Zika and Guillain-Barré Syndrome

**89**

**Chapter 6**

Disease

**Abstract**

**1. Introduction**

**1.1 History**

*Raafat Hammad Seroor Jadah*

Guillain-Barre Syndrome and

Miller Fisher Variant in Zika Virus

Guillain-Barre syndrome (GBS) is a serious neurological disorder associated with a rapid progressive ascending muscle paralysis, and it is the most common neurological autoimmune disorder that affects the peripheral nervous system, which is usually triggered by viral or bacterial infection. GBS is rare in children and characterized by rapid progressive onset ascending muscle weakness associated with pain and sensory dysfunction. Miller Fisher syndrome (MFS), a variant of GBS, is rare in pediatric population which is typically manifested by ataxic gait, ophthalmoplegia, and areflexia since it is rare in children. It is vitally important to early diagnose this condition and to initiate early treatment to prevent further complications and long-term morbidity. Since the outbreak of Zika virus, the incidence of GBS has been increased. Zika virus associated with autoimmune anti-ganglioside antibodies trigger which lead to GBS development. Zika virus infection should be strongly considered in patients who present with classical signs of Miller Fisher syndrome, especially travelers and residents from endemic areas.

**Keywords:** Guillain-Barre, Miller Fisher, autoimmune, Zika, outbreak, ataxia

system causing a rapid progressive demyelinating polyneuropathy [2, 3].

In 1916, two French Neurologists Georges Charles Guillain and Jean Alexandre Barre and French Physiologist Andre Strohl reported an original paper encountered new syndrome in two soldiers with muscle weakness, absence of deep tendon reflexes and sensory impairment and described the key diagnosis of albumincytologic disassociation in the cerebrospinal fluid along with changes in electromyography and nerve conduction studies. Both patients were managed with massage therapy and Strychnine injection and showed clinical recovery after few months [1]. GBS is rare but the commonest cause for acute ascending paralytic polynephropathy. GBS is considered to be an acute immune-mediated disorder that causes peripheral polyneuropathy. Most cases of GBS are preceded by either viral or bacterial infection, which triggers the immune system affecting the peripheral nervous

The incidence of GBS has been increased since the outbreak of certain infections such as Zika virus epidemic in Latin America in 2015. GBS is the most leading cause of acute ascending muscle paralysis with an annual incidence of 1–2 per 100,000 persons per year worldwide. GBS is more common in males than females [2, 3].

## **Chapter 6**

## Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease

*Raafat Hammad Seroor Jadah*

## **Abstract**

Guillain-Barre syndrome (GBS) is a serious neurological disorder associated with a rapid progressive ascending muscle paralysis, and it is the most common neurological autoimmune disorder that affects the peripheral nervous system, which is usually triggered by viral or bacterial infection. GBS is rare in children and characterized by rapid progressive onset ascending muscle weakness associated with pain and sensory dysfunction. Miller Fisher syndrome (MFS), a variant of GBS, is rare in pediatric population which is typically manifested by ataxic gait, ophthalmoplegia, and areflexia since it is rare in children. It is vitally important to early diagnose this condition and to initiate early treatment to prevent further complications and long-term morbidity. Since the outbreak of Zika virus, the incidence of GBS has been increased. Zika virus associated with autoimmune anti-ganglioside antibodies trigger which lead to GBS development. Zika virus infection should be strongly considered in patients who present with classical signs of Miller Fisher syndrome, especially travelers and residents from endemic areas.

**Keywords:** Guillain-Barre, Miller Fisher, autoimmune, Zika, outbreak, ataxia

## **1. Introduction**

#### **1.1 History**

In 1916, two French Neurologists Georges Charles Guillain and Jean Alexandre Barre and French Physiologist Andre Strohl reported an original paper encountered new syndrome in two soldiers with muscle weakness, absence of deep tendon reflexes and sensory impairment and described the key diagnosis of albumincytologic disassociation in the cerebrospinal fluid along with changes in electromyography and nerve conduction studies. Both patients were managed with massage therapy and Strychnine injection and showed clinical recovery after few months [1].

GBS is rare but the commonest cause for acute ascending paralytic polynephropathy. GBS is considered to be an acute immune-mediated disorder that causes peripheral polyneuropathy. Most cases of GBS are preceded by either viral or bacterial infection, which triggers the immune system affecting the peripheral nervous system causing a rapid progressive demyelinating polyneuropathy [2, 3].

The incidence of GBS has been increased since the outbreak of certain infections such as Zika virus epidemic in Latin America in 2015. GBS is the most leading cause of acute ascending muscle paralysis with an annual incidence of 1–2 per 100,000 persons per year worldwide. GBS is more common in males than females [2, 3].

GBS is a rapid demyelinating peripheral neuropathy that typically manifest as ascending muscle weakness that is symmetric in nature associated with reduced or absent deep tendon reflexes. GBS has been also associated with pain along with sensory impairment [4].

GBS is an acute immune-mediated demyelinating polyneuropathy and it is the commonest cause of acute muscle paralysis in pediatric age group patients [5, 6].

MFS is a rare neurological disorder which was initially recognized in 1932 by James Collier as a classical triad of ophthalmoplegia, ataxia and absent deep tendon reflexes. Later in 1956 Charles Miller Fisher a Canadian Neurologist described and reported details isolated clinical entity of three patients who presented with ophthalmoplegia, ataxia and areflexia [7].

MFS has an annual incidence of 0.9 per 1000,000 populations and affect males more than females at ratio of 2:1 and commonly affect Asian population especially at their fourth decade of life [7].

MFS most commonly preceded by *Campylobacter jejuni* infection and has strong association with positive anti-GQ1b antibodies [7].

Zika virus infection has been associated with different neurological disorders such as microcephaly and since the initial outbreak of Zika virus infection the number of GBS cases has been increased in endemic countries [8].

## **2. Pathophysiology and immunopathology**

The neurological symptoms and signs of GBS usually take place 4 weeks after the initial respiratory or gastrointestinal infection which account for about

**91**

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease*

two-third of GBS cases in adult population. The immune system will be stimulated secondary to infectious antigen with *Campylobacter jejuni* (*C. jejuni*) being the most common infectious pathogenic agent which account for 25–50% of adult GBS cases [9]. These infectious antigens cause stimulation of both cellular and hormonal systems leading to axonal damage and demyelination of the peripheral nerve and

Monocytes, T-cells, especially CD4+ T-helper cells and B-cells in order of frequency, have been commonly implicated in the immunopathology of GBS cases especially in the acute inflammatory demyelinating polyradiculoneuropathy

More than 80% of the patients with Miller Fisher syndrome have anti-GQ1b IgG antibodies which mainly activate the compliment system especially at the presynaptic nerve ending and perisynaptic Schwann cells which has been implicated in the

GBS is a rapid inflammatory ascending symmetric muscle weakness associated with reduced or complete absent of deep tendon reflexes. The most common symptom is inability to walk. The frequent findings on the clinical examination include hyperesthesia, autonomic dysfunction, sensory loss, ataxia, bilateral facial nerve

A number of clinical subtypes of Guillain-Barre Syndrome (GBS) are identified. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is considered to be the most common subtype and account for approximately of 90 percent of GBS patients in the Unites States. Patients with this subtype typically present with progressive ascending symmetric muscle weakness and areflexia associated with severe pain and autonomic dysfunction such as fluctuation in blood pressure, urinary incontinence or syncope. This clinical subtype typically shows a slow nerve conduction velocity with no clear anti-ganglioside antibodies

Other subtype of GBS is the acute motor axonal neuropathy (AMAN) that accounts for 5% of Guillain-Barre syndrome (GBS) patients in United States. This subtype purely presents with motor weakness without sensory symptoms. Nerve conduction study shows axonal polyneuropathy with normal sensory nerve action potential. Patients with acute motor axonal motor neuropathy have strong association with *Campylobacter jejuni* (*C. jejuni*) infection with positive antibodies against

The acute motor-sensory axonal neuropathy (AMSAN) is a rare and severe variant of GBS [15], which has similar clinical features to acute motor axonal neuropathy but with predominantly sensory loss and positive antibodies against GM1 and GD1a. Nerve conduction study showed axonal polyneuropathy with reduced or

The pharyngeal-cervical brachial syndrome (PCB) is another rare subtype of GBS [16]. Patient with PCB syndrome typically present with rapid and progressive oropharyngeal and shoulder muscle weakness associated with absent deep tendon reflexes in the upper limbs. The nerve conduction study in patients with PCB syndrome is generally normal but sometimes showed axonal neuropathy in the arms.

PCB syndrome associated with positive IgG anti-GT1a antibodies [17].

*DOI: http://dx.doi.org/10.5772/intechopen.93128*

nerve roots (**Figure 1**) [11].

pathogenesis of MFS [11, 12].

palsy and third cranial nerve palsy [4, 13].

**3.1 Clinical subtypes of Guillain-Barre syndrome (GBS)**

gangliosides GM1, GD1a, GaINac-GD1a and GD1b [14].

absent sensory nerve action potential [14].

**3. Clinical features**

association [14].

(AIDP) [11].

**Figure 1.** *Basic structure of motor neuron [10].*

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease DOI: http://dx.doi.org/10.5772/intechopen.93128*

two-third of GBS cases in adult population. The immune system will be stimulated secondary to infectious antigen with *Campylobacter jejuni* (*C. jejuni*) being the most common infectious pathogenic agent which account for 25–50% of adult GBS cases [9]. These infectious antigens cause stimulation of both cellular and hormonal systems leading to axonal damage and demyelination of the peripheral nerve and nerve roots (**Figure 1**) [11].

Monocytes, T-cells, especially CD4+ T-helper cells and B-cells in order of frequency, have been commonly implicated in the immunopathology of GBS cases especially in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) [11].

More than 80% of the patients with Miller Fisher syndrome have anti-GQ1b IgG antibodies which mainly activate the compliment system especially at the presynaptic nerve ending and perisynaptic Schwann cells which has been implicated in the pathogenesis of MFS [11, 12].

## **3. Clinical features**

*Current Concepts in Zika Research*

sensory impairment [4].

thalmoplegia, ataxia and areflexia [7].

association with positive anti-GQ1b antibodies [7].

**2. Pathophysiology and immunopathology**

number of GBS cases has been increased in endemic countries [8].

at their fourth decade of life [7].

GBS is a rapid demyelinating peripheral neuropathy that typically manifest as ascending muscle weakness that is symmetric in nature associated with reduced or absent deep tendon reflexes. GBS has been also associated with pain along with

GBS is an acute immune-mediated demyelinating polyneuropathy and it is the commonest cause of acute muscle paralysis in pediatric age group patients [5, 6]. MFS is a rare neurological disorder which was initially recognized in 1932 by James Collier as a classical triad of ophthalmoplegia, ataxia and absent deep tendon reflexes. Later in 1956 Charles Miller Fisher a Canadian Neurologist described and reported details isolated clinical entity of three patients who presented with oph-

MFS has an annual incidence of 0.9 per 1000,000 populations and affect males more than females at ratio of 2:1 and commonly affect Asian population especially

MFS most commonly preceded by *Campylobacter jejuni* infection and has strong

Zika virus infection has been associated with different neurological disorders such as microcephaly and since the initial outbreak of Zika virus infection the

The neurological symptoms and signs of GBS usually take place 4 weeks after the initial respiratory or gastrointestinal infection which account for about

**90**

**Figure 1.**

*Basic structure of motor neuron [10].*

GBS is a rapid inflammatory ascending symmetric muscle weakness associated with reduced or complete absent of deep tendon reflexes. The most common symptom is inability to walk. The frequent findings on the clinical examination include hyperesthesia, autonomic dysfunction, sensory loss, ataxia, bilateral facial nerve palsy and third cranial nerve palsy [4, 13].

#### **3.1 Clinical subtypes of Guillain-Barre syndrome (GBS)**

A number of clinical subtypes of Guillain-Barre Syndrome (GBS) are identified. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is considered to be the most common subtype and account for approximately of 90 percent of GBS patients in the Unites States. Patients with this subtype typically present with progressive ascending symmetric muscle weakness and areflexia associated with severe pain and autonomic dysfunction such as fluctuation in blood pressure, urinary incontinence or syncope. This clinical subtype typically shows a slow nerve conduction velocity with no clear anti-ganglioside antibodies association [14].

Other subtype of GBS is the acute motor axonal neuropathy (AMAN) that accounts for 5% of Guillain-Barre syndrome (GBS) patients in United States. This subtype purely presents with motor weakness without sensory symptoms. Nerve conduction study shows axonal polyneuropathy with normal sensory nerve action potential. Patients with acute motor axonal motor neuropathy have strong association with *Campylobacter jejuni* (*C. jejuni*) infection with positive antibodies against gangliosides GM1, GD1a, GaINac-GD1a and GD1b [14].

