al., 2007). An asymptomatic infection rate of 8%–12% was estimated, the highest rate being in children under the age of 10 years. Commonly, arthralgia persists for weeks to months following acute illness, pain shifting from joint to joint, often worse on rising in the morning. Postillness fatigue, lassitude and depression, common after dengue infections, are rare after chikungunya disease (de Ranitz et al., 1965).
CHIKV may result in a severe systemic disease as documented on Reunion where of 33 adults admitted to the Medical Intensive Care Unit of the South Reunion Hospital during the 2005–06 outbreak, 16 died (Lemant et al., 2008). Three of these were under the age of 40 years, one a 26-year-old admitted with encephalopathy and the other, a 23-year-old with a prior splenectomy admitted in shock, both with fatal outcome. A majority of the older patients in this series had important preexisting conditions, the most common being diabetes mellitus. Fourteen had encephalopathy with focal neurological signs. A 63-year-old woman died suddenly with fulminant myopathy. Biopsy revealed CHIKV myocardial inclusions.
Postoutbreak surveillance was carried out for 3 years on an estimated 240,000 persons with a CHIKV illness that included symptomatic acute arthritis. Thirty-six percent reported the persistence of symptoms 15 months after disease onset, and 21% had at least one recurrence of arthritic event (Sissoko et al., 2009). Among those over 45 years of age with persistent joint pain, patients were likely to have had an acute illness arthritic pain intensity score during acute illness of at least 7 on a 0–10 scale and/or had pre-existing osteoarthritis conditions (Renault et al., 2007). Complications accompanying CHIKV illnesses included respiratory failure, cardiovascular decompensation, meningoencephalitis or other central nervous system signs, acute hepatitis, severe cutaneous lesions, or kidney failure. More than half of these cases were 65 years of age or older and more than one-third died (Renault et al., 2007). Three adult Venezuelans with virologically confirmed disease developed extensive acute nasal skin necrosis early in the course of a life-threatening illness characterized by shock and organ dysfunction (Torres et al., 2016). There is evidence of occasional direct person-to-person spread of CHIKV, presumably via infected mucosal secretions (Rolph et al., 2016).
Neurological sequelae were assessed 3 years after CHIKV illness. Between September 2005 and June 2006, of 57 patients with acute phase CHIKV-associated CNS disease, 24 continued to exhibit CHIKV-associated encephalitis, the latter corresponding to an attack rate of 8.6 per 100,000 persons. Encephalitis was observed at both extremes of age, attack rates per 100,000 persons were 187 and 37, below 1 year and over 65 years, respectively. The case fatality rate of CHIKV-associated encephalitis was 16.6% and the proportion of children discharged with persistent disabilities varied between 30% and 45%. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults (Gerardin et al., 2016).
In children, CHIKV infections are predominantly silent or mild (Halstead et al., 1969a; Balmaseda et al., 2016). The incubation period of chikungunya fever is usually 2–4 days. In infants, the disease typically begins with the abrupt onset of fever, followed by flushing of the skin. Febrile convulsions occur frequently (Jadhav et al., 1965). After 3–5 days of fever, a generalized maculopapular rash and lymphadenopathy are noted. Conjunctival injection, swelling of the eyelids, pharyngitis, and signs and symptoms of upper respiratory tract disease are common. No enanthem is seen. Some infants have a biphasic fever, and arthralgia may be quite severe, although it is not seen frequently (Jadhav et al., 1965; Carey et al., 1969; Halstead et al., 1969a; Nimmannitya et al., 1969; Brighton et al., 1983; Balmaseda et al., 2016). In Nicaragua, 2.9% of children over the age of 9 years had arthritis (Balmaseda et al., 2016).
