By Anne Hege Aamodt, Espen Dietrichs and Hanne Flinstad Harbo

Anne Hege Aamodt (left) and Hanne F. Harbo introducing the program at the closing ceremony for the Norwegian YotB2015

After an invitation from the European Brain Council, we arranged the Norwegian Year of the Brain in 2015 (YotB2015) – 20 years after the first Year of the Brain in Norway. The Norwegian Neurological Association, the Norwegian Brain Council and Nansen Neuroscience Network coordinated YotB2015 and took the initiative to organize different events and activities. The main goals of YotB2015 were to increase the focus on knowledge and research on brain diseases that would lead to improved prevention, treatment and patient care.

Professor Espen Dietrichs, Norwegian delegate to the WFN presenting one of many lectures during the Norwegian YotB2015.

Upon establishing a national committee in 2014, we exchanged ideas and distributed tasks to stimulate the arrangement of events, media reach and interest-based political work. Many neurological departments, patient organizations, professional organizations and research networks announced the Norwegian Year of the Brain, scheduling activities and events around the country.

The formal opening ceremony was held in February 2015 in the Assembly Hall at the University of Oslo. State Secretary Anne Grethe Erlandsen from the Ministry of Health and Care Service opened the meeting before President Raad Shakir of the WFN, Mary Baker, past president of the European Brain Council, and several Norwegian health leaders, neuroscientists and patients held their lectures and talks.

YotB2015 meeting about treatment of neurological disorders, Oslo University Hospital.

Through the year, more than 60 meetings open to the public were held around the country, including lectures and discussions on different perspectives on neuroscience at hospitals, cultural centres and libraries. In Molde, Norway, YotB2015 meetings were part of an international literature festival. And in Oslo, several large meetings on various neuro-related topics were held, including “Literature and the Brain,” “Music and the Brain” and “Food and the Brain.” In addition, there were multiple professional meetings to market the YotB2015 logo, including the 27th National Neurological Congress, the Spring Meeting in the Norwegian Neurological Association, meetings within the Norwegian Academy of Science and Letters and the 1st National Meeting on Endovascular Intervention in Acute Stroke. YotB2015 was also marketed in a stroke campaign. A popular science book about the brain was published by the Norwegian delegate to the WFN, Espen Dietrichs, one of the initiators of both YotB1995 and YotB2015.

From left to right: Brain musicians Kristoffer Lo, John Pà¥l Inderberg and Henning Sommerro; Director of the National Health Directorate Bjørn Guldvog; State Secretary Anne Grethe Erlandsen from the Ministry of Health and Care Service and the Nobel Laureate Edvard Moser together with Hanne Harbo from the Norwegian Brain Council. (Photo courtesy: Norwegian Brain Council.)

During the YotB2015, many neurological topics and challenges were presented in mass media with numerous interviews on TV, radio and newspapers. Information on coming events was continuously updated on the website of the Norwegian Neurological Association and the Norwegian Brain Council. Information was also conveyed through social media platforms, Twitter and Facebook. During the fall, the Norwegian Brain Council also arranged a Facebook campaign called “With a Heart for the Brain,” which generated more than 1 million likes.

Ragnar Stien, one of the initiators of the Norwegian YotB in both 1995 and 2015, and the audience in Domus Academica at the University of Oslo at the meeting “The Literature and the Brain.”

Erlandsen led December’s closing ceremony. The Director of the National Health Directorate and Nobel laureate Edvard Moser held inspiring lectures on the impact of neuroscience and brain disorders. In addition, so-called “brain music” that was specially composed for the Nobel Prize Award Ceremony in 2014 by two music professors at the Norwegian University of Science and Technology, was presented live for the first time during the closing ceremony.

From left to right: Anne Hege Aamodt, president of Norwegian Neurological Association; Olga Bobrovnikova, renowned pianist battling MS and European Brain Council ambassador; Raad Shakir, WFN president; and Hanne F. Harbo, head of the Norwegian Brain Council. (Photo courtesy: Lise Johannessen Norwegian Medical Society.)