The acute motor-sensory axonal neuropathy (AMSAN) is a rare and severe variant of GBS [15], which has similar clinical features to acute motor axonal neuropathy but with predominantly sensory loss and positive antibodies against GM1 and GD1a. Nerve conduction study showed axonal polyneuropathy with reduced or absent sensory nerve action potential [14].

The pharyngeal-cervical brachial syndrome (PCB) is another rare subtype of GBS [16]. Patient with PCB syndrome typically present with rapid and progressive oropharyngeal and shoulder muscle weakness associated with absent deep tendon reflexes in the upper limbs. The nerve conduction study in patients with PCB syndrome is generally normal but sometimes showed axonal neuropathy in the arms. PCB syndrome associated with positive IgG anti-GT1a antibodies [17].

Miller Fisher syndrome is one of the GBS variant. It is an uncommon neurological disorder which account of about 5% of GBS cases. Patients with Miller Fisher syndrome typically present with clinical trial of ophthalmoplegia which is bilateral symmetric in most patients, ataxia and absent deep tendon reflexes. The commonest initial presenting symptoms in patients with Miller Fisher syndrome is diplopia (double vision) which is due to acute onset-ophthalmoplegia. Other less frequent signs and symptoms of MFS include headache, difficulty swallowing and photophobia (**Table 1**). MFS is an immune-mediated neurological disorder and more than 80% of patients with MFS showed positive IgG anti-GQ1b antibodies. Electrophysiological findings in patients with MFS commonly showed reduced sensory nerve action potentials and absent H reflexes (**Figure 2** and **Table 2**) [7, 12, 18].

Bickerstaff brainstem encephalitis currently considered to be another variant of Fisher syndrome associated with central nervous system involvement. Patients with Bickerstaff brainstem encephalitis typically present with ophthalmoplegia, ataxia, hyperreflexia and altered sensorium [19].

Bickerstaff brainstem encephalitis is an immune-mediated neurological disorder usually preceded by infection and associated with positive anti-GQ1b antibodies [19].


#### **Table 1.**

*Clinical symptoms associated with MFS.*

**93**

virus [28].

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease*

**Type Clinical symptoms Electrophysiological** 

Muscle weakness with sensory and autonomic dysfunction

Muscle weakness with no sensory impairment

Muscle weakness with sensory involvement

Oropharyngeal and shoulder muscle weakness

ataxia and areflexia

**findings**

velocity

Axonal

Axonal

potential

arms

Slow nerve conduction

polyneuropathy with normal sensory nerve action potential

polyneuropathy with absent or reduced sensory nerve action

Generally normal, occasional axonal neuropathy in the

Reduced sensory nerve action potential and absent H-reflexes

**Serological tests**

No clear anti-ganglioside antibodies association

Positive anti-ganglioside antibodies GM1, GD1a, GaINac-GD1a, and

Positive antibodies against GM1 and GD1a

Positive IgG anti-GT1a

Positive IgG anti-GQ1b

antibodies

antibodies

GD1b

Zika virus belongs to the virus family Flaviviridae. This virus was first isolated in 1947 from a monkey in the Zika forest of Uganda. Zika virus spread mainly by Aedes mosquitos as well as by intrauterine transmission, blood and sexual intercourse [20]. Most cases of Zika virus infection are associated with mild symptoms such as fever, headache, maculopapular skin rash, red eyes (conjunctivitis) and

The outbreak of Zika virus infection in Brazil in 2015 has been associated with a more serious neurological complication such as Guillain-Barre syndrome [24]. This outbreak has been also resulted in increase in the incidence of babies with micro-

During Zika outbreak in Brazil, patients who developed Guillain-Barre syndrome secondary to Zika virus infection were found to have a higher level of antiganglioside antibodies of both IgM and IgG isotypes as compared to other patients

Since Zika virus associated with serious devastating neurological complications such as Guillain-Barre syndrome and congenital anomalies in the newborn babies, several methods have been developed in order to detect the virus in early course of infection. Nonstructural protein 1 (NS1) is considered to be an essential biomarker for early detection and diagnosis of Zika virus. The development of double-antibody sandwich ELISA (DAS-ELISA) has been also used for early and rapid detection of ZIKA-NS1 protein in patients who newly infected with Zika

At the present time, there is no antiviral treatment or specific vaccines approved for patients infected with Zika virus. Supportive care remains the main modality of managing these patients, yet the challenge remains to prevent congenital Zika

*DOI: http://dx.doi.org/10.5772/intechopen.93128*

Miller Fisher syndrome Ophthalmoplegia,

*Summary of the clinical subtypes of Guillain-Barre syndrome.*

Acute inflammatory demyelinating polyradiculoneuropathy

Acute motor axonal neuropathy

Acute motor-sensory axonal neuropathy

Pharyngeal-cervical brachial variant

**Table 2.**

joint or muscle pain [21–23].

with Zika infection in the absence of GBS [27].

syndrome in pregnant women [29].

cephaly [25, 26].

**Figure 2.** *Percentage of different subtypes of GBS [14, 18].*

**Type Clinical symptoms Electrophysiological findings Serological tests** Acute inflammatory demyelinating polyradiculoneuropathy Muscle weakness with sensory and autonomic dysfunction Slow nerve conduction velocity No clear anti-ganglioside antibodies association Acute motor axonal neuropathy Muscle weakness with no sensory impairment Axonal polyneuropathy with normal sensory nerve action potential Positive anti-ganglioside antibodies GM1, GD1a, GaINac-GD1a, and GD1b Acute motor-sensory axonal neuropathy Muscle weakness with sensory involvement Axonal polyneuropathy with absent or reduced sensory nerve action potential Positive antibodies against GM1 and GD1a Pharyngeal-cervical brachial variant Oropharyngeal and shoulder muscle weakness Generally normal, occasional axonal neuropathy in the arms Positive IgG anti-GT1a antibodies Miller Fisher syndrome Ophthalmoplegia, ataxia and areflexia Reduced sensory nerve action potential and Positive IgG anti-GQ1b antibodies

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease DOI: http://dx.doi.org/10.5772/intechopen.93128*

#### **Table 2.**

*Current Concepts in Zika Research*

**Table 2**) [7, 12, 18].

hyperreflexia and altered sensorium [19].

• Double vision (diplopia): most common

• Difficulty swallowing (dysphagia) • Light intolerance (photophobia)

*Clinical symptoms associated with MFS.*

• Abnormal gait (ataxia) • **Less frequent symptoms**

• Headache

**Table 1.**

Miller Fisher syndrome is one of the GBS variant. It is an uncommon neurological disorder which account of about 5% of GBS cases. Patients with Miller Fisher syndrome typically present with clinical trial of ophthalmoplegia which is bilateral symmetric in most patients, ataxia and absent deep tendon reflexes. The commonest initial presenting symptoms in patients with Miller Fisher syndrome is diplopia (double vision) which is due to acute onset-ophthalmoplegia. Other less frequent signs and symptoms of MFS include headache, difficulty swallowing and photophobia (**Table 1**). MFS is an immune-mediated neurological disorder and more than 80% of patients with MFS showed positive IgG anti-GQ1b antibodies. Electrophysiological findings in patients with MFS commonly showed reduced sensory nerve action potentials and absent H reflexes (**Figure 2** and

Bickerstaff brainstem encephalitis currently considered to be another variant of Fisher syndrome associated with central nervous system involvement. Patients with Bickerstaff brainstem encephalitis typically present with ophthalmoplegia, ataxia,

Bickerstaff brainstem encephalitis is an immune-mediated neurological disorder usually preceded by infection and associated with positive anti-GQ1b antibodies [19].

**92**

**Figure 2.**

*Percentage of different subtypes of GBS [14, 18].*

*Summary of the clinical subtypes of Guillain-Barre syndrome.*

Zika virus belongs to the virus family Flaviviridae. This virus was first isolated in 1947 from a monkey in the Zika forest of Uganda. Zika virus spread mainly by Aedes mosquitos as well as by intrauterine transmission, blood and sexual intercourse [20]. Most cases of Zika virus infection are associated with mild symptoms such as fever, headache, maculopapular skin rash, red eyes (conjunctivitis) and joint or muscle pain [21–23].

absent H-reflexes

The outbreak of Zika virus infection in Brazil in 2015 has been associated with a more serious neurological complication such as Guillain-Barre syndrome [24]. This outbreak has been also resulted in increase in the incidence of babies with microcephaly [25, 26].

During Zika outbreak in Brazil, patients who developed Guillain-Barre syndrome secondary to Zika virus infection were found to have a higher level of antiganglioside antibodies of both IgM and IgG isotypes as compared to other patients with Zika infection in the absence of GBS [27].

Since Zika virus associated with serious devastating neurological complications such as Guillain-Barre syndrome and congenital anomalies in the newborn babies, several methods have been developed in order to detect the virus in early course of infection. Nonstructural protein 1 (NS1) is considered to be an essential biomarker for early detection and diagnosis of Zika virus. The development of double-antibody sandwich ELISA (DAS-ELISA) has been also used for early and rapid detection of ZIKA-NS1 protein in patients who newly infected with Zika virus [28].

At the present time, there is no antiviral treatment or specific vaccines approved for patients infected with Zika virus. Supportive care remains the main modality of managing these patients, yet the challenge remains to prevent congenital Zika syndrome in pregnant women [29].

### **4. Diagnosis of Guillain-Barre syndrome and Miller Fisher variant**

The diagnosis of GBS and Miller Fisher variant is often made clinically based on the symptoms and clinical signs of the patients [30]. A more detail and supporting investigational studies such cerebrospinal fluid (CSF) analysis, electrophysiological tests such as nerve conduction studies, ultrasonographic and MRI imaging along with serologic testing can be carried out to confirm the diagnosis of GBS and other variants such as MFS [31].

Electrophysiological findings in patients with GBS suggestive of demyelination process in the form of reduce motor conduction velocity (MCV), prolonged motor distal latency and increase F wave latency. The findings of conduction block with absent H-reflex are considered to be the commonest and early sign in GBS [32].

Patients with Fisher-Bickerstaff syndrome (FBS) typically showed sensory axonal neuropathy in the form of reduced sensory nerve action potential (SNAP) amplitude in the absence of demyelination parameters [33].

The use of imaging studies such as peripheral nerve ultrasound and MRI are helpful diagnostic tools to diagnose inflammatory peripheral nerve roots [34].

The findings of MRI findings in patients with Miller-Fisher syndrome can range from cranial nerve involvement especially the optic nerve to severe cerebral white matter lesions [35, 36].

Another important biomarker which help confirming the diagnosis of GBS is the cerebrospinal fluid (CSF) analysis which typically show albuminocytologic dissociation (elevated protein level with normal cell count in cerebrospinal fluid) which has been also seen in patients with MFS and Bickerstaff brainstem encephalitis [37].

Although the diagnosis of MFS is based mainly on the classical trial of ophthalmoplegia, areflexia and ataxia which developed approximately within 1 week to 10 days after the initial infection, serologic tests can be used to confirm the diagnosis. The presence of anti-GQ1b antibodies, which was first described in 1992, provides a strong diagnostic marker for MFS [38].

The yield of this serological marker is high if the test done within 4 weeks after initial clinical onset [39].

### **5. Treatment practice of Guillain-Barre syndrome and Miller Fisher variant**

Since GBS is a demyelinating polyneuropathy that cause rapid ascending muscle paralysis it is vitally important to admit patients with GBS to the intensive care unit for close monitoring and observation as over 30% of GBS patients can develop respiratory failure [40].

Currently plasmapheresis and intravenous immunoglobulin (IVIG) are the only effective therapies for GBS [41].

The timing of plasmapheresis has a significant impact on the clinical outcome if it is done within 2 weeks from the initial clinical onset as it reduces the time needed for ventilator support and improves motor function and walking without any help. The use of IVIG also shown to yield a good response in patients with GBS, however the use of plasmapheresis and IVIG were equally effective in GBS patients and combined therapy showed no significant difference in the final patients' clinical outcomes as compared to a single therapy. There is no role of corticosteroids therapy in the management of GBS even if it is used in high dose in the initial phase of GBS [40].

In patients with MFS IVIG have shown to speed the recovery of ophthalmoplegia and ataxia. However, IVIG and plasmapheresis have no significant impact on the overall outcome in patients with Miller Fisher syndrome [42].

