Abstract

Dengue fever is a vector-borne disease, transmitted by female mosquito Aedes aegypti. The common symptoms may be in the form of high-grade fever, headache, periorbital pain, myalgia, arthralgia, fatigue, nausea, vomiting and skin rashes in mild cases to renal, hepatic, hemorrhagic tendencies, shock and neurological involvement in severe cases. Incidences of neurological symptoms varied from 0.5% to 21% in recent years. Guillain-Barre syndrome (GBS) may be one of the rare presentations following dengue viral infection with only 20 cases of GBS reported worldwide and most of the cases being in pediatric age group, whereas very few cases have been reported in adults. Hence, we are reporting a case of a 24-year-old male presenting with GBS, which occurred during recovery phase of dengue fever.

Introduction

Dengue fever is a common vector-borne disease, transmitted by female mosquito Aedes aegypti. It is also called break-bone fever, caused by dengue virus which is an RNA virus, and belongs to Flaviviridae family, genus Flavivirus. There are 5 serotypes of dengue virus (DEN1, DEN2, DEN3, DEN4 and DEN5). Fifth serotype was announced in 2013.¹ Dengue fever has worldwide distribution but is predominantly seen in tropical and subtropical countries, like India. The World Health Organization (WHO) estimates an annual incidence of approximately 50 million infections, with approximately 5,00,000 people with dengue hemorrhagic fever. For the past 10 years, incidences of dengue fever are constantly increasing in India and from 1998 to 2009, 82,320 cases (6.32 per million population) were reported, which increased to 2,13,601 cases (34.8 per million population) from 2010 to 2017. 

Dengue fever may present with variable symptoms which usually begin 4-6 days after infection and last for up to 10 days. These symptoms may be in the form of high-grade fever, headache, periorbital pain, myalgia, arthralgia, fatigue, nausea, vomiting and skin rashes (3-5 days after onset of fever) in mild cases to renal, hepatic, hemorrhagic tendencies, shock and neurological involvement in severe cases.

Incidences of neurological symptoms varied from 0.5% to 21% in recent years.^2,3 These may be in the form of encephalitis, meningoencephalitis, stroke, cerebellar syndromes, transverse myelitis and Guillain-Barre syndrome (GBS).

GBS may be one of the rare presentations following dengue viral infection and only 20 cases of GBS have been reported worldwide with most of the cases being in pediatric age group, and very few cases reported in adults.^4,5 Hence, we are reporting a case of GBS which occurred during recovery phase of dengue fever. 

Case Report

A 24-year-old male patient was admitted in medical ward with history of fever, headache, body ache, nausea, vomiting and retro-orbital pain for last 2 days. He was examined and found to have mild throat congestion without hepatosplenomegaly, chest was clear and there were no signs of meningeal irritation. For above febrile illness, patient was investigated and was found to have mild leukopenia (3,200/mm³) with thrombocytopenia (48,000/mm³). Malaria Parasite Quantitative Buffy Coat Test (MPQBC) and Scrub typhus serology was negative but Dengue serology (NS1 antigen) was found positive. Patient responded well with symptomatic therapy and hence was discharged after 5 days of admission. He remained asymptomatic for 2 days after discharge and then suddenly developed weakness of both the lower limbs, which progressed rapidly to involve both upper limbs over a period of 6-10 hours to the extent that he was not able to move the limbs and get up from lying down posture. He was readmitted in our ward and was further investigated, which revealed that he had history of paresthesia and numbness in both extremities without cranial nerve and bladder-bowel involvement. Patient was examined thoroughly and was found to have normal vital signs. Neurological examination revealed normal mental function and cranial nerves. Motor system examination revealed hypotonia in all 4 limbs, power 1/5 in both lower limbs, whereas 2/5 in both upper limbs. Deep tendon reflexes (DTR) were absent in both upper and lower limbs, plantars were found flexor bilaterally. Sensory system and other neurological examination including signs of meningeal irritation were found normal. 

On the basis of history and clinical examination, we made our provisional diagnosis of post-Dengue GBS.

For confirmation of the above diagnosis, patient was investigated extensively which revealed that complete blood count (platelet 1.5 lacs/mm³), renal function test, human immunodeficiency virus (HIV), hepatitis B and hepatitis C, immunological profile, chest X-ray, ECG, USG abdomen were normal, whereas liver function tests were slightly deranged (AST-60 IU/L and ALT-194 IU/L) and Dengue NS1 was negative, whereas IgM Dengue was found positive.

Patient underwent lumbar puncture and cerebrospinal fluid (CSF) was examined, which revealed albumino­cytological dissociation (protein-82 mg/dL, cell count-2 cells/mm³ only lymphocytes). Nerve conduction study was done in median, ulnar, peroneal and sural nerves and revealed reduced compound muscle action potential (CMAP) amplitude with delayed F wave latency and prolonged R median suggestive of both demyelinating and axonal neuropathy.