We have been working continuously to strengthen the priority area of brain diseases and neuroscience. The Year of the Brain and the neuro field were discussed in the Norwegian Parliament during 2015. We have also had an audience at the health minister and discussed the focus on brain disorders. The Norwegian Brain Council also received a separate post in the fiscal budget for 2016. During the closing ceremony, the state secretary declared that the Ministry of Health and Care Service will make a status report for brain disorders. A few days later, the Health Committee in the Norwegian Parliament underscored the need for a national plan on brain health in Norway.

The Norwegian YotB2015 has resulted in increased interest and knowledge on neurological disorders. Our message that one in three will experience brain disorders and that the neuro field needs to be prioritized stronger has sparked interest. We have achieved political understanding for brain disorders as a focus area and will work further with this issue. We will follow up the announced status report, which should result in a National Brain Plan.

By Bart Lutters and Peter J. Koehler

Portrait of Jan Ingenhousz (1730-1799)

Electroconvulsive therapy (ECT) is considered a highly effective treatment for drug-resistant depression. The discovery of ECT has generally been attributed to the Italian psychiatrist Ugo Cerletti (1877-1963), who, in April 1938, managed to induce seizures by applying electricity directly to the head of a schizophrenic patient. Even though Cerletti’s achievement has greatly contributed to the widespread implementation of cranial electrotherapy, the first reports on this seemingly hostile procedure date back even earlier.

The notion that cranial electrotherapy may provide a useful therapy for melancholic patients can be traced back to a letter written by the Dutch scientist Jan Ingenhousz (1730-1799) in 1783. In his letter, Ingenhousz told his correspondent, none other than Benjamin Franklin (1705-1790), of an electric accident that he had recently endured. While Ingenhousz had attempted to reconstruct a thunderstorm in his laboratory, a powerful shock accidently struck his head:

The yarr [Leyden jar] by which I was struck contained about 32 pints. It was nearly fully charged when I recived the explosion from the conductor supported by that jarr. The flash enter’d the corner of my hat. Then, it entered my forehead and passed thro the left hand, in which I held the chaine communicating with the outward coating of the yarr. I neither saw, heared nor [sensed?] the explosion by which I was struck down. I lost all my senses, memory, understanding and even sound judgment.

Portrait of Benjamin Franklin (1705-1790) by Charles Willson Peale (1772)

My first sensation was a peine [pain] on the forehead. The first object I saw was the post of a door. I combined the two ideas together and thought I had hurt my head against the horizontal piece of timber supported by the pos[ts?], which was impossib[le] as the door was wide and high. After having answered unadequately to some questio[ns] which were asked me by the people in the room, I determined to go home … yet I was more than two minutes considering whether, to go hom[e] I must go to the right or the left hand.

Having found my lodgings, and consider[ing] that my memory was become very weak, I thought it prudent to put down in writing th[e] history of the case. I placed the paper before me, dipt the pen in the ink, but when I applyed it to the paper, I found I had entirely forgotten the art of writing and reading and did not know more what to doe with the pen, than a savage, who never knew there was such an art found out. (Papers of Benjamin Franklin, n.d., Vol. 40, Unit 209. Interpreted by Stanley Finger)

In deficient English, Ingenhousz clearly describes a case of retrograde amnesia, a common consequence of head injury, which would be more thoroughly described by Benjamin Brodie (1817-1880) in 1857. This amnestic phenomenon was familiar to Franklin, who had previously suffered an electric blow to the head himself:

I had a Paralytick Patient in my Chamber, who’s Friends brought him to receive some Electric Shocks. I made them join Hands so as to receive the Shock at the same time, and I charg’d two large Jars to give it. By the Number of those People, I was oblig’d to quit my usual Standing, and plac’d myself inadvertently under an Iron Hook which hung from the Ceiling down to within two Inches of my Head, and communicated by a Wire with the outside of the Jars. I attempted to discharge them, and in fact did so; but I did not perceive it, tho’ the charge went thro’ me, and not through the Persons I entended it for. I neither saw the Flash, heard the Report, nor felt the Stroke. When my Senses returned, I found myself on the Floor. I got up, not knowing how that had happened. I then again attempted to discharge the Jars; but one of the Company told me they were already discharg’d, which I could not at first believe, but on Trial found it true. They told me they had not felt it, but they saw I was knock’d down by it, which had greatly surprised them. On recollecting myself, and examining my Situation, I found the Case clear.

Illustrations of melancholic patients treated with cranial electrotherapy by Giovanni Aldini (1762-1834)

Just like Ingenhousz, Franklin had not been able to recall the electric accident. Despite monumental blows to their heads, neither of the two men reported any permanent damage. On the contrary, as appears from Ingenhousz’ continuing account, he experienced something quite astonishing the morning after his accident:

My mental faculties were at that time [the next morning] not only returned, but I felt the most lively joyce in finding, as I thought at the time, my judgment infinitely more acute. It did seem to me I saw much clearer the difficulties of everything, and what did formerly seem to me difficult to comprehend, was now become of an easy Solution. I found moreover a liveliness in my whole frame, which I never had observed before.

Franklin was fascinated by the story of his Dutch correspondent. Ingenhousz had not only survived the accident, but had experienced a considerable improvement in his mood following the accident. Even though Franklin himself had not noticed any perks of his electric mishap, both men agreed that cranial electrotherapy could potentially provide an effective therapy for melancholic patients. Consequently, they both set out to persuade various “mad-doctors” in London and Paris to expose the heads of their melancholic patients to cranial electricity.

In 1787, four years after Ingenhousz’ letter to Franklin, John Birch (1745-1815), an English surgeon and electrotherapist, proclaimed the healing of a melancholic porter and a suicidal singer by means of cranial electrotherapy. Birch’s achievements were soon followed by similar reports from Giovani Aldini (1762-1834) and T. Gale. Even though none of these physicians made any reference to Franklin or Ingenhousz, given the chronology of events, it seems plausible that the two prominent scientists inspired them.

It is time to include Jan Ingenhousz and Benjamin Franklin in the ECT story. Ingenhousz, a talented physician-scientist best known for his discovery of photosynthesis, was the first to report the positive effects of cranial electricity and to advise the procedure for the treatment of melancholic patients. Franklin, already widely celebrated for his electric research, owns his share in the conception of cranial electrotherapy, as well. Finally, even though Cerletti was probably the first to induce seizures by means of cranial electricity, the early cranial electrotherapists Birch, Aldini and Gale deserve credit for pioneering cranial electrotherapy.

Sources

Beale, N., & Beale, E. (2011). Echoes of Ingen Housz: The long lost story of the genius who rescued the Habsburgs from smallpox and became the father of photosynthesis. Hobnob Press.

Beaudreau, S. A., & Finger, S. (2006). Medical electricity and madness in the 18th century: the legacies of Benjamin Franklin and Jan Ingenhousz. Perspectives in biology and medicine, 49(3), 330-345.

Finger, S. (2012). Doctor Franklin’s medicine. University of Pennsylvania Press.

Finger, S., & Piccolino, M. (2011). The shocking history of electric fishes: from ancient epochs to the birth of modern neurophysiology. Oxford University Press.

Finger, S., & Zaromb, F. (2006). Benjamin Franklin and shock-induced amnesia. American Psychologist, 61(3), 240.

Shorter, E., & Healy, D. (2013). Shock therapy: a history of electroconvulsive treatment in mental illness. Rutgers University Press.

By Tamer Emara, Mohamed Sherif
Al-Kotb, Mayar Nawara, Hani Farouk A.
Mohamed, and Ahmed Elbokl

The Problem

Although ancient Egyptians were the first to describe the brain, the services that are provided to patients with disorders of the brain and the number of trained neurologists in Arab and African countries is at best centralized in large cities and at worst nonexistent.