**95**

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease*

**6. Prognosis of Guillain-Barre syndrome and Miller Fisher variant**

The overall prognosis of GBS is positive. Not all patients with GBS show complete recovery; however, most of these patients have a good outcome on one year

However, factors that indicate poor prognosis in GBS patients include old age and severe neurological deficit with cranial nerve injury at clinical onset, the need for mechanical ventilation and axonal damage in the nerve conduction study

MFS has an overall a good prognosis [45], and despite the fact it has self-limiting

course in most cases, Miller Fisher rarely progressive to respiratory failure [46]. The early diagnosis of MFS and early treatment with plasma exchange or intravenous immunoglobulins can reduce the severity of the disease and hasten the

The ataxia and ophthalmoplegia usually recover within 1 to 3 months after initial clinical onset with almost complete resolution within 6 months. The loss of deep tendon reflexes may persist however does not interfere with daily functional

Guillain-Barre syndrome is a serious neurological disorder associated with a rapid progressive ascending muscle paralysis. It is essential to provide maximum supportive medical care and start early therapy to prevent further deterioration and

Miller Fisher is a variant of Guillain-Barre syndrome is rare in pediatric population with an overall good prognosis. Early recognition and management of such uncommon neurological disorder will help in preventing further complications and

*DOI: http://dx.doi.org/10.5772/intechopen.93128*

recovery in patients with MFS [46].

improve the future outcome of the patients.

2.Severe focal neurological deficit at the initial presentation

4.Axonal demyelination in nerve conduction study

The author declares no conflict of interest.

ELISA enzyme-linked immunosorbent assay

GBS Guillain-Barre syndrome MFS Miller Fisher syndrome PCB pharyngeal-cervical brachial MRI magnetic resonance imaging IVIG intravenous immunoglobulin

follow up [43].

(**Table 3**) [44].

activities [47].

1.Elderly patients

3.Mechanical ventilation

*Poor prognostic factors in GBS [44].*

**7. Conclusion**

**Table 3.**

long-term morbidity.

**Conflict of interest**

**Abbreviations**

## **6. Prognosis of Guillain-Barre syndrome and Miller Fisher variant**

The overall prognosis of GBS is positive. Not all patients with GBS show complete recovery; however, most of these patients have a good outcome on one year follow up [43].

However, factors that indicate poor prognosis in GBS patients include old age and severe neurological deficit with cranial nerve injury at clinical onset, the need for mechanical ventilation and axonal damage in the nerve conduction study (**Table 3**) [44].

MFS has an overall a good prognosis [45], and despite the fact it has self-limiting course in most cases, Miller Fisher rarely progressive to respiratory failure [46].

The early diagnosis of MFS and early treatment with plasma exchange or intravenous immunoglobulins can reduce the severity of the disease and hasten the recovery in patients with MFS [46].

The ataxia and ophthalmoplegia usually recover within 1 to 3 months after initial clinical onset with almost complete resolution within 6 months. The loss of deep tendon reflexes may persist however does not interfere with daily functional activities [47].

2.Severe focal neurological deficit at the initial presentation

3.Mechanical ventilation

4.Axonal demyelination in nerve conduction study

#### **Table 3.**

*Current Concepts in Zika Research*

variants such as MFS [31].

matter lesions [35, 36].

initial clinical onset [39].

respiratory failure [40].

effective therapies for GBS [41].

**variant**

strong diagnostic marker for MFS [38].

**4. Diagnosis of Guillain-Barre syndrome and Miller Fisher variant**

amplitude in the absence of demyelination parameters [33].

The diagnosis of GBS and Miller Fisher variant is often made clinically based on the symptoms and clinical signs of the patients [30]. A more detail and supporting investigational studies such cerebrospinal fluid (CSF) analysis, electrophysiological tests such as nerve conduction studies, ultrasonographic and MRI imaging along with serologic testing can be carried out to confirm the diagnosis of GBS and other

Electrophysiological findings in patients with GBS suggestive of demyelination process in the form of reduce motor conduction velocity (MCV), prolonged motor distal latency and increase F wave latency. The findings of conduction block with absent H-reflex are considered to be the commonest and early sign in GBS [32]. Patients with Fisher-Bickerstaff syndrome (FBS) typically showed sensory axonal neuropathy in the form of reduced sensory nerve action potential (SNAP)

The use of imaging studies such as peripheral nerve ultrasound and MRI are helpful diagnostic tools to diagnose inflammatory peripheral nerve roots [34].

The findings of MRI findings in patients with Miller-Fisher syndrome can range from cranial nerve involvement especially the optic nerve to severe cerebral white

Another important biomarker which help confirming the diagnosis of GBS is the cerebrospinal fluid (CSF) analysis which typically show albuminocytologic dissociation (elevated protein level with normal cell count in cerebrospinal fluid) which has been also seen in patients with MFS and Bickerstaff brainstem encephalitis [37]. Although the diagnosis of MFS is based mainly on the classical trial of ophthalmoplegia, areflexia and ataxia which developed approximately within 1 week to 10 days after the initial infection, serologic tests can be used to confirm the diagnosis. The presence of anti-GQ1b antibodies, which was first described in 1992, provides a

The yield of this serological marker is high if the test done within 4 weeks after

Since GBS is a demyelinating polyneuropathy that cause rapid ascending muscle

Currently plasmapheresis and intravenous immunoglobulin (IVIG) are the only

The timing of plasmapheresis has a significant impact on the clinical outcome if it is done within 2 weeks from the initial clinical onset as it reduces the time needed for ventilator support and improves motor function and walking without any help. The use of IVIG also shown to yield a good response in patients with GBS, however the use of plasmapheresis and IVIG were equally effective in GBS patients and combined therapy showed no significant difference in the final patients' clinical outcomes as compared to a single therapy. There is no role of corticosteroids therapy in the management of GBS even if it is used in high dose in the initial phase of GBS [40]. In patients with MFS IVIG have shown to speed the recovery of ophthalmoplegia and ataxia. However, IVIG and plasmapheresis have no significant impact on the

**5. Treatment practice of Guillain-Barre syndrome and Miller Fisher** 

paralysis it is vitally important to admit patients with GBS to the intensive care unit for close monitoring and observation as over 30% of GBS patients can develop

overall outcome in patients with Miller Fisher syndrome [42].

**94**

*Poor prognostic factors in GBS [44].*

## **7. Conclusion**

Guillain-Barre syndrome is a serious neurological disorder associated with a rapid progressive ascending muscle paralysis. It is essential to provide maximum supportive medical care and start early therapy to prevent further deterioration and improve the future outcome of the patients.

Miller Fisher is a variant of Guillain-Barre syndrome is rare in pediatric population with an overall good prognosis. Early recognition and management of such uncommon neurological disorder will help in preventing further complications and long-term morbidity.

## **Conflict of interest**

The author declares no conflict of interest.

#### **Abbreviations**


<sup>1.</sup>Elderly patients

*Current Concepts in Zika Research*

## **Author details**

Raafat Hammad Seroor Jadah Department of Pediatrics, Bahrain Defence Force Hospital, Royal Medical Services, Kingdom of Bahrain

\*Address all correspondence to: nader212@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**97**

mf.1416200963

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease*

Gastrointestinal, respiratory and/or arboviral infections? What is the cause of the Guillain-Barre syndrome epidemics in Peru? Current status—2019. Travel Medicine and Infectious Disease. 2019;**30**:114-116. DOI: 10.1016/j.tmaid.2019.06.015

[10] Rodriguez Y, Rojas M, Pacheco Y, Acosta-Ampudia Y, Ramirez-Santana C, Monsalve DM, et al. Guillain-Barré syndrome, transverse myelitis and infectious disease. Cellular & Molecular Immunology. 2018;**15**(6):547-562. DOI:

10.1038/cmi.2017.142

[11] Liu S, Dong C, Ubogu EE. Immunotherapy of Guillain-Barre syndrome. Human Vaccines & Immunotherapeutics. 2018;**14**(11):2568-2579. DOI: 10.1080/21645515.2018.1493415

[12] Dagklis IE, Papaglannopoulos S, Theodoridou V, Kazis D, Argyopoulou O,

[13] Kilic B, Gungor S, Ozgor B. Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barre syndrome. The Turkish Journal of Pediatrics. 2019;**61**(2):200-208. DOI: 10.24953/

[14] Walling AD, Dickson G. Guillain-Barre syndrome. American Family Physician. 2013;**87**(3):191-197. Available from: https://www.ncbi.nlm.nih.gov/

[15] Liu DY, Hollenbacj JR, Gregorin JA, Wynbrandt JH. A case of acute motor sensory axonal neuropathy: A variant of Gillian-Barre syndrome, with possible syndrome of irreversible

Bostantjopoulou S. Miller-Fisher syndrome: Are anti-GAD antibodies implicated in its pathophysiology? Case Reports in Neurological Medicine. 2016;**2016**:3431849. DOI:

10.1155/2016/3431849

turkjped.2019.02.008

pubmed/23418763

*DOI: http://dx.doi.org/10.5772/intechopen.93128*

[1] Freitas MRG, Vidal CM, Orsini M. Guillain-Barre syndrome: Celebrating

Psiquiatria. 2017;**75**(8):600-603. DOI:

[3] Willison HJ, Jacobs BC, Van Doorn PA.

Guillain-Barre syndrome. Lancet. 2016;**388**(10045):717-727. DOI: 10.1016/

[4] Estridge R, Iskander M. Understanding Guillain-Barre syndrome. JAAPA. 2015;**28**(7):19-22. DOI: 10.1097/01.JAA.000466585.10595.f5

[5] Ramirez-Zamora M, Burgos-Ganuza CR, Alas-Valle DA, Vergara-Galan PE, Ortez-Gonzalez CI. Guillain-Barre syndrome in pediatric age:

Epidemiological, clinical and therapeutic profile in a hospital in El Salvador. Revista de Neurologia. 2009;**48**(6):292- 296. DOI: 10.33588/rn.4806.2008560

Degenszajn J. Miller Fisher syndrome: A rare variant of Guillain-Barre syndrome. Autopsy & Case Reports. 2012;**2**(3):57-

[6] Ryan MM. Pediatric Guillain-Barre syndrome. Current Opinion in Pediatrics. 2013;**25**(6):689-693. DOI: 10.1097/MOP.0b013e328365ad3f

[7] Bandeira LP, Palaoro LG,

61. DOI: 10.4322/acr.2012.027

[9] Rodrigues-Morales AJ, Failoc-Rojas VE, Diaz-Velez C.

[8] Koike H. Zika virus and Guillain-Barre syndrome. Brain and Nerve. 2018;**70**(2):113-120. DOI: 10.11477/

[2] Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira MLB, Cornblath DR. Diagnosis and management of Guillain-Barre syndrome in ten steps. Nature Reviews. Neurology. 2019;**15**(11):671-683. DOI: 10.1038/

a century. Arquivos de Neuro-

**References**

10.1590/0004-282X20170093

s41582-019-0250-9

S0140-6736(16)00339-1

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease DOI: http://dx.doi.org/10.5772/intechopen.93128*

## **References**

*Current Concepts in Zika Research*

**96**

**Author details**

Kingdom of Bahrain

Raafat Hammad Seroor Jadah

\*Address all correspondence to: nader212@hotmail.com

provided the original work is properly cited.