In older children, fever is accompanied by headache, myalgia, and arthralgia involving various joints. Residual arthralgia has been described but is uncommon (Hawman et al., 2013). Joint pain is typically polyarticular, bilateral, symmetrical and affects mainly the extremities (ankles, wrists, phalanges) but also larger joints (shoulders, elbows, and knees) (Manimunda et al., 2010; Sissoko et al., 2010; Thiberville et al., 2013). Joint symptoms can fluctuate in intensity, but do not usually vary by anatomical location. Swelling may also occur in the interphalangeal joints, wrists, and ankles, as well as pain along ligament insertions, notably in children. An early macular blush is followed by a maculopapular rash that accompanies or immediately precedes defervescence. At the same time, marked lymphadenopathy occurs. Febrile convulsions are observed commonly in younger children. Hemorrhagic findings, including a positive tourniquet test, are rare (Jadhav et al., 1965; Carey et al., 1969; Halstead et al., 1969a; Nimmannitya et al., 1969; Brighton et al., 1983). Chikungunya viruses were recovered from saliva obtained during acute illness in 10 of 13 children, some of whom had bleeding gums (Gardner et al., 2015).
Accompanying the massive 2005 CHIK outbreak in La Réunion, 30 children were hospitalized with neurological symptoms, eight of whom were infants (Robin et al., 2008). During the 2006 CHIK epidemic in South Central India, 14% of 66 children presenting with suspected CNS infection had CHIK in blood or CNS (Lewthwaite et al., 2009). Sequelae were studied in 35 Reunion babies infected perinatally. At 21 months, infected children exhibit poorer neurocognitive skills than uninfected peers as evidenced by lower global developmental quotient scores and diminished specific neurocognitive skills, even reaching abnormal ranges for coordination and language. The incidence of the global developmental delay in infected children was just over 50% (Gerardin et al., 2014). Rarely, infants younger than 6-months-old with CHIK may exhibit extensive bullous skin lesions with blistering covering up to 35% of the body surface area (Robin et al., 2010).
Early in pregnancy, CHIKV infections may infect the conception to result in fetal loss (Gerardin et al., 2008). Vertical transmission is rare. Of 678 women with ante or peripartum CHIKV infections prior to partuition, none of their babies circulated CHIK IgM antibodies. Perinatal infections of neonates occurred in Reunion, rising to nearly 50% when mothers were viremic in the week preceding delivery (Ramful et al., 2007). Of 39 babies born to mothers experiencing CHIKV infections at the time of delivery, all developed a febrile illness beginning on day 4. Delivery of infants by Caesarian section did not prevent CHIKV infections. Nine of these infants developed encephalopathy. Lymphopenia and thrombocytopenia were common, in some cases profound, but without severe bleeding. Most infants with CHIKV infections developed erythematous skin lesions and evidence of joint involvement.
Treatment is supportive. Antirheumatoid drugs may be effective for management of chronic arthritis; however, chloroquine phosphate 250 mg/day, once touted for management of acute arthritic pain (Brighton, 1984), had no effect in a double-blinded trial (De Lamballerie et al., 2008; Chopra et al., 2014). Analgesics or mild sedation may be required to control pain. Arthritis after illness may require continued treatment with antiinflammatory agents and graduated physiotherapy. Salicylates, because of their hemorrhagic potential, are contraindicated. Bed rest is advised during the febrile period. Antipyretics or cold sponging should be used to keep the body temperature below 40°C (104°F).
Febrile convulsions are treated with phenobarbital given intravenously or orally and continued until the temperature is normal. Severe or intractable convulsions may respond to intravenous diazepam.
Children who have lost excessive fluid because of vomiting, fasting, or thirsting and who cannot take oral fluids may require intravenous rehydration. Individuals with severe hemorrhagic phenomena should be studied for underlying hemostatic disorders.
Human neutralizing monoclonal antibodies directed against E2 or E1 significantly delay lethality of chikungunya-infected mice, both in prophylactic and therapeutic settings (Fric et al., 2013; Fong et al., 2014). It has been suggested that administration of chikungunya antibodies might protect infants exposed to infection perinatally (Couderc and Lecuit, 2015).