This occurs despite the argument that the burden of neurologic disorders in the developing world is higher than that in developed countries. In one study from Ethiopia, it was estimated that neurology cases constitute 20-25 percent of ER admissions. Stroke is the No. 1 cause of disability in the world. According to World Health Organization (WHO) records, stroke occurs 20 years earlier in developing countries when compared to developed ones, and only 3 percent of disabled individuals get rehabilitation services. Similarly, 90 percent of epilepsy cases occur in the developing world. ^1,2

The combined Arab and African population is 1.5 billion, around 23 percent of the world population. With current improvements in vaccination programs and water sanitation, the mean age of the population is increasing, and it is estimated that by 2030, the burden of noncommunicable disorders will be higher than communicable disorders in Africa.

The Situation in Egypt

From left to right: Dr. Jean Jabbour, a WHO representative and one of the guests of honor, greets Laila Negm, honorary meeting chairman. Gathered in back, from left to right: Professor Mahmoud Elmetieni, dean of the faculty of medicine, Ain Shams University; Professor Bahaa Zidan, head of Elgalaa Military Medical Compound and a guest of honor; and Professor Magd Zakaria, meeting chairman and head of the neurology department, Ain Shams University.

The number of trained neurologists is steadily growing. Specialized neurology services for stroke, epilepsy, headache, neurorehabilitation, and neuromuscular disorders, among others, are starting and successfully growing. These services can be found in Cairo and to a lesser extent in Alexandria and Assiut. Apart from this, the mere presence of a trained neurologist is an exception. It is a common scenario to find a community of 1 million to 3 million inhabitants who are served by one to two neurology consultants, who may be living in another place and shuttling back and forth. The brain drain happens from these areas to Cairo, in addition to other countries.

The Situation in Africa

Neurology education in many sub-Saharan African countries is almost nonexistent. Around 90 percent of African universities do not have master degrees or other forms of formal training modules in neurology. Most of the trained neurologists get their training abroad. Many leave their countries because there are no posts for neurologists in the university or the ministry of health. The number of trained neurologists in many countries can be counted on two hands. For instance, only 11 countries in Africa have more than 10 neurologists per country, five countries in Africa have only five to 10 neurologists per country, and 23 countries in Africa have one to four neurologists per country.

In countries with good neurology training programs, well-established neurology services can only be found in central cities, and patients have to travel for hundreds of miles to find a good neurology service.

We Had a Plan

The Treat and Teach Initiative

For the aforementioned reasons, Ain Shams University has been endorsing an initiative called Treat and Teach, which is designed to develop short- and intermediate-term strategies to reduce the gap in the number of trained neurologists and the deficiency of neurology education programs in Africa. We are trying to complement the current efforts to improve neurology education in Africa with an initiative that has a mix of online education and on-site clinical training, while working on establishing medical services that may include a stroke unit, memory clinic, neurorehabilitation units, or a neurology department. Master degrees will be given from Ain Shams University, Cairo, and work will be done to establish local master degrees in rural centers. This could lead to national neuroscience services run by local providers.

The Conference

To promote this initiative, Ain Shams University organized the First Arab African Teleneurology Conference: A Treat and Teach Initiative. Held in the League of Arab States January 19–20, 2016, the conference was designed for medical and non-medical stakeholders. Representatives of Ain Shams University, the League of Arab States, Egyptian ministries of health, foreign affairs and communications, Egyptian military hospitals, the American Telemedicine Association and WHO joined the discussions, in addition to 247 attendees representing 12 countries and 13 universities.

