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  In this Article
 »  Abstract
 » Introduction
 » Historical Aspects
 » Epidemiology
 » Muscle Involvement
 » Nerve Involvement
 »  Postinfectious F...
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

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REVIEW ARTICLE
Year : 2015  |  Volume : 63  |  Issue : 4  |  Page : 497-516

Dengue-associated neuromuscular complications


1 Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh, India
2 Department of Microbiology, King George Medical University, Lucknow, Uttar Pradesh, India
3 Department of Pathology, Ram Manohar Lohiya Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication4-Aug-2015

Correspondence Address:
Ravindra Kumar Garg
Department of Neurology, King George Medical University, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.161990

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 » Abstract 

Dengue is associated with many neurological dysfunctions. Up to 4% of dengue patients may develop neuromuscular complications. Muscle involvement can manifest with myalgias, myositis, rhabdomyolysis and hypokalemic paralysis. Diffuse myalgia is the most characteristic neurological symptom of dengue fever. Dengue-associated myositis can be of varying severity ranging from self-limiting muscle involvement to severe dengue myositis. Dengue-associated hypokalemic paralysis often has a rapidly evolving course; benign nature; excellent response to potassium; and, often leads to diagnostic confusion with other dengue-associated neuromuscular disorders. Rhabdomyolysis is the most severe form of muscle involvement and may be life-threatening. Guillain-Barrι syndrome is another frequent neuromuscular dengue-associated complication. Dengue-associated Guillain-Barrι syndrome responds very well to intravenous immunoglobulins. Predominant spinal gray matter involvement has been reported in a patient presenting with areflexic paraparesis. Mononeuropathies often manifest with paralysis of the diaphragm due to phrenic nerve dysfunction. Brachial plexopathy, in the form of neuralgic amyotrophy, has been described much more frequently than lumbo-sacral plexopathy. Early recognition of these neuromuscular complications is needed for successful treatment and to prevent further disabilities.


Keywords: Guillain-Barré syndrome; hypokalemic paralysis; myalgia; myositis; neuralgic amyotrophy; peripheral neuropathy; plexopathy; rhabdomyolysis


How to cite this article:
Garg RK, Malhotra HS, Jain A, Malhotra KP. Dengue-associated neuromuscular complications. Neurol India 2015;63:497-516

How to cite this URL:
Garg RK, Malhotra HS, Jain A, Malhotra KP. Dengue-associated neuromuscular complications. Neurol India [serial online] 2015 [cited 2019 Jul 17];63:497-516. Available from: http://www.neurologyindia.com/text.asp?2015/63/4/497/161990



 » Introduction Top


Dengue infection is a widely prevalent mosquito-borne viral disease predominantly prevalent in tropical and sub-tropical regions of the world. Dengue fever affects persons of all age groups. Severe dengue is a potentially life-threatening condition. Severe dengue is characterized by leakage of plasma into the tissues, fluid accumulation, respiratory distress, mucosal bleed, or multi-organ failure.

Dengue is also associated with many neurological complications. These complications include encephalitis/encephalopathy, meningitis, myelitis, cerebellitis, acute disseminated encephalomyelitis and many neuromuscular complications. Neurological complications of dengue are, frequently, part of severe dengue infection. [1],[2]

Dengue virus, an enveloped single-stranded RNA virus, belongs to the family Flaviviridae and genus Flavivirus. There are four distinct subtypes of the Dengue virus (Dengue virus type 1-4). Dengue virus is transmitted to humans by the mosquito Aedes aegypti and Aedes albopictus. The incubation period is approximately 4-10 days. Dengue fever, in the majority of patients, presents with a flu-like illness and infrequently causes death. Dengue is clinically characterized by severe headache, retro-orbital eye pain, myalgias, arthralgias, rash, and mild hemorrhagic manifestations. The symptoms usually last for 2-7 days. Severe complications of dengue infection include dengue hemorrhagic fever or dengue shock. Severe dengue is often preceded by a number of warning signs. These appear 3-7 days after the onset of the initial symptoms and are indicative of serious complications; by this time, the fever usually subsides [3],[4] [Table 1].
Table 1: Revised WHO dengue case classification 2009