In some instances, isolation of CHIKV or serologic evidence of recent infection has been obtained in persons with severe hemorrhagic findings and in individuals dying during an acute febrile illness. (Jadhav et al., 1965; Sarkar et al., 1965; Munasinghe and Rajasuriya, 1966; Carey et al., 1969; Renault et al., 2012). Infants with chikungunya may experience residual neurologic deficits after febrile convulsions (Couderc and Lecuit, 2009; Gerardin et al., 2016).
In addition, neurologic and myocardial involvement has been reported during chikungunya infection in adults (Chatterjee et al., 1965; Carey et al., 1969; Couderc and Lecuit, 2009). In adults, arthralgia may persist for weeks, and exercise may prolong this symptom. Typically, pain shifts from joint to joint and is worse in the morning and on first use of the joint. Swelling of ankles, wrists, and fingers occurs frequently. In older patients, the sequelae may resemble rheumatoid arthritis (Bouquillard and Combe, 2009). In the Reunion Island outbreak, 57% of adult patients experienced long-duration symptoms, half of which impaired daily activities (Sissoko et al., 2009). Chronic rheumatic manifestations were associated with age, severity of initial acute illness pain, and presence of osteoarthritis (Sissoko et al., 2009). A destructive arthropathy after illness has been reported (Brighton and Simson, 1984; Manimunda et al., 2010). CHIKV infection might coincide with other pathologic processes and result in death of the individual. Carefully studied, virologically documented cases have shown neither thrombocytopenia nor severe neutropenia (Jadhav et al., 1965; Manimunda et al., 2010).
Until more is known of the pathogenesis of CHIKV infection, estimating the frequency with which death can be attributed directly to chikungunya fever will be difficult.
The CHIMERE cohort study provides the first assessment of neurocognitive functions of infants infected by maternal-fetal transmission of CHIKV at birth, on average 21 months after.
Infection (Gerardin et al., 2014). Overall, infected children exhibit poorer neurocognitive skills than uninfected peers, as evidenced by lower global development quotient scores and diminished specific neurocognitive skills, even reaching abnormal ranges for coordination and language. Thus, incidence of global neurodevelopmental delay (GND) in infected children is just over 50% but with a caveat: CHIKV encephalopathy gives the poorest neurocognitive outcome and prostration also gives rise to a certain degree of neurocognitive dysfunction. Furthermore, CHIKV is an independent predictor for GND, infected children carrying a threefold risk of GND after adjustment for maternal social situation and neonatal characteristics, such as SGA and head circumference. Foremost is the concern that CHIKV-specific neonatal prostration, which was previously thought to have a favorable outcome, is more likely to lead to GND than the absence of infection. Hence, neurocognitive dysfunctions were more frequent in nonsevere p-CHIKV-infected children than in uninfected peers.
The Yap outbreak of 2007 provided a description of ZIKV infection as a febrile exanthema that occurred on a background of prior dengue infections (Duffy et al., 2009). In this outbreak, 31 patients who had ZIKV identified in blood plus 18 others with serologically confirmed ZIKV infections experienced an acute, short-duration febrile exanthem. The most commonly reported symptoms were rash (90%), fever, measured or reported (65%), arthritis or arthralgia (65%), nonpurulent conjunctivitis (55%), myalgia (48%), headache (45%), retro-orbital pain (39%), edema (19%), and vomiting (10%). The body temperature of 12 patients measured by a healthcare provider did not exceed 37.9°C. The median duration of rash was 6 days (range, 2–14), and that of arthralgia was 3.5 days (range, 1–14).