Discussions Focused On

1. The high prevalence of neurologic disorders, their impact on the community in terms of mortality and morbidity, and the importance of time-to-start management and clinical expertise to manage these sophisticated cases.
2. The clear deficiency in trained neurologists in rural parts of Arab countries and in most African countries.
3. The increasing numbers of trained neurologists and specialized neurology services in large cities, such as Cairo, the challenge to use these experiences in rural areas and avoid the brain drain problem, and the importance of establishing stronger inter-African communications to bridge geographical barriers.
4. Presentations from international experts in the field illustrating experiences from the Mayo Clinic, Harvard, California and the U.K.; experiences from Egypt and Sudan were also presented.
5. The great potential and readiness for change in many sub-Saharan countries. Africa is a young continent, with an average age of 17 to 20 years old. Africa will have the largest workforce in the world in the next 25 years, and seven out of 10 of the fastest growing economies in the world are sub-Saharan African countries. Government spending on health care worldwide is the highest in Africa (18.4 percent). The number of Internet users in Africa multiplied 70 times from 2000 to 2010.
6. As a proof of concept, four speakers invited from the U.S. used telecommunication technologies to give live interactive sessions showing scientific information and giving second opinions about selected cases.

A round table discussion worked on the action plan of launching the Treat and Teach Initiative. There were six objectives for this round table discussion:

1. Governance and planning
2. Human resources
3. Technology
4. Sustainability
5. Regulations
6. Research

Results and Recommendations of the Meeting

Meeting roundtable participants include, from left to right: Tamer Emara, the meeting’s scientific coordinator, associate professor of neurology and the head of the teleneurology unit, Ain Shams University, Cairo; Professor Hani Aref, neurology department, Ain Shams University; Professor Magd Zakaria, meeting chairman and head of the neurology department, Ain Shams University; and Moderator Amr Abd Elmoneim, assistant professor of neurology, Ain Shams University.

1. Ain Shams University has agreed to start the first teleneurology unit in Egypt. Ain Shams has signed several agreements with Egyptian hospitals and African universities to start a proof of concept phase of hospital-to-hospital acute care teleneurology service that would be complemented with bilateral mobility to facilitate service development in remote areas. Similar agreements with international centers of excellence are also underway.
2. Additionally, Ain Shams University, WHO, Egyptian ministries of health and foreign affairs, military forces, and the Arab League are currently collaborating to establish an Arab African center of excellence for neurology, neurosurgery and teleneurology, which would serve as a regional center of excellence to support best medical practices and education. The management of this center should provide a self-sustained investment model that would facilitate public-private partnerships. Ain Shams University is currently preparing an initial proposal for this project. A copy of this project will be delivered to the Egyptian government and another copy to the meeting of Arab Ministers of Health meeting.

Conclusions: The Happy End

1. It is of utmost importance to nurture local neurology leaders by giving them the right mix of scientific and management skills, in addition to logistically supporting their starting neurology programs.
2. Although we think highly of new telecommunication technologies as a way to bypass geographical barriers, we are aware of its limitations. Neurology, as all other medical specialties, requires direct face-to-face interactions with mentors and patients alike, thus the essential role of bilateral mobility in the Treat and Teach Initiative.
3. Sustainability is always a key issue in developing services. It is estimated that 90 percent of telemedicine projects stop after a few years. The role of education, in addition to telemedicine practice, is essential to ensure the sustainability of this project. Thinking of the spoke as a “hub in evolution” is mandatory in our view to promote the growth and progress of the best medical care to this large population of the world. The other important guarantee for sustainability is the integration of telemedicine practice in everyday work.
4. Work should be done to establish centers of excellence that are strategically located and connected to peripheral hubs in a model that allows growth, dissemination of knowledge and sustainability. This lies within a health care system that offers support to everyone in the community. The self-sustained investment model and the idea of promoting local neurology champs would ideally offer physicians working in remote areas more self-actualization values, in addition to a decent financial revenue that can help reverse the brain leak of trained clinicians.
5. The research programs of these centers should be targeted toward the actual needs of this part of the world, developing the concepts and finding new solutions for better health care delivery. The real change would be to gain the ability to produce knowledge.