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At the time of the mosquito bite, Dengue virus gets injected into the cutaneous tissues before reaching the blood circulation. The virus first affects the epidermal dendritic cells (Langerhans cells). Infected dendritic cells subsequently migrate to lymph nodes, and through the lymphatic system, infection further disseminates and produces a viremia. A severe form of the disease is pathologically characterized by endothelial cell abnormalities, vascular leakage, and coagulopathy. Characteristic changes in many internal organs, like the lungs, kidneys, liver, and spleen, are marked by extensive areas of hemorrhage, edema and mononuclear infiltrates. [5] The increased vascular permeability is thought to be caused by many mechanisms like a cytokine storm, cytotoxic T-cell invasion, complement activation and virus-induced endothelial injuries. [6] Autoimmunity, via a phenomenon of molecular mimicry, may also lead to damage and dysfunction of platelets and endothelial cells. [7]

Neuromuscular disorders are a group of disorders that affect various components of the peripheral nervous system, including the anterior horn cells, nerve roots, plexuses, nerves, neuromuscular junctions, and muscles. Dengue viral infection affects all the components of the peripheral nervous system [Table 2]. In this review, we have focused on various neuromuscular complications associated with Dengue virus infection. An extensive review of the published literature was carried out using the PubMed, Scopus and Google Scholar databases. We used the keywords 'dengue and Guillain-Barré syndrome,' 'dengue and myositis,' 'dengue and neurological,' 'dengue and neuropathy,' 'dengue and plexopathy,' and 'dengue and hypokalemic paralysis.'
Table 2: Classification of dengue-associated neuromuscular disorders

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 » Historical Aspects Top


The dengue infection was first described by David Bylon in 1779, in Cairo and Java. [8] The first detailed description of dengue infection was written by Rush during the 1780 dengue epidemic in Philadelphia. [9] Cases of dengue hemorrhagic fever were described in the Philippines in 1952. Ashburn and Craig, in 1907, helped to establish that dengue fever was transmitted by mosquitoes. [10] In 1943, Ren Kimura and Susumu Hotta first isolated the Dengue virus. In 1944, the Dengue virus was also isolated by the American microbiologists, Albert Bruce Sabin and Walter Schlesinger. Thomas, in 1880, had written a treatise regarding the neurological complications of dengue infection. In a detailed description of dengue, he wrote, "partial paralysis is also one of the occasional complications. Peripheral paralysis, or paresis of the fore-arm and brachial muscles, now and then occurs. I have seen cases where the patient could raise the arm above the head, but it would fall immediately to his side again, he manifestly not having the power to hold it there." [11] Ghiannoulatos in 1931, reported a case of dengue-associated severe paralysis during the Athens epidemic (in 1928). In this particular patient, a typical attack of dengue fever was followed by paralysis of both upper and lower limbs (which at that time was described as "pseudotabes"). [12],[13]


 » Epidemiology Top


Over one-third of the world's population is, currently, at risk of developing Dengue virus infection and the disease is endemic in more than 100 countries. The South American, Southeast Asian and the Western Pacific regions are the most seriously affected regions. The World Health Organization reported a worldwide incidence of approximately 50-100 million dengue infections taking place annually. Approximately, 500,000 cases with severe dengue require hospitalization each year. About 22,000 deaths occur every year. Children are more severely affected. [3],[4]