From this outbreak, there are no published descriptions that make it possible to compare Zika and chikungunya arthralgia by location, intensity, or presence of inflammatory signs, for example, redness, warmth, or swelling. However, in the large Zika epidemic that occurred on French Polynesia in 2013–14, there were patients with wrist and finger arthralgia or swollen ankles (Cao-Lormeau et al., 2014). There is no indication that Zika arthralgia was disabling. Despite the fact that ZIKV infections were estimated to have involved 73% of the Yap population over the age of 3, or ~ 7000 persons, there were no deaths, hospitalizations, or hemorrhagic complications. In a smaller series of cases that occurred in Central Java in 1976, adolescents and adults experienced a short duration infection characterized by high fever, stomach pain, prostration and malaise, but no rash (Olson et al., 1981). Despite continuous surveillance for the occurrence and causes of “fevers of unknown origin” in SE Asia by well-funded laboratory groups for > 30 years beginning in the 1960s, in Indonesia, the Philippines, Malaysia, Thailand, and Vietnam no further outbreaks of ZIKV disease were reported.
On Yap, symptomatic Zika disease occurred more frequently in females than males despite evidence of a higher ZIKV infection rate in males. Disease was more common in adults than in children. The ratio between inapparent infection and overt disease was 4.4:1 (Duffy et al., 2009).
Beginning with patients with Zika febrile syndromes observed during the French Polynesian outbreak, ZIKV was found in saliva and infections were observed to be sexually transmitted (Musso et al., 2015a,b). Further, ZIKV was isolated from semen even months following infection (Atkinson et al., 2016, 2017). ZIKV frequently appears in the urine where it persists and may be recovered as RNA longer than from acute-phase blood (Gourinat et al., 2015). Studies in susceptible subhuman primates have demonstrated this same unusual property of ZIKV starting as a blood-borne infection then spreading to mucosal tissues and appearing in the urine and cerebral spinal fluid (Dudley et al., 2016; Koide et al., 2016; Osuna et al., 2016).
Guillain-Barré syndrome (GBS) is characterized by rapidly evolving ascending weakness, mild sensory loss and hypo- or areflexia, progressing to a nadir over a period of up to 4 weeks (Wang et al., 2015). Cerebrospinal fluid shows an albuminocytologic dissociation. There are different GBS variants. Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common form of GBS. In AIDP, the immune attack is directed at peripheral nerve myelin sheath with secondary bystander axon loss. An axonal variant of GBS (AMAN) is associated with Campylobacter jejuni infection, a common and widespread cause of GBS and a poor prognostic factor. As a group, patients with AMAN have a more rapid progression of weakness to an earlier nadir than in AIDP resulting in prolonged paralysis and respiratory failure over a few days. Other rare phenotypic variants have been described with a pure sensory variant, and variants with restricted autonomic manifestations or a pharyngeal-cervical- brachial pattern. A nadir of weakness is reached within 2 weeks in half of cases and in 90% by 4 weeks. Some patients progress rapidly to become ventilator dependent within hours or days, while others have very mild progression for several weeks and never lose ambulation. Occasional patients will have a stuttering or stepwise progression. Weakness ranges from mild-to-severe flaccid quadriplegia and in up to 30% respiratory failure within a few days of onset. Dysautonomia affects most patients, and consists most commonly of sinus tachycardia, but patients may experience bradycardia, labile blood pressure with hyper- and hypotension, orthostatic hypotension, cardiac arrhythmias, neurogenic pulmonary edema, changes in sweat. Even more confusing a mimicking of a spinal cord lesion is observed in 5% of cases, many experience bladder (urinary retention) and gastrointestinal (constipation, ileus, gastric distension, diarrhea, fecal incontinence) dysfunction. Molecular mimicry is suggested as a pathogenetic mechanism of AMAN-type GBS because of the strong association with C. jejuni infection. The lipopolysaccharide capsule of the C. jejuni shares epitopes with GM1- and GD1a-producing crossreacting antibodies. GM1 is found in high concentration at the nodes of Ranvier, where antibody binding might be particularly disruptive to nerve function (Dimachkie and Barohn, 2013).