Department of Pediatrics, Bahrain Defence Force Hospital, Royal Medical Services,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Freitas MRG, Vidal CM, Orsini M. Guillain-Barre syndrome: Celebrating a century. Arquivos de Neuro-Psiquiatria. 2017;**75**(8):600-603. DOI: 10.1590/0004-282X20170093

[2] Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira MLB, Cornblath DR. Diagnosis and management of Guillain-Barre syndrome in ten steps. Nature Reviews. Neurology. 2019;**15**(11):671-683. DOI: 10.1038/ s41582-019-0250-9

[3] Willison HJ, Jacobs BC, Van Doorn PA. Guillain-Barre syndrome. Lancet. 2016;**388**(10045):717-727. DOI: 10.1016/ S0140-6736(16)00339-1

[4] Estridge R, Iskander M. Understanding Guillain-Barre syndrome. JAAPA. 2015;**28**(7):19-22. DOI: 10.1097/01.JAA.000466585.10595.f5

[5] Ramirez-Zamora M, Burgos-Ganuza CR, Alas-Valle DA, Vergara-Galan PE, Ortez-Gonzalez CI. Guillain-Barre syndrome in pediatric age: Epidemiological, clinical and therapeutic profile in a hospital in El Salvador. Revista de Neurologia. 2009;**48**(6):292- 296. DOI: 10.33588/rn.4806.2008560

[6] Ryan MM. Pediatric Guillain-Barre syndrome. Current Opinion in Pediatrics. 2013;**25**(6):689-693. DOI: 10.1097/MOP.0b013e328365ad3f

[7] Bandeira LP, Palaoro LG, Degenszajn J. Miller Fisher syndrome: A rare variant of Guillain-Barre syndrome. Autopsy & Case Reports. 2012;**2**(3):57- 61. DOI: 10.4322/acr.2012.027

[8] Koike H. Zika virus and Guillain-Barre syndrome. Brain and Nerve. 2018;**70**(2):113-120. DOI: 10.11477/ mf.1416200963

[9] Rodrigues-Morales AJ, Failoc-Rojas VE, Diaz-Velez C. Gastrointestinal, respiratory and/or arboviral infections? What is the cause of the Guillain-Barre syndrome epidemics in Peru? Current status—2019. Travel Medicine and Infectious Disease. 2019;**30**:114-116. DOI: 10.1016/j.tmaid.2019.06.015

[10] Rodriguez Y, Rojas M, Pacheco Y, Acosta-Ampudia Y, Ramirez-Santana C, Monsalve DM, et al. Guillain-Barré syndrome, transverse myelitis and infectious disease. Cellular & Molecular Immunology. 2018;**15**(6):547-562. DOI: 10.1038/cmi.2017.142

[11] Liu S, Dong C, Ubogu EE. Immunotherapy of Guillain-Barre syndrome. Human Vaccines & Immunotherapeutics. 2018;**14**(11):2568-2579. DOI: 10.1080/21645515.2018.1493415

[12] Dagklis IE, Papaglannopoulos S, Theodoridou V, Kazis D, Argyopoulou O, Bostantjopoulou S. Miller-Fisher syndrome: Are anti-GAD antibodies implicated in its pathophysiology? Case Reports in Neurological Medicine. 2016;**2016**:3431849. DOI: 10.1155/2016/3431849

[13] Kilic B, Gungor S, Ozgor B. Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barre syndrome. The Turkish Journal of Pediatrics. 2019;**61**(2):200-208. DOI: 10.24953/ turkjped.2019.02.008

[14] Walling AD, Dickson G. Guillain-Barre syndrome. American Family Physician. 2013;**87**(3):191-197. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/23418763

[15] Liu DY, Hollenbacj JR, Gregorin JA, Wynbrandt JH. A case of acute motor sensory axonal neuropathy: A variant of Gillian-Barre syndrome, with possible syndrome of irreversible

lithium-effectuated neurotoxicity. Case Reports in Medicine. 2020;**2020**:4683507. DOI: 10.1155/2020/4683507

[16] Pradhan RR, Yadav SK, Yadav SK Sr. Pharyngeal-cervical-branchial variant of Guillain-Barre syndrome in children. Cureus. 2020 Feb;**12**(2):e6983. DOI: 10.7759/cureus.6983

[17] Wakerley BR, Yuki N. Pharyngealcervical-branchial variant of Guillain-Barre syndrome. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;**85**(3):339-344. DOI: 10.1136/ jnnp-2013-305397

[18] Aranyi Z, Kovacs T, Sipos I, Bereczki D. Miller Fisher syndrome: Brief overview and update with a focus on electrophysiological findings. European Journal of Neurology. 2012;**19**(1):15-20. DOI: 10.1111/j.1468-1331.2011.03445.x

[19] Kuwabara S. Fisher syndrome and Bickerstaff brainstem encephalitis. Brain and Nerve. 2015;**67**(11):1371-1376. DOI: 10.11477/mf.1416200308

[20] Karam E, Giraldo J, Rodrigues F, Hernandez-Pereira CE, Rodrigues-Morales AJ, Blohm GM, et al. Ocular flutter following zika virus infection. Journal of Neurovirology. 2017;**23**(6):932-934. DOI: 10.1007/ s13365-017-0585-1

[21] Wikan N, Smith DR. Zika virus: History of a newly emerging arbovirus. The Lancet Infectious Diseases. 2016;**16**(7):e119-e126. DOI: 10.1016/ S1473-3099(16)30010-X

[22] Guillier A, Amazan E, Aoun A, Baubion E, Derancourt C. Zika virus infection: A review. Annales de Dermatologie et de Vénéréologie. 2017;**144**(8-9):518-524. DOI: 10.1016/j. annder.2017.05.013

[23] Zombrano LI, Fuentes-Barahona IC, Soto-Fernandez RJ, Zuniga C, de

Silva JC, Rodrigues-Morales AJ. Guillain-Barre syndrome associated with zika virus infection in Honduras, 2016-2017. International Journal of Infectious Diseases. 2019;**84**:136-137. DOI: 10.1016/j.ijid.2019.05.008

[24] Koppolu V, Shantha RT. Zika virus outbreak: A review of neurological complications, diagnosis, and treatment options. Journal of Neurovirology. 2018;**24**(3):255-272. DOI: 10.1007/ s13365-018-0614-8

[25] Pastrana A, Albarracin M, Hoffmann M, Delturco G, Lopez R, Gil R, et al. Congenital zika syndrome in Argentina: Case series study. Archivos Argentinos de Pediatría. 2019;**117**(6):e635-e639. DOI: 10.5546/ aap.2019.e635

[26] Villamil-Gomez WE, Sanchez-Herrera AR, Hernandez H, Hernandez-Iriarte J, Diaz-Ricardo K, Castellanos J, et al. Guillain-Barre syndrome during the zika virus outbreak in Sucre, Columbia, 2016. Travel Medicine and Infectious Disease. 2017;**16**:62-63. DOI: 10.1016/j. tmaid-2017.03.012

[27] Rivera-Correa J, de Siqueira IC, Mota S, do Rosario MS, Pereira de Jesus PA, LCJ A, et al. Anti-ganglioside antibodies in patients with zika virus infection-associated Guillain-Barre syndrome in Brazil. PLoS Neglected Tropical Diseases. 2019;**13**(9):e0007695. DOI: 10.1371/journal.pntd.0007695

[28] Zhang L, Du X, Chen C, Chen Z, Zhang L, Han Q, et al. Development and characterization of doubleantibody sandwich ELISA for detection of Zika virus infection. Viruses. 2018;**10**(11):634. DOI: 10.3390/ v10110634

[29] Ferraris P, Yssel H, Misse D. Zika virus infection: An update. Microbes and Infection. 2019;**21**(8-9):353-360. DOI: 10.1016/j.micinf.2019.04.005

**99**

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease*

syndrome and chronic inflammatory demyelinating polyneuropathies. Handbook of Clinical Neurology. 2017;**146**:125-138. DOI: 10.1016/ B978-0-12-804279-3.00009-5

Kaminskas DA, Zagorski NM, Liow KK. Miller Fisher syndrome: A case report highlighting heterogeneity of clinical features and focused differential diagnosis. Hawaii Journal of Medicine & Public Health. 2016;**75**(7):196-199. Available from: https://www.ncbi.nlm.

[38] Yepishin IV, Allison RZ,

nih.gov/pubmed/27437164

s0025-7753(01)71980-x

[39] Rojas-Garcia R, Gallardo E,

[40] Dimachkie MM, Barohn RJ. Guillain-Barre syndrome and variants. Neurologic Clinics. 2013;**31**(2):491-510.

DOI: 10.1016/j.ncl.2013.01.005

[41] Verboon C, Doets AY, Galassi G, Davidson A, Waheed W, Pereon Y, et al. Current treatment practice of Guillain-Barre syndrome. Neurology. 2019;**93**(1):e59-e76. DOI: 10.1212/ WNL.0000000000007719

[42] Van Doorn PA. Diagnosis, treatment

[44] Gonzalez-Suarez I, Sanz-Gallego I, Rodriguez de Rivera FJ, Arpa J. Guillain-Barre syndrome: Natural history

and prognosis of Guillain-Barre syndrome (GBS). Presse Médicale. 2013;**42**(6 Pt 2):e193-e201. DOI: 10.1016/j.lpm.2013.02.328

[43] Wang Y, Lang W, Zhang Y, Ma X, Zhou C, Zhang HL. Long-term prognosis of Guillain-Barre syndrome not determined by treatment options? Oncotarget. 2017;**8**(45):79991-80001. DOI: 10.18632/oncotarget.20620

Serrano-Munuera C, de Luna N, Ortiz E, Roig C, et al. Anti-GQ1b antibodies: Usefulness of its detection for the diagnosis of Miller-Fisher syndrome. Medicina Clínica (Barcelona). 2001;**116**(20):761-764. DOI: 10.1016/

*DOI: http://dx.doi.org/10.5772/intechopen.93128*

[30] Villamil-Gomez W, Silvera LA, Paez-Castellanos J, Rodriguez-Morales AJ. Guillain-Barre syndrome after Chikungunya infection: A case in Columbia. Enfermedades Infecciosas y Microbiología Clínica. 2016;**34**(2):140- 141. DOI: 10.1016/j.eimc.2015.05.012

[31] Al Othman B, Raabe J, Kini A, Lee AG. Update: The Miller Fisher variants of Guillain-Barre syndrome. Current Opinion in Ophthalmology. 2019;**30**(6):462-466. DOI: 10.1097/

[32] Sudulgunta SR, Sodalgunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barre syndrome: Clinical profile and management. German Medical Science. 2015;**13**(16):1-15. DOI: 10.3205/000220.

[33] Alberti MA, Povedano M, Montero J, Casasnovas C. Early

10.1016/j.nrl.2017.05.012

jocn.2016.12.049

electrophysiological findings in Fisher-Bickerstaff syndrome. Neurología. 2017. pii:S0213-4853(17)30241-4. DOI:

[34] Doets AY, Jacobs BC, Van Doorn PA. Advances in management of Guillain-Barre syndrome. Current Opinion in Neurology. 2018;**31**(5):541-550. DOI: 10.1097/WCO.0000000000000602

[35] Malhotra A, Zhang M, Wu X, Jindal S, Durand D, Makhani N. MRI findings of optic pathway involvement in Miller Fisher syndrome in 3 pediatric patients and a review of the literature. Journal of Clinical Neuroscience. 2017;**39**:63-67. DOI: 10.1016/j.

[36] Xu Y, Liu L. Miller-Fisher syndrome associated with unilateral cerebral white matter lesions. Neurologia i Neurochirurgia Polska. 2015;**49**(5):344- 347. DOI: 10.1016/j.pjnns.2015.07.008

[37] Illes Z, Blaabjerg M. Cerebrospinal

fluid findings in Guillain-Barre

ICU.0000000000000611

eCollection 2015

*Guillain-Barre Syndrome and Miller Fisher Variant in Zika Virus Disease DOI: http://dx.doi.org/10.5772/intechopen.93128*

[30] Villamil-Gomez W, Silvera LA, Paez-Castellanos J, Rodriguez-Morales AJ. Guillain-Barre syndrome after Chikungunya infection: A case in Columbia. Enfermedades Infecciosas y Microbiología Clínica. 2016;**34**(2):140- 141. DOI: 10.1016/j.eimc.2015.05.012

*Current Concepts in Zika Research*

DOI: 10.1155/2020/4683507

10.7759/cureus.6983

jnnp-2013-305397

lithium-effectuated neurotoxicity. Case Reports in Medicine. 2020;**2020**:4683507. Silva JC, Rodrigues-Morales AJ. Guillain-Barre syndrome associated with zika virus infection in Honduras, 2016-2017. International Journal of Infectious Diseases. 2019;**84**:136-137. DOI: 10.1016/j.ijid.2019.05.008

[24] Koppolu V, Shantha RT. Zika virus outbreak: A review of neurological complications, diagnosis, and treatment options. Journal of Neurovirology. 2018;**24**(3):255-272. DOI: 10.1007/

s13365-018-0614-8

aap.2019.e635

tmaid-2017.03.012

[25] Pastrana A, Albarracin M, Hoffmann M, Delturco G, Lopez R, Gil R, et al. Congenital zika syndrome in Argentina: Case series study. Archivos Argentinos de Pediatría. 2019;**117**(6):e635-e639. DOI: 10.5546/

[26] Villamil-Gomez WE,

Sanchez-Herrera AR, Hernandez H, Hernandez-Iriarte J, Diaz-Ricardo K, Castellanos J, et al. Guillain-Barre syndrome during the zika virus outbreak in Sucre, Columbia, 2016. Travel Medicine and Infectious Disease. 2017;**16**:62-63. DOI: 10.1016/j.