The majority of information regarding dengue-associated neurological complications, including that of neuromuscular disorders, is in the form of isolated case reports and small case series. Many large studies, that were aimed to explore the clinical aspects of dengue fever, recorded infrequent occurrences of neurological (including neuromuscular) complications. For example, in Jamaica, 401 cases of suspected viral neurological infections were evaluated for a possible Dengue virus infection. The frequency of neurological dengue was 13.5% (54/401). Acute flaccid paralysis/Guillain-Barré syndrome was noted in 3.7% (2/54) of the patients. [14] In Pakistan, out of 2313 dengue patients, 60 deaths were reported. The diagnosis, at presentation, was dengue fever in 5 (8.3%), dengue hemorrhagic fever without shock in 16 (26.6%), dengue shock syndrome in 20 (33%), and expanded dengue syndrome in 19 (31.7%) patients. The expanded dengue syndrome included encephalopathy in 12 (20%) patients, intracerebral bleed in 3 (5%) patients, multi-organ failure in 3 (5%) patients, and Guillain-Barré syndrome in 1 (1.6%) patient. [15] In West Bengal, India, the spectrum of dengue fever was analyzed in 300 patients. In this study, 70% of cases developed some type of complications. Approximately, 5% of all patients had central nervous system involvement, 0.66% had rhabdomyolysis and myositis, and 0.33% had secondary vasculitis. Death occurred in 3% of the cases. In the southern part of India, a prospective study was undertaken to document rare manifestations of dengue fever in 175 hospitalized patients. Unusual and rare manifestations of dengue were documented in 115 patients (66%). Neurological complications were seen in 7.4% of patients. [16] In a study from the central part of India, out of 138 serologically confirmed dengue patients, 10 patients had some form of neurological disorders. Hypokalemic paralysis was seen in 2 patients and one patient each had myositis and Gullain-Barre syndrome. [17]

In another study from North India, among 88 hospitalized patients of dengue infection, 12 patients presented with an acute neuromuscular weakness. In the majority, motor weakness developed on the 2 nd -4 th day of illness. Ten of 12 patients showed hypokalemia. Serum creatinine phosphokinase (CPK) and serum glutamic-oxaloacetic the transaminase were raised in 8 out of 12 patients. All of the 12 patients had a low platelet count. Cerebrospinal fluid (CSF) was normal in all the patients. [18] A recent prospective study, focusing on the neurological complications of dengue infection, recorded that 9.26% (45/486) of dengue patients developed nervous system involvement. Seventeen patients had neuromuscular complications. In this study, the significant predictors of peripheral nervous system involvement were a higher mean body temperature, rash, and elevated hematocrit. Among patients with peripheral nervous system involvement, 13% had myositis, and 9% each had dengue-associated hypokalemic paralysis and Guillain-Barre syndrome. Neuralgic amyotrophy, another peripheral nervous system complication, was seen in 7% of dengue infected patients. [19]


 » Muscle Involvement Top


Muscle involvement in patients with dengue infection can manifest with myalgias, myositis, rhabdomyolysis and hypokalemic paralysis.

Myalgia

Myalgia is characterized by pain, tenderness, and mild muscle swelling. Diffuse myalgia is one of the characteristic symptoms of dengue fever and noted during the early phase of the illness. Muscle pain commonly affects the back and proximal limb muscles. Patient may experience difficulty in walking because of muscle pain. [20]

Myalgia has been reported in up to 93% of dengue patients. [21] In a large study from Peru, Bolivia, Ecuador, and Paraguay, among 1716 confirmed dengue cases, 90.1% (n = 1546) of patients experienced myalgia. [22] Myalgia was found to be less frequent among western travellers returning from dengue endemic countries. Among 334 laboratory-positive US residents, who travelled to overseas destinations, myalgia was reported in only 30% of the patients. [23] Adult patients were more likely to have myalgia than pediatric patients. [24],[25] Myalgia was more frequent with Dengue virus−1 (n = 613) and Dengue virus−3 (n = 653) infections, in comparison to Dengue virus−2 (n = 52) and Dengue virus−4 (n = 228) infections. [22]

The exact pathogenesis of myalgia in dengue infection is not precisely known. Possibly, diffuse viral invasion of muscles (at the time of viremia) and the subsequent inflammatory changes in the muscles result in muscle pain.