References:

1. Neurology Training and Practice in Ethiopia. Belachew Degefe Arasho,  Zebenigus Mehila, Schaller Bernhard, and Guta Zenebe. Sudanese journal of public health 2008
2. World federation of neurology council of delegates meeting, at Sydney, Australia. World. Neurology 2005; V20 N4.

By Avindra Nath, MD, and James Sejvar, MD

James Sejvar, MD

Avindra Nath, MD

In recent years, there has been an emergence of several major viral infections with devastating neurological consequences, including West Nile virus, dengue, chikungunya, enterovirus D68, Ebola and now Zika virus. Increased global travel and climate change, leading to changing patterns of vector distribution and behavior are among the major reasons for the emergence of these infections. Zika virus is the most recent epidemic that is having devastating effects on human populations in affected regions, and is rapidly spreading across the South American continent.

Epidemiology

Zika virus was first identified from a primate in 1947 in the Zika forest of Uganda.¹ The first human cases occurred in Africa and then in Southeast Asia in the 1960s.^2,3 During the intervening years, Zika virus was associated with isolated cases or small outbreaks mainly in Africa. In 2007, there was an outbreak in Yap, the Federated States of Micronesia, where nearly three-quarters of the population was infected.^{4, 5} This represented the largest outbreak of Zika virus infection to that point. In 2013, there was an epidemic in French Polynesia, which was associated with a reported increase in cases of the autoimmune peripheral nerve disorder Guillain-Barre syndrome, although a causal association between Zika virus and Guillain-Barre syndrome was never established.

In December 2014, Zika virus was first detected in Brazil. Although it is unknown how it was introduced into Brazil, some hypothesize that a traveler attending the 2014 football/soccer World Cup introduced the virus. The outbreak in Brazil was fast moving and large. Tens of thousands of people became ill, and likely millions of people were infected. Similar to French Polynesia, shortly after the beginning of the Zika virus outbreak, clinicians began reporting larger-than-expected numbers of Guillain-Barre syndrome. Many of these people had reported a febrile rash illness compatible with Zika in the days or weeks before their weakness onset. In addition, clinicians in Brazil noted a 20-fold increase in microcephaly in 2015, compared to previous years, with microcephalic babies born approximately eight to nine months after the first recognition of Zika virus. Some of the infants’ mothers reported a rash illness compatible with Zika virus infection while pregnant, leading to the suspicion that the microcephaly was somehow associated with Zika virus infection.

Nearly 90 percent of the cases of microcephaly occurred in the northeastern region of the country,^{6, 7} areas experiencing some of the heaviest burdens of Zika virus infection as well. French Polynesian health authorities reported an unusual increase in central nervous system malformations in babies born during a Zika virus outbreak on the islands from 2014 to 2015.⁶ The infection has now spread across most of South America and Mexico. To date, few cases have been reported in the United States among travelers returning from Zika virus-affected regions.^{8, 9}

Virology and Pathophysiology

Zika virus is a positive-sense, single-stranded RNA virus (genome 10.7 K nucleotides) belonging to the flaviviridae family, which includes dengue, yellow fever, Japanese encephalitis, St. Louis encephalitis and West Nile virus. It has the ability to cross the placenta and cause developmental brain abnormalities in children, suggesting that the virus likely infects neural stem cells. The severity of brain malformations may be related to the stage of fetal development at the time of infection. Microcephaly would be the most common manifestation, but if infection were to occur in earlier stages of fetal development, anencephaly or lissencephaly may occur.

The pathophysiology of ascending paralysis and myelitis in adults is unknown. However, mice injected with the virus can develop paralysis, suggesting direct invasion by the virus, although an immune-mediated, post-viral syndrome is also possible. It remains unknown if once infected and recovered if an individual develops long-term immunity or not, and if recurrent infections or relapses can occur. Questions regarding long-term viral persistence in tissue reservoirs also remain unanswered.