Patient was treated with intravenous immunoglobulin (IVIg) for 5 days and started improving in form of power in both upper and lower limbs significantly (4/5 in both upper limbs and 3/5 in both lower limbs), hence was discharged and advised to follow-up in the outpatient clinic.

Discussion

Dengue fever is one of the leading causes of mortality and morbidity in tropical and subtropical regions of the world. Dengue fever may present with variable clinical presentation which may be in the form of mild febrile illness to dengue shock syndrome, dengue hemorrhagic fever and neurological complications.  

Neurological manifestations in dengue fever are rare. Verma et al described neurological complications in dengue patients and noted that they have been categorized into three groups on the basis of possible pathological mechanisms:⁶

• Neurotropic complications such as encephalitis, myelitis and myositis 
• Systemic complications such as hypokalemic periodic paralysis 
• Post-infectious immune-mediated complications such as GBS, opsoclonus-myoclonus syndrome.

GBS is one of the rarest neurological presentations following dengue fever seen in adults. It is an acute fulminating polyradiculoneuropathy possibly auto­immune, post-infectious or post-vaccination in nature; males are predominantly involved. It is characterized by rapidly progressive areflexic motor paralysis with or without sensory involvement and without bowel-bladder involvement. Common variants of GBS are acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy and acute motor sensory axonal neuropathy and Miller-Fisher syndrome.

Approximately 70% of cases of GBS occur 1-3 weeks after an acute infectious process. The common infectious agents which can cause GBS are Campylobacter jejuni, cytomegalovirus (CMV), Epstein-Barr virus, HIV, influenza and mycoplasma. The rare causes may be Zika and dengue viral infection.

The exact mechanism is unknown but possibly it may be due to cell-mediated immunological response to non-self antigen that misdirects to host nerve tissue through a resemblance of epitope mechanism (molecular mimicry).^7,8 Dengue virus would initiate this immunological event, leading to the disease. Myelin or axons could be the target of this immune response. 

Diagnosis of GBS is mainly based on clinical and laboratory findings. 

The following is the criteria for diagnosis of GBS (Asbury criteria):⁹

Required

• Progressive weakness
• Areflexia 
• Duration <4 weeks
• Exclude other causes (vasculitis, toxins, porphyria).

Supportive 

• Symmetrical weakness
• Mild sensory involvement
• Cranial nerve involvement 
• Absence of fever 
• Typical CSF finding (albumin-cytological dissociation)
• Nerve conduction study suggestive of demyelination.

GBS can be treated by IVIg (2 g/kg body weight divided in 5 daily doses) or plasmapheresis, as they are equally effective for typical GBS. Glucocorticoids have not been found to be effective in the treatment of GBS.

Conclusion

GBS is a rare neurological complication of dengue infection which is generally underestimated. It should always be considered if a patient of dengue fever during the infection or in recovery phase develops progressive areflexic paralysis. The patient should be diagnosed and treated as early as possible to reduce morbidity and mortality. Thus, our case report calls attention to physicians for the possibility of GBS in association with dengue fever.

About the Authors

Mahesh Dave, Shubham Kumar Sharma, Jitendra Singh Chaudhary

Senior Professor and HOD

Senior Resident

Resident

Dept. of Medicine, RNT Medical College, Udaipur, Rajasthan

REFERENCES

1. Mustafa MS, Rasotgi V, Jain S, Gupta V. Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control. Med J Armed Forces India. 2015;71(1):67-70.
2. Murthy JM. Neurological complications of dengue infection. Neurol India. 2010;58(4):581-4. 
3. Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12(9):906-19.
4. Tanwar VS, Saini A, Sukhija G, Kaur P. Post dengue Guillain-Barre syndrome: a rare case scenario. Int J Adv Med. 2016;3(4):1077-9.
5. Qureshi NK, Begum A, Saha PR, Hossain MI. Guillain-Barre syndrome following dengue fever in adult patient. J Med. 2012;13(2):246-9.
6. Verma R, Sharma P, Garg RK, Atam V, Singh MK, Mehrotra HS. Neurological complications of dengue fever: Experience from a tertiary center of North India. Ann Indian Acad Neurol. 2011;14(4):272-8. 
7. Hauser SL, Amato AA. Guillain-Barre syndrome and other immune-mediated neuropathies. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (Eds.). Harrison’s Principles of Internal Medicine. 18th Edition, New York: McGraw-Hill; pp. 3473-77.
8. Hughes RA, Hadden RD, Gregson NA, Smith KJ. Pathogenesis of Guillain-Barré syndrome. J Neuroimmunol. 1999;100(1-2):74-97.
9. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol. 1990;27 Suppl:S21-4.