[27] Rivera-Correa J, de Siqueira IC, Mota S, do Rosario MS, Pereira de Jesus PA, LCJ A, et al. Anti-ganglioside antibodies in patients with zika virus infection-associated Guillain-Barre syndrome in Brazil. PLoS Neglected Tropical Diseases. 2019;**13**(9):e0007695. DOI: 10.1371/journal.pntd.0007695

[28] Zhang L, Du X, Chen C, Chen Z, Zhang L, Han Q, et al. Development and characterization of double-

antibody sandwich ELISA for detection

[29] Ferraris P, Yssel H, Misse D. Zika virus infection: An update. Microbes and Infection. 2019;**21**(8-9):353-360. DOI: 10.1016/j.micinf.2019.04.005

of Zika virus infection. Viruses. 2018;**10**(11):634. DOI: 10.3390/

v10110634

[16] Pradhan RR, Yadav SK, Yadav SK Sr. Pharyngeal-cervical-branchial variant of Guillain-Barre syndrome in children. Cureus. 2020 Feb;**12**(2):e6983. DOI:

[17] Wakerley BR, Yuki N. Pharyngealcervical-branchial variant of Guillain-Barre syndrome. Journal of Neurology,

Neurosurgery, and Psychiatry. 2014;**85**(3):339-344. DOI: 10.1136/

[18] Aranyi Z, Kovacs T, Sipos I, Bereczki D. Miller Fisher syndrome: Brief overview and update with a focus on electrophysiological findings. European Journal of Neurology. 2012;**19**(1):15-20. DOI: 10.1111/j.1468-1331.2011.03445.x

[19] Kuwabara S. Fisher syndrome and Bickerstaff brainstem encephalitis. Brain and Nerve. 2015;**67**(11):1371-1376.

Rodrigues F, Hernandez-Pereira CE, Rodrigues-Morales AJ, Blohm GM, et al. Ocular flutter following zika virus infection. Journal of Neurovirology. 2017;**23**(6):932-934. DOI: 10.1007/

[21] Wikan N, Smith DR. Zika virus: History of a newly emerging arbovirus.

[22] Guillier A, Amazan E, Aoun A, Baubion E, Derancourt C. Zika virus infection: A review. Annales de Dermatologie et de Vénéréologie. 2017;**144**(8-9):518-524. DOI: 10.1016/j.

[23] Zombrano LI, Fuentes-Barahona IC,

Soto-Fernandez RJ, Zuniga C, de

The Lancet Infectious Diseases. 2016;**16**(7):e119-e126. DOI: 10.1016/

S1473-3099(16)30010-X

annder.2017.05.013

DOI: 10.11477/mf.1416200308

[20] Karam E, Giraldo J,

s13365-017-0585-1

**98**

[31] Al Othman B, Raabe J, Kini A, Lee AG. Update: The Miller Fisher variants of Guillain-Barre syndrome. Current Opinion in Ophthalmology. 2019;**30**(6):462-466. DOI: 10.1097/ ICU.0000000000000611

[32] Sudulgunta SR, Sodalgunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barre syndrome: Clinical profile and management. German Medical Science. 2015;**13**(16):1-15. DOI: 10.3205/000220. eCollection 2015

[33] Alberti MA, Povedano M, Montero J, Casasnovas C. Early electrophysiological findings in Fisher-Bickerstaff syndrome. Neurología. 2017. pii:S0213-4853(17)30241-4. DOI: 10.1016/j.nrl.2017.05.012

[34] Doets AY, Jacobs BC, Van Doorn PA. Advances in management of Guillain-Barre syndrome. Current Opinion in Neurology. 2018;**31**(5):541-550. DOI: 10.1097/WCO.0000000000000602

[35] Malhotra A, Zhang M, Wu X, Jindal S, Durand D, Makhani N. MRI findings of optic pathway involvement in Miller Fisher syndrome in 3 pediatric patients and a review of the literature. Journal of Clinical Neuroscience. 2017;**39**:63-67. DOI: 10.1016/j. jocn.2016.12.049

[36] Xu Y, Liu L. Miller-Fisher syndrome associated with unilateral cerebral white matter lesions. Neurologia i Neurochirurgia Polska. 2015;**49**(5):344- 347. DOI: 10.1016/j.pjnns.2015.07.008

[37] Illes Z, Blaabjerg M. Cerebrospinal fluid findings in Guillain-Barre

syndrome and chronic inflammatory demyelinating polyneuropathies. Handbook of Clinical Neurology. 2017;**146**:125-138. DOI: 10.1016/ B978-0-12-804279-3.00009-5

[38] Yepishin IV, Allison RZ, Kaminskas DA, Zagorski NM, Liow KK. Miller Fisher syndrome: A case report highlighting heterogeneity of clinical features and focused differential diagnosis. Hawaii Journal of Medicine & Public Health. 2016;**75**(7):196-199. Available from: https://www.ncbi.nlm. nih.gov/pubmed/27437164

[39] Rojas-Garcia R, Gallardo E, Serrano-Munuera C, de Luna N, Ortiz E, Roig C, et al. Anti-GQ1b antibodies: Usefulness of its detection for the diagnosis of Miller-Fisher syndrome. Medicina Clínica (Barcelona). 2001;**116**(20):761-764. DOI: 10.1016/ s0025-7753(01)71980-x

[40] Dimachkie MM, Barohn RJ. Guillain-Barre syndrome and variants. Neurologic Clinics. 2013;**31**(2):491-510. DOI: 10.1016/j.ncl.2013.01.005

[41] Verboon C, Doets AY, Galassi G, Davidson A, Waheed W, Pereon Y, et al. Current treatment practice of Guillain-Barre syndrome. Neurology. 2019;**93**(1):e59-e76. DOI: 10.1212/ WNL.0000000000007719

[42] Van Doorn PA. Diagnosis, treatment and prognosis of Guillain-Barre syndrome (GBS). Presse Médicale. 2013;**42**(6 Pt 2):e193-e201. DOI: 10.1016/j.lpm.2013.02.328

[43] Wang Y, Lang W, Zhang Y, Ma X, Zhou C, Zhang HL. Long-term prognosis of Guillain-Barre syndrome not determined by treatment options? Oncotarget. 2017;**8**(45):79991-80001. DOI: 10.18632/oncotarget.20620

[44] Gonzalez-Suarez I, Sanz-Gallego I, Rodriguez de Rivera FJ, Arpa J. Guillain-Barre syndrome: Natural history

and prognostic factors: A retrospective review of 106 cases. BMC Neurology. 2013;**13**:95. DOI: 10.1186/1471-2377-13-95

[45] Teener JW. Miller Fisher's syndrome. Seminars in Neurology. 2012;**32**(5):512-516. DOI: 10.1055/s-0033-1334470

[46] Mwansa H, Obiekezie O, Kaneria S. A case of Miller Fisher syndrome. The American Journal of Medicine. 2019;**132**(6):e591-e592. DOI: 10.1016/j. amjmed.2019.01.014

[47] Bukhari S, Taboada J. A case of Miller Fisher syndrome and literature review. Cureus. 2017;**9**(2):e1048. DOI: 10.7759/cureus.1048

**101**

**Chapter 7**

**Abstract**

evidence-based guidelines.

**1. Introduction**

exercise, neuromuscular electrical stimulation

Virus Infection

*Thomas Harbo and Henning Andersen*

Neuromuscular Effects and

Rehabilitation in Guillain-Barré

Syndrome Associated with Zika

The 2015–2017 Zika Virus outbreak caused a high increase in patients with Guillain-Barré syndrome (GBS), a post infectious autoimmune disease of the peripheral nerves. The severity of GBS can range from mild impairment with fast recovery to complete paralysis including severe respiratory or autonomic failure. Recovery may take months and even years and may be incomplete despite disease modifying treatment with IVIG or plasma exchange. Therefore, optimal supportive care and effective rehabilitation remain crucial. Multidisciplinary rehabilitation is recommended but may be challenging in the acute phase because of limited patient participation due to profound muscle weakness and severe pain. Inactive denervated muscles will inevitably undergo rapid degeneration resulting in wasting, weakness, and contractures as major long-term complications in severely affected patients. In this chapter, the current evidence of rehabilitation on the short- and long-term motor function in GBS is reviewed, including newly obtained experiences with neuromuscular electrical stimulation (NMES). Rehabilitation remains an area lacking well designed and controlled clinical studies and thus a clear lack of

**Keywords:** Guillain Barré syndrome, prognosis, chronic disability, rehabilitation,

**Guillain Barré Syndrome (GBS)** is an acute inflammatory disease affecting peripheral nerves and nerve roots [1, 2]. Most commonly, GBS is preceded by an infection a few weeks prior to neuropathic symptoms [3]. Thus, incidence of GBS can increase during outbreaks of infectious diseases. This was most recently observed during the 2015 to 2017 Zika Virus epidemic in the French Polynesia and Latin America with a highly increased incidence of GBS in several countries [4–9]. GBS typically presents with muscle weakness and sensory symptoms combined with loss of tendon reflexes. Symptoms initially present in the lower extremities progressing to the upper extremities and the respiratory and cranial muscles [10]. The progressive phase usually last for days to weeks with most patients reaching nadir within four weeks of symptom debut followed by a plateau phase and a slow

## **Chapter 7**

*Current Concepts in Zika Research*

and prognostic factors: A

10.1186/1471-2377-13-95

2012;**32**(5):512-516. DOI: 10.1055/s-0033-1334470

amjmed.2019.01.014

10.7759/cureus.1048

[45] Teener JW. Miller Fisher's syndrome. Seminars in Neurology.

[46] Mwansa H, Obiekezie O, Kaneria S. A case of Miller Fisher syndrome. The American Journal of Medicine. 2019;**132**(6):e591-e592. DOI: 10.1016/j.

[47] Bukhari S, Taboada J. A case of Miller Fisher syndrome and literature review. Cureus. 2017;**9**(2):e1048. DOI:

retrospective review of 106 cases. BMC Neurology. 2013;**13**:95. DOI:

**100**

## Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika Virus Infection

*Thomas Harbo and Henning Andersen*

## **Abstract**

The 2015–2017 Zika Virus outbreak caused a high increase in patients with Guillain-Barré syndrome (GBS), a post infectious autoimmune disease of the peripheral nerves. The severity of GBS can range from mild impairment with fast recovery to complete paralysis including severe respiratory or autonomic failure. Recovery may take months and even years and may be incomplete despite disease modifying treatment with IVIG or plasma exchange. Therefore, optimal supportive care and effective rehabilitation remain crucial. Multidisciplinary rehabilitation is recommended but may be challenging in the acute phase because of limited patient participation due to profound muscle weakness and severe pain. Inactive denervated muscles will inevitably undergo rapid degeneration resulting in wasting, weakness, and contractures as major long-term complications in severely affected patients. In this chapter, the current evidence of rehabilitation on the short- and long-term motor function in GBS is reviewed, including newly obtained experiences with neuromuscular electrical stimulation (NMES). Rehabilitation remains an area lacking well designed and controlled clinical studies and thus a clear lack of evidence-based guidelines.

**Keywords:** Guillain Barré syndrome, prognosis, chronic disability, rehabilitation, exercise, neuromuscular electrical stimulation

## **1. Introduction**

**Guillain Barré Syndrome (GBS)** is an acute inflammatory disease affecting peripheral nerves and nerve roots [1, 2]. Most commonly, GBS is preceded by an infection a few weeks prior to neuropathic symptoms [3]. Thus, incidence of GBS can increase during outbreaks of infectious diseases. This was most recently observed during the 2015 to 2017 Zika Virus epidemic in the French Polynesia and Latin America with a highly increased incidence of GBS in several countries [4–9]. GBS typically presents with muscle weakness and sensory symptoms combined with loss of tendon reflexes. Symptoms initially present in the lower extremities progressing to the upper extremities and the respiratory and cranial muscles [10]. The progressive phase usually last for days to weeks with most patients reaching nadir within four weeks of symptom debut followed by a plateau phase and a slow

recovery. Beside the typical presentation of sensory and motor neuropathy, patients may have clinical variants like the triad of ophthalmoplegia, ataxia and areflexia known as the Miller Fischer Syndrome, pure motor, paraparetic or pharyngeacervical-brachial variant [11], and in association with Zika Virus infection a case of GBS with ocular flutter, ataxia, tetraparesis and areflexia has been reported [12]. Furthermore, neuropathy can be classified as demyelinating or axonal according to the electrophysiological examination [13].