During the large Zika epidemic on the French Polynesian islands during 2013–14, cases of Guillain-Barre syndrome (GBS) were identified and quickly associated with ZIKV infection (Cao-Lormeau et al., 2016). Cases of GBS were identified 5 weeks after the onset of the Zika epidemic, peaking between weeks 9 and 12 with a total of 42 cases identified. All had IgM ZIKV antibodies. Based on a 66% attack rate of ZIKV infection in the general population of French Polynesia, the risk of Guillain-Barre syndrome was estimated to be 0.24 per 1000 Zika virus infections. The median age of the patients in this outbreak was 42 years (confidence limits, 36–56) and 31 (74%) were men. Most patients (88%) had a recent history of viral syndrome characterized by rash (81%), arthralgia (74%), and fever (58%) a median of 6 days before the onset of neurological manifestations. The main characteristics of this post-Zika GBS were the short interval between the onset of neurological symptoms after Zika disease and also the rapid progression of neuromotor disabilities to their nadir (median of 6 days) and the short plateau phase (median of 4 days).
Typically GBS begins with changes in sensation or pain along with muscle weakness, beginning in the feet and hands. This often spreads to the arms and upper body with both sides being involved. The symptoms develop over hours to a few weeks. During the acute phase, the disorder can be life threatening resulting in difficulties with breathing and requiring mechanical ventilation. Occasionally, changes in the function of the autonomous nervous system are noted requiring intensive cardiovascular support. GBS in French Polynesia fits this standard description presenting with generalized muscle weakness in 74% of cases. Other presenting signs were an inability to walk (44%), facial palsy (64%) while 93% of patients had increased (> 0.52 g/L) protein concentration in the CSF. Sixteen patients (38%) were admitted to intensive care units with 12 (29%) requiring respiratory assistance (Cao-Lormeau et al., 2016). All cases of GBS received intravenous immunoglobulins, and one had plasmapheresis. The median duration of hospital stay was 11 days for all patients, and 51 days (16–70) for a group of 16 patients who were admitted into intensive care. There were no deaths. Three months after discharge from the hospital, 24 (57%) patients were able to walk without assistance.
Among the 42 patients in French Polynesia, 37 underwent electrophysiological examination during the first week (Cao-Lormeau et al., 2016). All nerves tested showed similar results during a motor nerve conduction study with prolonged distal latencies and marked reduction of the distal compound muscle action potential (CMAP) amplitude. This is indicative of severe conduction alteration in the distal nerve segments. No substantial slowing in conduction or block in intermediate motor nerve segments was observed. In radial and sural nerves, the amplitude and conduction velocity of sensitive potentials were not significantly altered. A repeat nerve conduction study 4 months after hospital discharge was done on 19 GBS patients. These findings are suggestive of an acute motor axonal neuropathy (AMAN). The disappearance of the distal motor conduction alterations during the follow-up in a subset of patients who did not develop abnormal temporal dispersion or conduction slowing in intermediate nerve segments was consistent with “reversible conduction failure” described for GBS cases classified as AMAN. The clinical outcome of Zika virus Guillain-Barre syndrome was generally favorable. Despite the rapid onset and short plateau phase, the rapid evolution was similar to that seen in other patient groups with the AMAN type of Guillain-Barre syndrome. Three months after discharge, 24 (57%) of GBS patients were able to walk without assistance.
Congenital Zika Syndrome (CZS) may be defined as a fetus with evidence of ZIKV infection and any of the following: (1) severe microcephaly (> 3 SD below the mean), partially collapsed skull, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and neurologic impairment; (2) brain anomalies, including cerebral cortex thinning, abnormal gyral patterns, increased fluid spaces, subcortical calcifications, corpus callosum anomalies, reduced white matter, and cerebellar vermis hypoplasia; (3) ocular findings, such as macular scarring, focal pigmentary retinal mottling, structural anomalies (microphthalmia, coloboma, cataracts, and posterior anomalies), chorioretinal atrophy, or optic nerve hypoplasia/atrophy; (4) congenital contractures, including unilateral or bilateral clubfoot and congenital arthrogryposis multiplex or (5) neurological impairment, such as pronounced early hypertonia/spasticity with extrapyramidal symptoms, motor disabilities, cognitive disabilities, hypotonia, irritability/excessive crying, tremors, swallowing dysfunction, vision impairment, hearing impairment, and epilepsy (Moore et al., 2017).