Electromyography (EMG) is usually normal but in patients with an elevated creatinine phosphokinase (CPK), mild myopathic changes have been recorded. [26] Other histopathological changes that were seen included a mild to moderate perivascular mononuclear infiltrate, lipid accumulation, mild mitochondrial proliferation, few central nuclei, foci of muscle necrosis, and fiber type grouping. [27]

The myalgias are often transient and self-limiting. Severe muscle pain often responds to paracetamol.

Myositis

Myositis is defined as inflammation of skeletal muscles. Myositis is clinically characterized by pure motor weakness of all four limbs. In a series, 40 children of benign acute myositis were evaluated. The dengue virus was positive in 20 (50%) children. CPK was markedly elevated (more than 1000 IU/L) in 18 (45%) patients. CPK was more than 500 IU/L in 11 (27.5%) patients and in the remaining patients, it ranged between 200 and 500 IU/L. Guillain-Barre syndrome was the most common referral diagnosis. [28] Dengue-associated myositis can be of varying severity, ranging from self-limiting mild muscle weakness to severe dengue myositis resulting in complete quadriplegia and respiratory insufficiency. Deaths were also noted in severe cases. [29] Concomitant myocarditis has been reported along with myositis. [30]

In dengue endemic areas, dengue myositis should be included in the differential diagnosis of pediatric acute flaccid paralysis. Dengue myositis in children is usually a benign illness. Dengue myositis is differentiated from other causes of walking difficulty by the presence of calf and thigh muscle tenderness on stretching, normal power and deep tendon reflexes, and an elevated CPK. [27],[31] Dengue myositis, particularly in children, may mimic many other musculo-skeletal disorders, such as traumatic muscle injuries, muscle and joint hematomas, osteomyelitis, or septic arthritis.

After an extensive search, we collected a total 34 studies of dengue-associated myositis that have been reported so far. Dengue-associated myositis is common in a younger age group (range: 3-56 years; mean: 24.6 years; median: 26 years). The majority of affected patients were male (male: female = 26:8). The onset of weakness varies from 3 days to 36 days (mean: 9.4 days; median: 5 days). Muscle weakness is frequently accompanied by muscular pain. Serum CPK is often markedly elevated (mean: 10,558 IU/L; range: 162-117,200 IU/L). In the majority of patients, there was spontaneous and complete recovery (3 died; rest recovered within 7 days). Occasionally, corticosteroids were used. Out of the 28 patients, 2 patients with extensive and severe myositis with bulbar and respiratory involvement died. These 2 patients had markedly elevated serum CPK [Table 3].
Table 3: Review of clinical characteristics, laboratory parameters, and outcome of patients with dengue-associated myositis

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The electromyography (EMG) findings, in general, are consistent with the mild myopathic pattern. EMG usually reveals polyphasic and normal-to-short duration motor unit potentials, but spontaneous activity is absent. In addition, EMG can show early recruitment of motor-unit action potentials with normal morphology. [28]

Muscle edema, hemorrhage, metabolic alterations and changes in vascular endothelial cells are responsible for muscle dysfunction in dengue myositis. Cytokines, such as tumor necrosis factor, released during the viremia, lead to intense inflammation and subsequent damage to muscle fibers. Muscle histopathology, in these patients, revealed the presence of interstitial hemorrhage, myonecrosis and myophagocytosis [26],[31] [Figure 1].