Transmission

The virus is transmitted by the Aedes species of mosquitoes ¹⁰, in particular Aedes aegypti, the vector involved with transmission of dengue, a closely related flavivirus. Additionally, experimental evidence suggests the virus can be transmitted by Asian tiger mosquitoes (Aedes albopictus) ^{11, 12}, which can survive in cold temperatures. Most arboviruses have an intermediary host or “reservoir.” For West Nile virus, birds, particularly corvids, serve as these reservoirs. For Venezuelan, Western and Eastern equine encephalitis viruses, horses serve this role, and for Japanese encephalitis virus, it is primarily pigs. However, the transmission of Zika virus generally occurs directly between humans and mosquitos. There is some evidence that human-to-human transmission may occur through sexual intercourse, and the virus has also been detected in saliva, so the potential for oral transmission also exists. The virus has been isolated from the amniotic fluid of pregnant women and blood and tissues of newborns, suggesting materno-fetal transmission.¹³ So far, an intermediary host has not been identified.

Clinical Manifestations

Female Aedes aegypti mosquito

The majority of Zika virus infections ­­­— 80 percent — are clinically asymptomatic.⁴ Among persons who develop symptoms, Zika virus infection is generally considered to be mild, causing fever, rash and body aches. Some may develop conjunctivitis. Symptoms usually last one week.

The full spectrum of neurological complications from this viral infection remains unknown. The epidemiological association between microcephaly and the infection seems strong. In Brazil, annual reported rates of microcephaly would generally be somewhere around 150 cases per year. Reportedly, between October 2015 and January 2016, more than 3,500 babies were born with the condition. CT brain scans show evidence of widespread calcification. Other malformations, such as anencephaly and lissencephaly, might also occur. It remains uncertain if other organs may be involved in addition to the brain. However, the differential diagnosis of microcephaly is broad. Hence, when presented with a patient with microcephaly, it remains important to consider other common causes, such as genetic, craniostenosis, and infections, such as toxoplasmosis, rubella, varicella zoster virus and cytomegalovirus. Intrauterine cerebral anoxia, exposure to drugs, alcohol and other toxins, malnutrition and metabolic disorders such as phenylketonuria can also cause microcephaly. Patients with microcephaly often have developmental delay, difficulty with gait and balance, mental retardation, seizures and hyperactivity.

Guillain-Barre syndrome appears to be a recurring possible complication of Zika virus infection. Following the introduction of Zika virus into French Polynesia, clinicians began reporting larger-than-expected numbers of Guillain-Barre syndrome cases on the island.¹⁴ Following the introduction of Zika virus to Brazil in December 2014, again, reports surfaced of large numbers of Guillain-Barre syndrome cases. In Brazil, few cases of Guillain-Barre syndrome had laboratory confirmation of Zika virus, but currently the primary method of diagnostic testing is through the detection of viral RNA through polymerase chain reaction. In Guillain-Barre syndrome, by the time the clinical features of limb weakness develop, it is unlikely that there would still be circulating virus, and, as such, detection of viral RNA would not be expected. Less commonly, some patients have been thought to have a myelitis or polio-like manifestations. Currently, it is unclear if these are all related or if indeed both spinal cord and peripheral nerves can be involved. Thus, in Brazil, epidemiologic evidence and the close temporo-spatial clustering of both Guillain-Barre syndrome and Zika virus cases provides intriguing circumstantial evidence for an association.