The relationship of CZS and ZIKV infection of the mother and fetus has been documented and studied in several large clinical series (Franca et al., 2016; Martines et al., 2016a,b; Noronha et al., 2016). Eighty-eight pregnant Brazilian women with Zika-like symptoms were enrolled a prospective 2015–16 study (Brasil et al., 2016). Of these women, 72 (82%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 5 to 38 weeks of gestation. Predominant clinical features of the mother’s illness were a pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, lymphadenoapthy, and headache. Only 28% had fever (short-term and low-grade). Fetal Doppler ultrasonography was positive in 12 of 42 women with confirmed ZIKV infections (58%) but was negative in all 16 ZIKV-negative women. ZIKV infections in these women resulted in fetal deaths at 36 and 38 weeks of gestation (2 fetuses), in utero growth restriction with or without microcephaly (5 fetuses), ventricular calcifications or other central nervous system (CNS) lesions (7 fetuses), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7 fetuses).
In a follow-up prospective cohort of 134 ZIKV-positive pregnant women who presented with rash there were 125 birth outcomes, 58 (46.4%) resulted in CZS among whom were 9 fetal losses (7.2%). Thirty-seven of these ZIKV-exposed fetuses had structural or imaging abnormalities, while 12 babies (9.5%) had abnormal clinical neurological findings during the first months of life. In this series, only the gestational age of fetus at time of maternal ZIKV infection correlated with incidence and severity of CZS. There was a protective effect of ZIKV infection at later gestational time points. The odds of an abnormal pregnancy outcome decreased by 5% for every additional week of gestation prior to infection. Although ZIKV disease severity in the mother, as determined by the duration and intensity of symptoms, varied from mild (4.6%), to moderate (74.8%) to severe (20.6%), the severity of mother’s Zika disease did not correlate with outcome of fetal CZS. Pregnancy or infant outcomes were not associated with ZIKV viral load in mother’s acute phase blood or urine as measured by PCR. Finally, there was no statistically significant effect of preexisting dengue antibodies on clinical severity of maternal ZIKV infection or her ZIKV RNA load and there was no effect of preexisting dengue antibodies on abnormal birth outcomes in ZIKV-infected pregnant women (Halai et al., 2017).
A retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with laboratory evidence of congenital Zika virus infection, but a normal head size at birth provided evidence that all these infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome (van der Linden et al., 2016). This included decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation took place on the second day of life. It was determined that head growth decelerated as early as 5 months of age, and 11 infants had microcephaly. Thus, after prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities.
Important heterogenicities in incidence of CZS in Brazil have been reported. Beginning in March 2015, ZIKV infections were introduced and spread in northeast Brazil (de Oliveira et al., 2017). In that year, the rise and fall of reported Zika cases and of CZS and of GBS were synchronous. Between peak reported Zika cases and peak CZS, there was a lapse of 18 weeks. Early in 2016, Zika virus spread widely throughout Brazil, except the South. A parallel curve of GBS cases was observed in the northeast, but predicted cases of CZS did not occur. It was speculated that 2015 CZS cases were caused by dengue or chikungunya viruses, or due to a cofactor or that in 2016 pregnancies were not permitted to go to term, thus reducing ZIKV CZS cases. There is no evidence, based upon global observations, that DENV or CHIKV are responsible for more than a few CZS cases. The cofactor, widely postulated, is that previous dengue infection changed the course of ZIKV infections in pregnant women. Results reported by Halai et al. directly contradict this hypothesis (Halai et al., 2017). Severe reduction in term pregnancies throughout Brazil in 2016 is not a viable hypothesis. A possible explanation, testable by serosurveys, is that ZIKV infection rates in northeast Brazil in 2015 were vastly under- reported. These high rates produced the epidemic of CZS but in 2016, Zika case reporting improved and infection rates were far below those of 2015 and not high enough to produce a bulge in CZS cases.