Several pieces of experimental evidence suggest that viral invasion of the muscles possibly occurs during the acute stage of the illness. For example, the virus particles were demonstrated in the spleen, liver, and heart muscles, immediately after the intracerebral inoculation of dengue virus. In this study, dengue type 2 virus was inoculated intracerebrally in 20 adult Swiss albino mice. Thigh muscles were removed after the viral inoculation. Electron microscopic studies of the striated muscles revealed destruction of myofibrils, rarefaction of the sarcoplasmic reticulum network and changes in the mitochondria. Aggregates of electron-dense material, as well as glycogen particles, were also seen in the cytoplasm. [42] In another study, Salgado and co-workers have demonstrated the presence of virus in postmortem samples of heart tissues of a patient with dengue virus myocarditis. These workers, in another set of in vitro experiments, demonstrated that human myoblasts infected with dengue virus resulted in increased expression of the inflammatory genes and protein IP-10 (interferon gamma-induced protein 10) by the myotubes. In addition, the infected myotubes also had elevated intracellular calcium concentration. [43] The dengue virus can infect muscle satellite cells. which are responsible for muscle repair after injury. Dengue virus infection has also been found to impair the ability of dengue virus - infected muscle satellite cells to upregulate myosin heavy chain I protein levels, suggesting that an immune mechanism may be responsible for the muscle damage. [44]
Figure 1: (a - d) Photomicrographs of formalin fixed paraffin embedded muscle biopsy showing extensive interstitial hemorrhage and myophagocytosis of interspersed muscle fibers (arrows). No inflammatory infiltrate is evident (H and E, ×100; ×200; ×200; ×100, respectively). (d) Photomicrograph of formalin fixed paraffin embedded muscle biopsy showing splaying of muscle fibres with interstitial hemorrhage (straight arrow). There is suggestion of lipid accumulation (curved arrow) in addition (H and E, ×100)

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Dengue-associated myositis usually resolves spontaneously, and most patients do not require any treatment. Corticosteroids have no definite role to play.

Hypokalemic paralysis

Hypokalemic paralysis is characterized by muscle weakness or paralysis with a rapid fall in blood potassium level. Dengue-associated hypokalemic paralysis has extensively been reported from the Indian subcontinent, frequently during dengue epidemics. These patients present with acute, pure, severe motor paralysis of all the four limbs. Dengue-associated hypokalemic paralysis often has a rapidly evolving course, benign nature, and an excellent response to potassium administration. [18],[45]

So far, reports of a total of 42 cases of dengue-associated hypokalemic paralysis are available on a literature search. Analysis of available reports indicates a wide age range of 3-62 years (mean 30.1 years and median 28 years) of the affected patients. The majority of affected patients were male (male: female = 15:1). The onset of weakness occurred on an average between 2 nd and 5 th day of fever; it developed over a period of 4-24 h. In the majority of patients, deep tendon reflexes were usually absent or diminished. The mean potassium levels were 2.23 (range: 1.4-3.5; median: 2.2) meq/L while the mean platelet count was 76583.3/mm 3 (20,000-240,000; median 68,500/mm 3 ). CPK levels were also usually elevated to a mean of 553.2 (range: 45-2646; median: 451) IU/L. Nerve conduction studies and EMG had not been adequately performed. Available EMG data suggested normal study in the majority of patients. The recovery was quick following oral or intravenous potassium administration [Table 4].
Table 4: Review of clinical characteristics, laboratory parameters, and outcome of patients with dengue-associated hypokalemic paralysis

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The precise significance of raised creatine phosphokinase enzyme level during or after the attacks of hypokalemic paralysis is not clear. Comi and co-workers described 6 patients with a clinical presentation similar to that of dengue-associated hypokalemic paralysis as "potassium depletion myopathy." In all these patients, pathological muscle examination revealed evidence of damage to muscle fibers along with fiber regeneration. The clinical manifestations and morphological changes had reversed after potassium repletion. It has been suggested that hypokalemia leads to vasoconstriction and subsequent muscle ischemia resulting in elevation in CPK levels. [61]

Guillain-Barre syndrome is the single most important differential diagnosis of hypokalemic paralysis. This differentiation is crucial because patients with dengue-associated Guillain-Barre syndrome may require treatment with intravenous immunoglobulins. On the contrary, patients with dengue-associated hypokalemic paralysis quickly improve soon after potassium is administered. Both conditions present with areflexic quadriparesis. Some asymmetricity in reflexes (one or two reflexes may be intact) along with preserved sensations and a flexor plantar response may also be observed. Another differential diagnosis of dengue-associated hypokalemic paralysis is the first attack of hypokalemic periodic paralysis. Usually, the patients of hypokalemic periodic paralysis are younger (presenting in the first or second decade), may have a family history and a probable precipitating event, and usually require potassium administration for immediate recovery [45] [Table 5].
Table 5: Differential diagnosis of dengue-associated myositis, hypokalemic paralysis and Guillain-Barre syndrome