**The prognosis** of GBS is very heterogeneous. Some patients are mildly affected with a fast recovery and no disabilities irrespective of receiving any treatment. Between 20 and 30% of patients develop complete paralysis, severe respiratory or autonomic failure and receive treatment in the intensive care unit (ICU) for months [14]. In a group of prolonged mechanically ventilated patients, 31% were able to walk after one year and 58% after maximum time of follow up [15]. The sudden increase of patients with Zika Virus-related GBS was a challenge for health care systems in low income countries such as Brazil with limited resources for diagnostics, treatment, ICU capacity as well as rehabilitation facilities [1, 2]. Despite the lack of evidence, multidisciplinary supportive care and rehabilitation are important in GBS. In the acute phase, consensus- based recommendations include (1) monitoring of respiratory and autonomic function in a setting with available artificial ventilation and neuro-intensive care, (2) prophylactic antithrombotic treatment for deep vein thrombosis, (3) pain management, (4) management of nutrition as well as bladder and bowel dysfunction and (5) physiotherapy to prevent muscle shortening and joint contractures [16]. All of these interventions should be followed by a rehabilitation and exercise program to regain physical abilities as fast as possible. Recovery can take months and even years and end up with significant chronic disabilities despite immunomodulatory treatment. As shown in the largest prospective cohort of patients with GBS studied to date, a large proportion of patients had long-term motor dysfunction with 17% of patients from Europe and America were unable to walk unaided after 12 months [17], emphasizing the importance of identifying more effective neuromuscular rehabilitation. Motor dysfunctions such as weakness, wasting and contractures are major long-term complications in severely affected patients. In this review, we present an overview of existing evidence of treatment to prevent muscle weakness and disabilities after GBS with special emphasis on the effect of neuromuscular rehabilitation in the acute and chronic phases of the disease.

## **2. Treatment and rehabilitation in GBS**

**Pharmacological treatment.** In several large randomized controlled clinical trials, treatment with plasma exchange (PE) or intravenous immunoglobulin (IVIG) initiated in the acute phase of GBS have proven effective. Compared to placebo, treatment with PE or IVIG result in reduced need for respiratory support and an increased chance to regain mobility and muscle strength after 1 month and 12 months [18, 19]. Despite immunomodulatory treatment, a group of patients with GBS still have a very poor prognosis. In a combined cohort study of 526 patients and a cross sectional study including 63 ventilated patients [15], 6% of patients with GBS required mechanical ventilation for more than two months. The prolonged mechanically ventilated patients had a median (range) length of stay at the ICU of 101 (97–126) days and at hospital of 129 (104–162) days, followed by 252 (177–403) days of clinical rehabilitation and 198 (183–502) days of outpatient rehabilitation. At 11 years follow-up, only 58% had regained ambulation and the median time to regain ambulation was

**103**

bilitation intervention.

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

548 (270–730) days. This emphasizes the need for more effective treatment in GBS. Recently, small clinical studies have indicated that monoclonal antibodies against complement proteins given in the early phase of the disease could have some benefit in GBS; however, larger studies are needed to confirm this [20, 21]. It is important to underline that there are currently no evidence-based pharmacological treatments

**Multidisciplinary rehabilitation.** Most patients with moderate to severe GBS are offered multidisciplinary rehabilitation, which means two or more coordinated interventions under medical supervision by a neurologist or rehabilitation physician. Multidisciplinary rehabilitation aims at regaining autonomy with the ability to perform all activities of daily living. This may include physiotherapy or occupational therapy and exercise programs, but also nursing, dietary advice, psychotherapy, speech therapy, and social rehabilitation depending on the needs of the individual patient. The individualized approach to multidisciplinary rehabilitation as well as a considerably variability in facilities between countries and hospitals compromise the possibility to design research trials to assess the efficacy of a multidisciplinary rehabilitation intervention. In a systematic review of rehabilitation interventions in patients with GBS [23], only five original studies could be identified evaluating the effectiveness of multidisciplinary rehabilitation. These studies include only one good quality randomized controlled study comparing high and low intensity rehabilitation in patients with remaining disability more than one year after GBS [24]. In this study, 79 adult patients were included 1–12 years after the GBS diagnosis and randomized to receive either individualized outpatient-based high-intensive rehabilitation (intervention, n = 40) or a lower intensity home-based program (control, n = 39). The intervention comprised three one-hour individualized sessions weekly for 12 weeks. Sessions included physical and occupational therapy for strengthening, endurance and gait training as well as specific rehabilitation tasks to improve everyday life activities as well as community and work functions. The control group completed a 30-minute maintenance training program twice weekly and was also allowed to perform other rehabilitation activities if needed. Outcome was assessed one year after the intervention and included measurements of activity level, participation, and perceived impact of disease-related problems. Based on the total and the motor scales of the Functional Independence Measure (FIM) in an intention to treat analysis, there was a small but statistically significant improvement in the high intensity rehabilitation group compared to the controls. Furthermore, 80% of the patients complying with the high intensity protocol had a clinically meaningful improvement in the FIM motor score (at least 3 points) compared with only 8% of controls. Adverse effects were not reported; however, only 22 (55%) of the 40 patients assigned to high intensity rehabilitation completed the study due to loss to follow up or inability or unwillingness to comply with the protocol. This low number of follow-up reduces the applicability and external validity of the study suggesting that applicability of the intervention is challenging. Other original studies have included: (1) one case control study (n = 34) of inpatient rehabilitation with a control group of healthy subjects [25], (2) one prospective case series (n = 35) of inpatient rehabilitation followed by a home-based training program [26], and (3) two retrospective case series (n = 39 and 24) of inpatient rehabilitation [27, 28]. In these studies, patients with GBS improved during multidisciplinary rehabilitation but the studies were not designed to distinguish between spontaneous recovery and the effect of the reha-

Despite several limitations, the authors of the review concluded that there is good evidence (Grade level II) to support ambulatory, outpatient multidisciplinary

available to prevent muscle atrophy or muscle weakness in GBS [22].

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

548 (270–730) days. This emphasizes the need for more effective treatment in GBS. Recently, small clinical studies have indicated that monoclonal antibodies against complement proteins given in the early phase of the disease could have some benefit in GBS; however, larger studies are needed to confirm this [20, 21]. It is important to underline that there are currently no evidence-based pharmacological treatments available to prevent muscle atrophy or muscle weakness in GBS [22].

**Multidisciplinary rehabilitation.** Most patients with moderate to severe GBS are offered multidisciplinary rehabilitation, which means two or more coordinated interventions under medical supervision by a neurologist or rehabilitation physician. Multidisciplinary rehabilitation aims at regaining autonomy with the ability to perform all activities of daily living. This may include physiotherapy or occupational therapy and exercise programs, but also nursing, dietary advice, psychotherapy, speech therapy, and social rehabilitation depending on the needs of the individual patient. The individualized approach to multidisciplinary rehabilitation as well as a considerably variability in facilities between countries and hospitals compromise the possibility to design research trials to assess the efficacy of a multidisciplinary rehabilitation intervention. In a systematic review of rehabilitation interventions in patients with GBS [23], only five original studies could be identified evaluating the effectiveness of multidisciplinary rehabilitation. These studies include only one good quality randomized controlled study comparing high and low intensity rehabilitation in patients with remaining disability more than one year after GBS [24]. In this study, 79 adult patients were included 1–12 years after the GBS diagnosis and randomized to receive either individualized outpatient-based high-intensive rehabilitation (intervention, n = 40) or a lower intensity home-based program (control, n = 39). The intervention comprised three one-hour individualized sessions weekly for 12 weeks. Sessions included physical and occupational therapy for strengthening, endurance and gait training as well as specific rehabilitation tasks to improve everyday life activities as well as community and work functions. The control group completed a 30-minute maintenance training program twice weekly and was also allowed to perform other rehabilitation activities if needed. Outcome was assessed one year after the intervention and included measurements of activity level, participation, and perceived impact of disease-related problems. Based on the total and the motor scales of the Functional Independence Measure (FIM) in an intention to treat analysis, there was a small but statistically significant improvement in the high intensity rehabilitation group compared to the controls. Furthermore, 80% of the patients complying with the high intensity protocol had a clinically meaningful improvement in the FIM motor score (at least 3 points) compared with only 8% of controls. Adverse effects were not reported; however, only 22 (55%) of the 40 patients assigned to high intensity rehabilitation completed the study due to loss to follow up or inability or unwillingness to comply with the protocol. This low number of follow-up reduces the applicability and external validity of the study suggesting that applicability of the intervention is challenging. Other original studies have included: (1) one case control study (n = 34) of inpatient rehabilitation with a control group of healthy subjects [25], (2) one prospective case series (n = 35) of inpatient rehabilitation followed by a home-based training program [26], and (3) two retrospective case series (n = 39 and 24) of inpatient rehabilitation [27, 28]. In these studies, patients with GBS improved during multidisciplinary rehabilitation but the studies were not designed to distinguish between spontaneous recovery and the effect of the rehabilitation intervention.

Despite several limitations, the authors of the review concluded that there is good evidence (Grade level II) to support ambulatory, outpatient multidisciplinary

*Current Concepts in Zika Research*

chronic phases of the disease.

**2. Treatment and rehabilitation in GBS**

the electrophysiological examination [13].

recovery. Beside the typical presentation of sensory and motor neuropathy, patients may have clinical variants like the triad of ophthalmoplegia, ataxia and areflexia known as the Miller Fischer Syndrome, pure motor, paraparetic or pharyngeacervical-brachial variant [11], and in association with Zika Virus infection a case of GBS with ocular flutter, ataxia, tetraparesis and areflexia has been reported [12]. Furthermore, neuropathy can be classified as demyelinating or axonal according to

**The prognosis** of GBS is very heterogeneous. Some patients are mildly affected

with a fast recovery and no disabilities irrespective of receiving any treatment. Between 20 and 30% of patients develop complete paralysis, severe respiratory or autonomic failure and receive treatment in the intensive care unit (ICU) for months [14]. In a group of prolonged mechanically ventilated patients, 31% were able to walk after one year and 58% after maximum time of follow up [15]. The sudden increase of patients with Zika Virus-related GBS was a challenge for health care systems in low income countries such as Brazil with limited resources for diagnostics, treatment, ICU capacity as well as rehabilitation facilities [1, 2]. Despite the lack of evidence, multidisciplinary supportive care and rehabilitation are important in GBS. In the acute phase, consensus- based recommendations include (1) monitoring of respiratory and autonomic function in a setting with available artificial ventilation and neuro-intensive care, (2) prophylactic antithrombotic treatment for deep vein thrombosis, (3) pain management, (4) management of nutrition as well as bladder and bowel dysfunction and (5) physiotherapy to prevent muscle shortening and joint contractures [16]. All of these interventions should be followed by a rehabilitation and exercise program to regain physical abilities as fast as possible. Recovery can take months and even years and end up with significant chronic disabilities despite immunomodulatory treatment. As shown in the largest prospective cohort of patients with GBS studied to date, a large proportion of patients had long-term motor dysfunction with 17% of patients from Europe and America were unable to walk unaided after 12 months [17], emphasizing the importance of identifying more effective neuromuscular rehabilitation. Motor dysfunctions such as weakness, wasting and contractures are major long-term complications in severely affected patients. In this review, we present an overview of existing evidence of treatment to prevent muscle weakness and disabilities after GBS with special emphasis on the effect of neuromuscular rehabilitation in the acute and

**Pharmacological treatment.** In several large randomized controlled clinical trials, treatment with plasma exchange (PE) or intravenous immunoglobulin (IVIG) initiated in the acute phase of GBS have proven effective. Compared to placebo, treatment with PE or IVIG result in reduced need for respiratory support and an increased chance to regain mobility and muscle strength after 1 month and 12 months [18, 19]. Despite immunomodulatory treatment, a group of patients with GBS still have a very poor prognosis. In a combined cohort study of 526 patients and a cross sectional study including 63 ventilated patients [15], 6% of patients with GBS required mechanical ventilation for more than two months. The prolonged mechanically ventilated patients had a median (range) length of stay at the ICU of 101 (97–126) days and at hospital of 129 (104–162) days, followed by 252 (177–403) days of clinical rehabilitation and 198 (183–502) days of outpatient rehabilitation. At 11 years follow-up, only 58% had regained ambulation and the median time to regain ambulation was

**102**

rehabilitation to obtain long-term improvements in levels of activity and participation in patients with GBS in the later stages of recovery. Further, the authors concluded that there is satisfactory (Grade level III) evidence to support (1) inpatient rehabilitation followed by outpatient rehabilitation thereby inducing functional recovery and (2) physical therapy and exercise to reduce joint contractures and muscle weakness. In another more recent case series of 51 patients with GBS, motor recovery following the acute pharmacological treatment response was assessed during the acute inpatient care as well as after outpatient and homebased rehabilitation [29]. A description of the intervention was not provided, but it included physical therapy for 61 ± 58 (mean ± SD) days for inpatients, 96 ± 70 days for outpatients, and 75 ± 15 days during home rehabilitation. Again, the natural history with spontaneous improvement after GBS and the lack of a control group impairs the possibility to draw any final conclusions based on this study regarding the effectiveness of rehabilitation. However, it was shown that muscle strength measured with a MRC sum score [30] and ambulation assessed with the GBS disability score [31] continue to improve beyond the first six months of rehabilitation.