The differential diagnosis for congenital Zika virus infection includes other congenital infections and other causes of microcephaly. Zika zoonoses may be equally widespread, but Zika disease, when recognized, has generally been mild exhibiting none of the sequelae prevalent during its circulation in the Americas from 2015.
Most patients with GBS begin to recover at 28 days with mean time to complete recovery being 200 days in 80% of cases (Ropper, 1992). Many have minor residual signs or symptoms reducing the effectiveness of recovery (Dimachkie and Barohn, 2013). As many as 10%–15% of patients have major residual neurologic deficits. In one study of 79 cases made 1 year after the onset, 8% had died (all older than 60), 4% remained bedbound or ventilator dependent, 9% were unable to walk unaided, 17% were unable to run, and 62% had made a complete or almost complete recovery (Hughes and Rees, 1997; Rees et al., 1998).
On careful examination, functionally significant residual deficits can be detected in the majority of GBS cases despite being scored as almost complete recovery. In one study, 40 GBS patients were studied a mean of 7 years after acute attack and compared to 40 healthy controls (Dornonville de la Cour and Jakobsen, 2005). More than half the patients showed residual neuropathy affecting large- and medium-sized myelinated motor and sensory fibers. These deficits were predominantly in the lower extremities and in some cases there was evidence of persistent dysautonomia.
Most AMAN patients have a more delayed recovery than AIDP patients. Some, however, recover more quickly (Dimachkie and Barohn, 2013). Motor nerve terminal degeneration provides a potential mechanism for rapid recovery in acute motor axonal neuropathy after Campylobacter infection (Ho et al., 1997). On motor-point biopsy, a denervation of the neuromuscular junction and reduction in the intramuscular nerve fiber count was observed. Since GM1 antibodies can bind at nodes of Ranvier, it was suggested that these might result in failure of electrical conduction. Recovery may be due to reversible changes of the sodium channels at nodes of Ranvier in the acute motor conduction block variant of AMAN or by degeneration followed by regeneration of motor nerve terminals and intramuscular axons (Honein and Jamieson, 2016; van der Linden et al., 2016).
The prognosis of newborns with congenital Zika syndrome varies with severity. Reported mortality rates among live-born infants range from four to 6%. The combination of Zika virus-related microcephaly and severe cerebral abnormalities generally has a poor prognosis, but little is known about the prognosis for congenitally infected infants with less severe or no apparent abnormalities at birth. Given ZIKV infection in pregnant women, it is recommended that comprehensive medical and developmental follow-up of infants be undertaken. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (van der Linden et al., 2016). It is far too early in this large outbreak of ZIKV CZS to understand, let alone predict outcome or to develop management strategies. These challenges will remain for years to come.
For infants with confirmed Zika virus infection, close follow-up is necessary. The appropriate follow-up evaluation depends upon whether or not the infant has clinical signs and symptoms of congenital Zika syndrome. All infants should have close monitoring of growth and development, repeat ophthalmologic examination, and auditory brainstem response testing. Fetuses or infants born to mothers who test positive for ZIKV infection should be studied sonographically or for clinical evidence of congenital Zika syndrome, a comprehensive evaluation (including ophthalmologic examination, laboratory tests, and specialist consultation) should be performed prior to hospital discharge.
The long-term management of either Guillain-Barre syndrome or the congenital Zika syndrome is beyond the scope of this chapter. Both syndromes may result in lifelong disability, although clearly the outlook for patients with CZS is considerably worse.