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The exact mechanism responsible for hypokalemic paralysis in patients with dengue infection is not known. The postulated mechanisms of hypokalemia are redistribution of potassium ions in the cells and transient renal tubular abnormalities leading to increased urinary potassium wasting. Redistribution of potassium in the cells possibly occurs due to increase in catecholamine levels and secondary insulin release. Hypokalemia in dengue is reported in up to 70% patients, but patients seldom develop paralysis. A genetic susceptibility is the likely explanation. Hypokalemic periodic paralysis has been found to be associated with mutations in two skeletal muscle genes. Most cases occur due to mutations in the alpha subunit of the L-type calcium channel gene (CACNA14) and some cases are observed secondary to mutations in the alpha subunit of the sodium channel gene (SCN4A). It is probable that dengue-associated hypokalemic paralysis represents some kind of channelopathy. [45]

Dengue-associated hypokalemic paralysis is responsive to even low doses of potassium supplementation. Recovery is rapid, complete (within 48 h) and without any residual deficits. Available data suggests that recovery usually starts between 6 and 12 h. The mean duration of complete recovery is 35.75 (4-120) h.

Rhabdomyolysis

Rhabdomyolysis is the most severe form of muscle involvement in a dengue infected patient. When plasma myoglobin exceeds 0.5-1.5 mg/dl, it leaks into the urine. Rhabdomyolysis is characterized by myalgia, elevated serum creatine kinase (at least 10 times of the upper limit) and myoglobinuria. [62],[63] During the summer of 2012, during the dengue fever epidemic in Kolkata, the spectrum of dengue fever was analyzed in 300 dengue infected patients. Approximately 70% cases developed some complications and 0.66% patients had rhabdomyolysis and myositis. [64] Studies of muscle biopsy specimens have revealed a range of findings from mild lymphocytic infiltrate to foci of severe muscle damage. [27]

We reviewed reports of 14 patients, available in the literature so far. Rhabdomyolysis occurred mainly in male patients (except in two female patients out of which one was suffering from systemic lupus erythematosus) of younger age (mean: 35.9 years; range: 17-66 years). Rhabdomyolysis occurred following an episode of fever of usually a week's duration (range 4-20 days; mean: 7.9 days; median 5.5 days). The serum CPK was markedly elevated (mean: 112482.9 IU/L; range: 99-742,900 IU/L; median: 48410 IU/L). The platelet count was often low (mean: 66818.2/mm 3 ; range: 6000-292,000/mm 3 ; median: 36000/mm 3 ) [Table 6].
Table 6: Review of clinical characteristics, laboratory parameters, and outcome of patients with dengue-associated rhabdomyolysis

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The most likely cause of dengue-induced rhabdomyolysis is cytokine-mediated damage of muscle cells. Cytokines, particularly tumor necrosis factor and interferon alpha, are released in response to a dengue viral infection. [77],[78] The subsequent mechanism involved in the damage of muscle tissue is an increase in intracellular free calcium, caused by depletion of adenosine triphosphate and/or by direct injury and disruption of the plasma membrane. Increased intracellular calcium results in a cascade of chemical reactions (like activation of proteases, mitochondrial abnormalities, and excessive production of reactive oxygen species) that are detrimental to muscle cells. Cellular changes ultimately result in muscle cell death.

Rhabdomyolysis can lead to acute renal failure and life-threatening electrolyte disturbances. However, if recognized early, these complications may easily be prevented. Usually, patients respond to treatment but some patients die because of multi-organ failure. Renal injury was demonstrated in an isolated case report with a renal biopsy. [76]

In most mild cases, adequate hydration, that is an essential component of the standard of care for dengue, will help in recovery from rhabdomyolysis. Progression to renal dysfunction may require hemodialysis.