**Exercise.** In a systematic review, Simatos and colleagues evaluated the available literature on exercise as an intervention in the rehabilitation of adult patients with GBS [32]. Studies between 1951 and 2016 were identified in PubMed searches and the quality of the studies was assessed and classified according to a modified version of the Centre for Evidence-Based Medicine level of evidence. Seven studies with exercise as the main intervention were identified, including four uncontrolled single cases with a low evidence level, one trial including multidisciplinary rehabilitation (reviewed in the previous section), [24], and two Dutch studies of a case series in an open label standardized exercise protocol (evidence level 5) [33, 34]. In the Dutch study, 16 patients were included between six months and 15 years after their GBS diagnosis as well as four patients with stable chronic inflammatory demyelinating polyradiculoneuropathy. All patients were ambulatory and reported fatigue as a major complaint. The exercise intervention consisted of three 45-minute bicycling sessions every week for 12 weeks. During the 12-week period, training intensity was gradually increased. The target heart rate increasing from 65% to a maximum of 90% of maximal heart rate and an increasing workload was applied on the bicycle home trainer. The intervention resulted in lower fatigue levels, increased isokinetic muscle strength and a higher peak oxygen uptake. Further, patients improved on a handicap scale and on the physical components score of the SF36 Quality of Life scale. Two patients did not complete the study for non-study related reasons, and 25% reported mild and transient muscle cramps, paresthesia, or pain. Overall, exercise as an intervention in patients with late disabilities and fatigue in GBS is feasible and may benefit some patients.

**Neuromuscular electrical stimulation (NMES).** In the acute phase of severe GBS, rehabilitation exercise is challenged by limited patient participation due to severe weakness or even paralysis. For practical reasons, exercise may also be challenged if patients are in the ICU, intubated and on ventilator support. Inactive and denervated muscles will indisputably and fast degenerate and muscle atrophy will develop [35, 36]. NMES is a method to induce muscle contractions without patient participation. This may be an alternative therapeutic approach in the acute phase of GBS, which can minimize inactivation and denervation wasting until patients have recovered to a level where a multidisciplinary rehabilitation effort can be initiated [37, 38]. In a small proof of concept study this has proven feasible with satisfactory safety. There was also a trend for an effect of

**105**

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

NMES on muscle wasting as an add on to established standard of care in the acute and subacute phases of GBS [39]. Seventeen patients with moderate to severe GBS were randomized to receive an hour of NMES on weekdays on the right or left quadriceps femoral muscle with the non-stimulated muscle serving as control. Stimulation was initiated within two weeks after the first sign of weakness and was continued through the acute hospital admission and the following inpatient rehabilitation. The median (range) time of participation was 27 days (10–95) and included 17 (4–53) stimulation sessions. During the study, each patient had a mean loss of lean body mass (muscle) of 3.4 kg, establishing that patients with GBS will experience substantial muscle wasting. NMES was found to be safe and feasible as an add on to standard supportive therapy and rehabilitation in the acute and subacute phases of GBS. There was a trend towards a preventive effect of NMES on muscle atrophy, but the study was not designed to explore effect on

**Virtual Motor Rehabilitation System.** Virtual Motor Rehabilitation (VMR) is a new technology combining novel rehabilitation software with low cost commercially available devices such as the Nintendo® Wii platform. To be effective, multidisciplinary rehabilitation in GBS is very time demanding including several daily sessions for as long as 6, 12 and 18 months [40]. Often the rehabilitation offered is limited due to lack of time and resources, and patients may find training tedious and monotonous, resulting in lack of compliance. Therefore, VMR could be an attractive supplement to the established rehabilitation regimen. The method is still under development and so far only one study has been published, describing VMR applied four and five months after admission in two patients with severe GBS as an add on to the conventional multidisciplinary rehabilitation [41]. In this study, the Nintendo® Wii Balance Board and a virtual environmental tool were applied in 20 rehabilitation sessions consisting of 30 minutes of traditional therapy and 30 minutes of VMR. Compliance was good and patients' status improved. VMR could be developed further to include more aspects of the rehabilitation process in the future. **Safety.** In anecdotal case reports and experimental animal studies it has been indicated that over-exercising during rehabilitation after GBS may damage motor units and cause paradoxical weakening, which has led to hesitation concerning the recommendation to do intensive and strenuous exercise [16]. The clinical data to support this concern are negligible and overall, it is reasonable to believe that the benefit of exercising weakened muscles after GBS excess the risk of harm. However, systematic registration of safety and complications should always be included in

Neuromuscular rehabilitation after GBS is important for the functional outcome of each individual patient. Studied rehabilitation interventions in the acute, subacute/intermediate, and chronic/long-term phase are summarized in **Figure 1**. However, the quality of the present evidence of rehabilitation efficacy is low, rehabilitation is both complex, time consuming and expensive, and there is currently no standardized care for patients with neuromuscular disabilities after GBS. Therefore, the rehabilitation effort may lack necessary resources and expertise. Because the monophasic course and spontaneous recovery in GBS challenge the interpretation of non-controlled studies, future large controlled studies and standardized sensitive efficacy outcome measures are needed to improve the interpretation of neuromus-

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

patient disability.

future studies.

**3. Conclusions**

cular rehabilitation trials in GBS.

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

NMES on muscle wasting as an add on to established standard of care in the acute and subacute phases of GBS [39]. Seventeen patients with moderate to severe GBS were randomized to receive an hour of NMES on weekdays on the right or left quadriceps femoral muscle with the non-stimulated muscle serving as control. Stimulation was initiated within two weeks after the first sign of weakness and was continued through the acute hospital admission and the following inpatient rehabilitation. The median (range) time of participation was 27 days (10–95) and included 17 (4–53) stimulation sessions. During the study, each patient had a mean loss of lean body mass (muscle) of 3.4 kg, establishing that patients with GBS will experience substantial muscle wasting. NMES was found to be safe and feasible as an add on to standard supportive therapy and rehabilitation in the acute and subacute phases of GBS. There was a trend towards a preventive effect of NMES on muscle atrophy, but the study was not designed to explore effect on patient disability.

**Virtual Motor Rehabilitation System.** Virtual Motor Rehabilitation (VMR) is a new technology combining novel rehabilitation software with low cost commercially available devices such as the Nintendo® Wii platform. To be effective, multidisciplinary rehabilitation in GBS is very time demanding including several daily sessions for as long as 6, 12 and 18 months [40]. Often the rehabilitation offered is limited due to lack of time and resources, and patients may find training tedious and monotonous, resulting in lack of compliance. Therefore, VMR could be an attractive supplement to the established rehabilitation regimen. The method is still under development and so far only one study has been published, describing VMR applied four and five months after admission in two patients with severe GBS as an add on to the conventional multidisciplinary rehabilitation [41]. In this study, the Nintendo® Wii Balance Board and a virtual environmental tool were applied in 20 rehabilitation sessions consisting of 30 minutes of traditional therapy and 30 minutes of VMR. Compliance was good and patients' status improved. VMR could be developed further to include more aspects of the rehabilitation process in the future.

**Safety.** In anecdotal case reports and experimental animal studies it has been indicated that over-exercising during rehabilitation after GBS may damage motor units and cause paradoxical weakening, which has led to hesitation concerning the recommendation to do intensive and strenuous exercise [16]. The clinical data to support this concern are negligible and overall, it is reasonable to believe that the benefit of exercising weakened muscles after GBS excess the risk of harm. However, systematic registration of safety and complications should always be included in future studies.

### **3. Conclusions**

*Current Concepts in Zika Research*

rehabilitation.

some patients.

rehabilitation to obtain long-term improvements in levels of activity and participation in patients with GBS in the later stages of recovery. Further, the authors concluded that there is satisfactory (Grade level III) evidence to support (1) inpatient rehabilitation followed by outpatient rehabilitation thereby inducing functional recovery and (2) physical therapy and exercise to reduce joint contractures and muscle weakness. In another more recent case series of 51 patients with GBS, motor recovery following the acute pharmacological treatment response was assessed during the acute inpatient care as well as after outpatient and homebased rehabilitation [29]. A description of the intervention was not provided, but it included physical therapy for 61 ± 58 (mean ± SD) days for inpatients, 96 ± 70 days for outpatients, and 75 ± 15 days during home rehabilitation. Again, the natural history with spontaneous improvement after GBS and the lack of a control group impairs the possibility to draw any final conclusions based on this study regarding the effectiveness of rehabilitation. However, it was shown that muscle strength measured with a MRC sum score [30] and ambulation assessed with the GBS disability score [31] continue to improve beyond the first six months of

**Exercise.** In a systematic review, Simatos and colleagues evaluated the available literature on exercise as an intervention in the rehabilitation of adult patients with GBS [32]. Studies between 1951 and 2016 were identified in PubMed searches and the quality of the studies was assessed and classified according to a modified version of the Centre for Evidence-Based Medicine level of evidence. Seven studies with exercise as the main intervention were identified, including four uncontrolled single cases with a low evidence level, one trial including multidisciplinary rehabilitation (reviewed in the previous section), [24], and two Dutch studies of a case series in an open label standardized exercise protocol (evidence level 5) [33, 34]. In the Dutch study, 16 patients were included between six months and 15 years after their GBS diagnosis as well as four patients with stable chronic inflammatory demyelinating polyradiculoneuropathy. All patients were ambulatory and reported fatigue as a major complaint. The exercise intervention consisted of three 45-minute bicycling sessions every week for 12 weeks. During the 12-week period, training intensity was gradually increased. The target heart rate increasing from 65% to a maximum of 90% of maximal heart rate and an increasing workload was applied on the bicycle home trainer. The intervention resulted in lower fatigue levels, increased isokinetic muscle strength and a higher peak oxygen uptake. Further, patients improved on a handicap scale and on the physical components score of the SF36 Quality of Life scale. Two patients did not complete the study for non-study related reasons, and 25% reported mild and transient muscle cramps, paresthesia, or pain. Overall, exercise as an intervention in patients with late disabilities and fatigue in GBS is feasible and may benefit

**Neuromuscular electrical stimulation (NMES).** In the acute phase of severe GBS, rehabilitation exercise is challenged by limited patient participation due to severe weakness or even paralysis. For practical reasons, exercise may also be challenged if patients are in the ICU, intubated and on ventilator support. Inactive and denervated muscles will indisputably and fast degenerate and muscle atrophy will develop [35, 36]. NMES is a method to induce muscle contractions without patient participation. This may be an alternative therapeutic approach in the acute phase of GBS, which can minimize inactivation and denervation wasting until patients have recovered to a level where a multidisciplinary rehabilitation effort can be initiated [37, 38]. In a small proof of concept study this has proven feasible with satisfactory safety. There was also a trend for an effect of

**104**

Neuromuscular rehabilitation after GBS is important for the functional outcome of each individual patient. Studied rehabilitation interventions in the acute, subacute/intermediate, and chronic/long-term phase are summarized in **Figure 1**. However, the quality of the present evidence of rehabilitation efficacy is low, rehabilitation is both complex, time consuming and expensive, and there is currently no standardized care for patients with neuromuscular disabilities after GBS. Therefore, the rehabilitation effort may lack necessary resources and expertise. Because the monophasic course and spontaneous recovery in GBS challenge the interpretation of non-controlled studies, future large controlled studies and standardized sensitive efficacy outcome measures are needed to improve the interpretation of neuromuscular rehabilitation trials in GBS.


#### **Figure 1.**

*Neuromuscular rehabilitation in three phases of Guillain Barré syndrome. Rehabilitation focus and studied interventions in three phases of Guillain Barré syndrome, the acute, subacute/intermediate, and chronic/ long-term phase. Level of evidence is indicated using the following grade system: Level 1, meta-analysis of multiple well designed randomized controlled trials; level 2, at least one randomized controlled trial; level 3–5, non-randomized controlled trials, descriptive studies or case series.*

## **4. Policy and procedures**

### **Neuromuscular Electrical Stimulation Protocol.**

Stimulation of the quadriceps muscle was performed using a STIWELL med4 stimulation unit, https://www.ottobock.co.th/neurorehabilitation/solutions/solutions-with-functional-electrical-stimulation/stiwell-med-4/(Otto Bock, Konigsee, Germany) and two large stimulation pads (6 × 8 cm). The intensity of electrical stimulation was titrated individually at entry and weekly during the study to the point of maximal contraction or the highest tolerable intensity. During the first session of stimulation, the skin under the pads was inspected every five minutes for redness or other signs of tissue damage. Trained physical therapists attached the equipment and titrated the stimulation intensity, but after being attached to the patient the individualized stimulation protocol ran automatically.