In other cases in which the virus was newly introduced, reported increases of Guillain-Barre syndrome cases have invariably appeared, including in Colombia, Venezuela and, more recently, El Salvador, which reported 46 Guillain-Barre syndrome cases in a five-week period from December 2015 to early January 2016. That is nearly three times more than the country would normally see in that timeframe. Laboratory substantiation of an association between Zika virus and Guillain-Barre syndrome has proved challenging, however. As noted, by the time of onset of weakness, the virus would be expected to be cleared from the body, and molecular techniques to identify the virus or viral RNA would not be expected to be positive. Detection of Zika virus-specific antibodies would provide evidence of current or prior infection. However, that method also has its challenges. Dengue virus is a closely related flavivirus to Zika, and invariably co-circulates in all areas currently associated with Zika virus. However, dengue virus infection has also rarely been associated with Guillain-Barre syndrome, and laboratory testing by serology is challenging due to the substantial cross-reactivity of antibodies between Zika virus and dengue virus.

Since these viruses are carried by the same mosquito vector and co-circulate at the same times of the year, it can be challenging to differentiate between infection with the two viruses.¹⁵ Development of a robust serologic assay that can reliably differentiate Zika virus from dengue and other closely related flaviviruses will be crucial in order to provide laboratory evidence of Zika-associated Guillain-Barre syndrome, as well as other late complications of Zika virus. Currently, the nature of the neuropathy is not known, as results of electrodiagnostics to determine the clinical sub-type of Guillain-Barre syndrome possibly associated with Zika virus has been rarely reported. It would be important to know if it is axonal or demyelinating and if it is immune mediated. This could affect treatment and prognosis. Recovery from demyelinating neuropathies is generally better than those due to axonal injury. Isolated reports suggest that the neuropathy may be demyelinating and may respond to treatment with intravenous immunoglobulin.¹⁴

Laboratory Diagnosis

Viremia occurs only during the first few days of the illness, but if blood samples are obtained during that time, virus can be detected by polymerase chain reaction.¹⁶ Following this phase, IgM antibodies can be demonstrated by ELISA or Western blot analysis. Previous epidemics have noted that there is cross reactivity between antibodies to Zika and other arboviruses such as dengue.⁵ The Centers for Disease Control and Prevention (CDC) has issued guidelines for the testing of infants born with possible Zika virus infection.¹⁷

Treatment and Prevention

Currently, there is no effective treatment or vaccine against the virus. Hence, prevention is key with control of mosquito populations and prevention of mosquito bites. Travel advisories have been issued for pregnant women not to travel to areas experiencing Zika virus outbreaks. For individuals who suffer from the neurological consequences of the infection, long-term supportive and symptomatic treatment is key. The socio-economic impact of the infection, particularly if the association between Zika virus and microcephaly holds true, will likely be huge and felt for decades. While the large number of cases of microcephaly is tragic, whatever the eventual cause turns out to be, it will result in large numbers of children with developmental disorders and begs for the need to train personnel in a wide variety of health disciplines, including neurology, rehabilitation, specialized nursing, social services, etc., to care for and treat this population. Ongoing surveillance for Zika virus in the Americas and elsewhere, to monitor its continued spread, as well as documentation of infection among travelers returning from affected areas will be critical. Development of more robust serologic assays that can differentiate Zika virus from other closely related flaviviruses will be an important tool to substantiate an association between Zika virus and devastating neurologic conditions, such as Guillain-Barre syndrome and microcephaly. Ultimately, the long-term epidemiologic pattern of Zika virus will be important to monitor.

References:

1. Weinbren, M.P. and M.C. Williams, Zika virus: further isolations in the Zika area, and some studies on the strains isolated. Trans R Soc Trop Med Hyg, 1958. 52(3): p. 263-8.
2. Simpson, D.I., Zika Virus Infection in Man. Trans R Soc Trop Med Hyg, 1964. 58: p. 335-8.
3. Olson, J.G., et al., Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg, 1981. 75(3): p. 389-93.
4. Duffy, M.R., et al., Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med, 2009. 360(24): p. 2536-43.
5. Lanciotti, R.S., et al., Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis, 2008. 14(8): p. 1232-9.
6. Control, E.C.f.D.P.a., Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillian Barre syndrome. 10 December 2015.
7. Bogoch, II, et al., Anticipating the international spread of Zika virus from Brazil. Lancet, 2016.
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