Myoneural junction

There is an isolated case report about worsening of symptoms of myasthenia gravis following a dengue infection. This particular case, a 36-year-old female with myasthenia gravis, noticed exacerbation of symptoms such as difficulty in swallowing, difficulty in opening eyelids and an increasing difficulty in breathing. Her symptoms improved along with the resolving dengue infection. [79] There are some other reports on the occurence of myasthenia gravis following other flavivirus infections as well. Virus-induced autoimmunity, possibly, led to myasthenia. [80] This association is contentious since myasthenia can worsen with any infection and the cause and effect relationship with dengue infection cannot be established with certainty.


 » Nerve Involvement Top


The various kinds of nerve involvement in patients with dengue infection are polyneuropathies, mononeuropathies, plexopathies and anterior horn cell involvement.

Guillain-Barré syndrome

Guillain-Barré syndrome is characterized by a rapidly evolving and symmetrical weakness of limbs. Classically, weakness progresses for a mean period of 10 days (up to 4 weeks) and after 1-2 weeks starts recovering spontaneously. [81] Guillain-Barré syndrome is broadly divided into two major subtypes: Acute inflammatory demyelinating polyneuropathy and the axonal subtypes, acute motor axonal neuropathy and acute motor and sensory axonal neuropathy.

Guillain-Barré syndrome is a frequent neuromuscular complication following a dengue virus infection. [48] In a report from Brazil during a dengue endemic, among 15 patients with Guillain-Barré syndrome, 7 cases (46.6%) tested positive for a dengue infection. Two of them had IgM dengue antibodies in CSF as well. [82]

We reviewed 17 reports (of 29 patients) having the association of Guillain-Barré syndrome with dengue infection. Guillain-Barré syndrome has been reported in dengue patients of all age groups (range: 18 months to 79 years; mean: 37.7 years; median: 40 years) and is equally common in both the sexes. Guillain-Barré syndrome in dengue infection usually occurs within 2 weeks (mean: 11.4 days; range: 2-30 days) of fever. Patients are usually afebrile by the time neurological manifestations appear. The majority of patients had a low platelet count while the patient was developing weakness, suggesting that Guillain-Barré syndrome was a manifestation of the active dengue infection. Usually, electrophysiology demonstrates demyelinating changes. The acute pure axonal motor-sensory variant of Guillain-Barré syndrome has also been described after the dengue virus infection. The CSF analysis often shows albuminocytological dissociation (raised protein and normal cell count) [Table 7].
Table 7: Review of clinical characteristics, laboratory parameters, and outcome of patients with dengue-associated Guillain-Barre syndrome

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In an isolated instance, Miller Fisher's syndrome has been observed following dengue virus infection. A 57-year-old-man developed a left-sided ophthalmoplegia associated with ataxia and areflexia while he had fever (39°C) for 2 days. Dengue fever was diagnosed by a definite criteria (IgM seroconversion, positive culture from serum and positive polymerase chain reaction, both in serum and CSF). Patient spontaneously recovered within a week. [85]

Excellent response to intravenous immunoglobulins suggests that dengue-associated Guillain-Barré syndrome is no different from other postinfectious Guillain-Barré syndromes. In patients with dengue-associated Guillain-Barré syndrome, the mean time to ambulate was 23.7 (range: 7-60) days.

Mononeuropathies

Mononeuropathies and mononeuritis multiplex following a dengue infection have frequently been described. In the 1940s, 13 military men in the central Pacific had mononeuropathies, 5-30 days after dengue fever resolution. In this series, the affected nerves were facial, palatal, long thoracic, peroneal and ulnar nerves. Two patients made a complete recovery while 7 patients had persistent weakness even after several months. [101] We, after a review of the literature, came across 6 more recent reports describing the involvement of a single peripheral nerve. Mononeuropathies, in dengue infected persons, manifested as paralysis of the diaphragm due to phrenic nerve dysfunction. Three patients with paralysis of the diaphragm had cough and breathlessness. Imaging showed an elevated diaphragm. Electrophysiology in all 3 cases revealed abnormalities of the phrenic nerve. We did not include patients with cranial mononeuropathies in this group. [102],[103],[104] An immune-mediated mechanism has been suggested for post-viral phrenic neuropathy. Dengue-associated mononeuropathies have a self-limiting course and do not require any specific treatment. Another mechanism responsible for mononeuropathies is compression of the nerve trunk in a hematoma. A low platelet count is usually responsible for the hematoma formation [105] [Table 8].
Table 8: Review of clinical characteristics, laboratory parameters, and outcome of patients with dengue-associated plexopathy/mononeuropathy

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Plexopathies

In dengue infected patients, a brachial plexopathy (neuralgic amyotrophy) has been described much more frequently than a lumbo-sacral plexopathy. [106] Patients with neuralgic amyotrophy present with an acute and severe shoulder pain, followed by weakness and wasting of the shoulder girdle muscles. All patients with dengue-associated brachial plexopathy had a self-resolving course. [37]

A patient with lumbar plexopathy presented with bilateral foot drop. In this patient, the lumbar plexus was compressed by a hematoma (because of a low platelet count) at the right inguinal and suprapubic region. This patient improved following the hematoma evacuation [36] [Table 8].

Anterior horn cells

Many flavivirus infections (like Japanese encephalitis) are known to manifest as a poliomyelitis-like syndrome. In an isolated report, predominant spinal gray matter involvement was reported in a dengue infected patient. This particular patient had the presence of dengue-associated myelitis but the clinical manifestations were unusual because upper motor neuron signs were not observed. Instead, there were dominant lower motor neuron signs in the form of atrophy and fasciculations. MRI revealed signal changes restricted to the gray matter of the spinal cord that preferentially corresponded to the anterior horn from the lower cervical to the upper thoracic cord. In this patient, the gray matter involvement was similar to that seen in poliomyelitis. [109]


 » Postinfectious Fatigue Syndrome Top


Postinfectious fatigue syndrome is defined as persisting fatigue and disability after apparent acute infections. In a study, among 250 dengue affected western travellers, postinfectious fatigue syndrome was reported in 8 (3.2%) patients. In a multivariate analysis, increased age, female sex, the presence of chills, and the absence of rashes were significantly associated with the development of fatigue in post-dengue infection. Five patients (2%) developed signs of dengue hemorrhagic fever, with petechial bleeding and thrombocytopenia. Two of the 10 patients had signs of hepatitis, 1 from an extended fatigue syndrome. All patients recovered from their respective ailments.

The mechanism for fatigue following the dengue infection is not known. Post-infectious fatigue syndrome is possibly a consequence of systemic immune alterations (triggered by the dengue virus). It has also been postulated that interactions of the immunological, endocrinal, musculoskeletal and neurological systems, possibly through the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, result in fatigue syndrome. [110]


 » Conclusion Top


A wide variety of neurological complications have been reported in dengue infected patients. In endemic countries, during the outbreak of dengue, the presence of dengue infection should always be considered if a patient presents with flaccid quadriparesis. The three major complications, myositis, hypokalemic paralysis and Guillain-Barré syndrome manifest with flaccid quadriparesis. Occasionally, these complications may even be life-threatening. Dengue is also associated with many infrequent but disabling complications such as plexopathies and mononeuropathies. Early recognition is needed for successful treatment and for preventing death and disabilities.

No specific treatment option against dengue is available. The current treatment is largely supportive. Neurological manifestations can be life-threatening, and prevention of dengue is the only option available. Vector control measures are generally effective in controlling dengue spread in the community but in many endemic regions, availability of vector control measures is dismal. An effective vaccine, which is likely to be available for human use soon, will go a long way in preventing the disabling neurological complications of the dengue virus infection.

 
 » References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]

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[Pubmed] | [DOI]



 

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