**Direct muscle fiber stimulation (MFS).** With MFS, contraction is induced directly through the muscle fiber membrane independent of the neuromuscular junction, which means that complete distally denervated muscle fibers can be activated. The disadvantage is that higher intensity stimulation, especially in atrophic muscle, is needed which may cause discomfort and skin irritation. MFS was applied by placing two pads over the proximal and distal part of the muscle (**Figure 2**) with triangular dual-phase stimulation pulses. The initiation protocol was 1 Hz frequency,

**107**

**Figure 2.**

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

250 ms pulse width, and 3/6 on/off ratio. The lowest pulse width with maximal contraction was chosen and frequency was increased to the highest tolerated level. **Neuromuscular electrical stimulation (NMES).** With NMES the muscle is activated through the muscle spindle and neuromuscular endplate. As a result, the contraction is more physiological and less electrical stimulation is needed. NMES was applied by one pad placed on the middle of the muscle bulk, where the neuromuscular transmission is located with rectangular dual-phase stimulation pulses. The protocol included four phases of 5, 15, 15, and 5 minutes, with frequencies of 10, 40, 60, 3 Hz, with a pulse width of 0.3 ms. Intensity could be adjusted from 0 to

*Electrical muscle stimulation. A healthy control subject with electrodes in place for direct muscle fiber* 

*stimulation of the left quadriceps femoris muscle by the STIWELL med4 stimulation unit.*

The intention was to stimulate patients five to seven days a week including 20 minutes of MFS followed by 40 minutes of NMES. Also, the NMES was applied

100 mA and was increased to the highest tolerated level.

to patients where no visible contraction could be observed.

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

#### **Figure 2.**

*Current Concepts in Zika Research*

**4. Policy and procedures**

**Figure 1.**

**Neuromuscular Electrical Stimulation Protocol.**

*non-randomized controlled trials, descriptive studies or case series.*

patient the individualized stimulation protocol ran automatically.

Stimulation of the quadriceps muscle was performed using a STIWELL med4 stimulation unit, https://www.ottobock.co.th/neurorehabilitation/solutions/solutions-with-functional-electrical-stimulation/stiwell-med-4/(Otto Bock, Konigsee, Germany) and two large stimulation pads (6 × 8 cm). The intensity of electrical stimulation was titrated individually at entry and weekly during the study to the point of maximal contraction or the highest tolerable intensity. During the first session of stimulation, the skin under the pads was inspected every five minutes for redness or other signs of tissue damage. Trained physical therapists attached the equipment and titrated the stimulation intensity, but after being attached to the

*Neuromuscular rehabilitation in three phases of Guillain Barré syndrome. Rehabilitation focus and studied interventions in three phases of Guillain Barré syndrome, the acute, subacute/intermediate, and chronic/ long-term phase. Level of evidence is indicated using the following grade system: Level 1, meta-analysis of multiple well designed randomized controlled trials; level 2, at least one randomized controlled trial; level 3–5,* 

**Direct muscle fiber stimulation (MFS).** With MFS, contraction is induced directly through the muscle fiber membrane independent of the neuromuscular junction, which means that complete distally denervated muscle fibers can be activated. The disadvantage is that higher intensity stimulation, especially in atrophic muscle, is needed which may cause discomfort and skin irritation. MFS was applied by placing two pads over the proximal and distal part of the muscle (**Figure 2**) with triangular dual-phase stimulation pulses. The initiation protocol was 1 Hz frequency,

**106**

*Electrical muscle stimulation. A healthy control subject with electrodes in place for direct muscle fiber stimulation of the left quadriceps femoris muscle by the STIWELL med4 stimulation unit.*

250 ms pulse width, and 3/6 on/off ratio. The lowest pulse width with maximal contraction was chosen and frequency was increased to the highest tolerated level.

**Neuromuscular electrical stimulation (NMES).** With NMES the muscle is activated through the muscle spindle and neuromuscular endplate. As a result, the contraction is more physiological and less electrical stimulation is needed. NMES was applied by one pad placed on the middle of the muscle bulk, where the neuromuscular transmission is located with rectangular dual-phase stimulation pulses. The protocol included four phases of 5, 15, 15, and 5 minutes, with frequencies of 10, 40, 60, 3 Hz, with a pulse width of 0.3 ms. Intensity could be adjusted from 0 to 100 mA and was increased to the highest tolerated level.

The intention was to stimulate patients five to seven days a week including 20 minutes of MFS followed by 40 minutes of NMES. Also, the NMES was applied to patients where no visible contraction could be observed.

## **5. Mini-dictionary of terms**

**Neuromuscular Electrical Stimulation**: A method to induce muscle contraction by applying an electrical impulse to the neuromuscular endplate by an electronic device.

**Multidisciplinary rehabilitation:** Two or more coordinated interventions for disabled patients to regain autonomy and functions of daily living. Usually, multidisciplinary rehabilitation is performed by physical therapists and occupational therapists but may include other professions.

**Motor dysfunction:** Several methods are used to describe motor dysfunction in GBS. Muscle weakness is a main feature of GBS, which develops quickly in the acute phase. Weakness can be assessed manually with the MRC score on a scale from 0 to 5. (0, paralysis with no visible contraction; 1, visible contraction but no limb movement; 2, limb movement only with gravity eliminated; 3, active movement against gravity; 4, active movement against gravity and resistance but reduced strength; 5, normal strength). Weakness may be quantified on a linear scale using a dynamometer [42]. In addition to weakness, chronic muscle dysfunction can result in muscle wasting, and muscle and joint contractures and shortening, which is very disabling.

**Impairment and disability:** Impairment is the direct damage caused by the disease, for example weakness of leg muscles (as described above) or loss of sensation, while disability is the loss of the function caused by the impairment, for example loss of ambulation. Often, the GBS disability score is used to describe the severity of the disease concerning the level of disability. (0, healthy; 1, minor symptoms and capable of running; 2, able to walk 10 m without assistance but unable to run; 3, able to walk 10 m across an open space with help; 4 bedridden or chair bound; 4, requiring assisted ventilation for at least part of the day; 6, death).

## **6. Key facts of neuromuscular rehabilitation in GBS**

Neuromuscular rehabilitation in Guillain Barré Syndrome can include


The prognosis of Guillain Barré Syndrome


**109**

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

• Most commonly, GBS is preceded by an infection, therefore, the incidence of GBS can increase during outbreaks of infectious diseases, which was most recently observed during the Zika Virus outbreak in the French Polynesia and Latin America with a high increase in the incidence of GBS in several

• Despite optimal evidence-based treatment with immunoglobulin and plasma exchange, a large proportion of patients with GBS will have substantial neuromuscular disabilities more than one year after disease onset. Among patients receiving mechanical ventilation, more than half will be able to walk

• In the acute phase of GBS, physical therapy is important to prevent muscle

• Patients may still improve their physical function several years after onset

• There is evidence to support high intensity multidisciplinary rehabilitation and exercise which improves level of activity and participation in the late and

• New approaches like Neuromuscular Electrical Stimulation and Virtual Motor Rehabilitation seem to be feasible methods in the acute and late stage recovery

of GBS, but efficacy needs to be explored in future studies.

FIM functional independence measure

NMES neuromuscular electrical stimulation

GBS Guillain Barré syndrome ICU intensive care unit

PE plasma exchange

IVIG intravenous immunoglobulin MFS muscle fiber stimulation

VMR virtual motor rehabilitation

**7. Summary points of neuromuscular rehabilitation in GBS**

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

shortening and joint contractures.

countries.

unassisted.

of GBS.

**Abbreviations**

chronic stages of GBS.

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

## **7. Summary points of neuromuscular rehabilitation in GBS**


## **Abbreviations**

*Current Concepts in Zika Research*

**5. Mini-dictionary of terms**

therapists but may include other professions.

tronic device.

**Neuromuscular Electrical Stimulation**: A method to induce muscle contraction by applying an electrical impulse to the neuromuscular endplate by an elec-

**Multidisciplinary rehabilitation:** Two or more coordinated interventions for disabled patients to regain autonomy and functions of daily living. Usually, multidisciplinary rehabilitation is performed by physical therapists and occupational

**Motor dysfunction:** Several methods are used to describe motor dysfunction in GBS. Muscle weakness is a main feature of GBS, which develops quickly in the acute phase. Weakness can be assessed manually with the MRC score on a scale from 0 to 5. (0, paralysis with no visible contraction; 1, visible contraction but no limb movement; 2, limb movement only with gravity eliminated; 3, active movement against gravity; 4, active movement against gravity and resistance but reduced strength; 5, normal strength). Weakness may be quantified on a linear scale using a dynamometer [42]. In addition to weakness, chronic muscle dysfunction can result in muscle wasting, and muscle and joint contractures and shortening, which is very disabling. **Impairment and disability:** Impairment is the direct damage caused by the disease, for example weakness of leg muscles (as described above) or loss of sensation, while disability is the loss of the function caused by the impairment, for example loss of ambulation. Often, the GBS disability score is used to describe the severity of the disease concerning the level of disability. (0, healthy; 1, minor symptoms and capable of running; 2, able to walk 10 m without assistance but unable to run; 3, able to walk 10 m across an open space with help; 4 bedridden or chair bound; 4,

requiring assisted ventilation for at least part of the day; 6, death).

Neuromuscular rehabilitation in Guillain Barré Syndrome can include

• Exercise and training to improve or maintain physical functioning.

• Neuromuscular electrical stimulation to prevent muscle wasting.

• Physical therapy to prevent muscle and joint shortening and contractures.

• Multidisciplinary rehabilitation with two or more coordinated interventions for disabled patients to regain autonomy and functions of daily living.

• Guillain Barré Syndrome is a heterogenous disorder with a monophasic course.

• Clinical severity ranges from mild impairment to complete paralysis combined

• In 20 to 30% of patients, mechanical ventilation is required at nadir of GBS.

• The most severely affected patients have a long recovery phase and a poor

• More than half of all mechanically ventilated patients are unable to walk unas-

**6. Key facts of neuromuscular rehabilitation in GBS**

The prognosis of Guillain Barré Syndrome

with respiratory and autonomic failure.

sisted at one year follow up.

**108**

prognosis.


*Current Concepts in Zika Research*

## **Author details**

Thomas Harbo\* and Henning Andersen Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

\*Address all correspondence to: tharbo@dadlnet.dk

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**111**

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

associated with Zika virus infection in Colombia. *N.Engl.J.Med.*, 375, (16) 1513- 1523 available from: PM:27705091

[7] Rodriguez-Morales AJ, Failoc-Rojas VE, Diaz-Velez C. Gastrointestinal, respiratory and/or arboviral infections? What is the cause of the Guillain-Barre syndrome epidemics in Peru? Current status - 2019. Travel.Med.Infect.Dis. 2019;**30**:114-116 available from:

[8] Villamil-Gomez WE,

available from: PM:28347781

[10] Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barre syndrome. Lancet. 2016;**388**(10045):717-727 available from: PM:26948435

[11] Wakerley BR, Yuki N. Mimics and chameleons in Guillain-Barre and Miller fisher syndromes. Pract.Neurol. 2015;**15**(2):90-99 available from:

Rodriguez F, Hernandez-Pereira CE, Rodriguez-Morales AJ, Blohm GM, et al. Ocular flutter following Zika virus infection. Journal of Neurovirology. 2017;**23**(6):932-934 available from:

[13] Hadden RD, Cornblath DR, Hughes RA, Zielasek J, Hartung HP,

PM:25239628

PM:29147884

[12] Karam E, Giraldo J,

Sanchez-Herrera AR, Hernandez H, Hernandez-Iriarte J, Diaz-Ricardo K, Castellanos J, et al. Guillain-Barre syndrome during the Zika virus outbreak in Sucre, Colombia, 2016. Travel.Med.Infect.Dis. 2017;**16**:62-63

[9] Zambrano LI, Fuentes-Barahona IC, Soto-Fernandez RJ, Zuniga C, da Silva JC, Rodriguez-Morales AJ. Guillain-Barre syndrome associated with Zika virus infection in Honduras, 2016-2017. Int.J.Infect.Dis. 2019;**84**:136- 137 available from: PM:31096053

PM:31265907

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

[1] Leonhard SE, Conde RM, de Assis Aquino GF, Jacobs BC. Diagnosis and treatment of Guillain-Barre syndrome during the Zika virus epidemic in Brazil: A national survey study. J.Peripher.Nerv. Syst. 2019a;**24**(4):340-347 available

[2] Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira MLB, Cornblath DR, et al. Diagnosis and management of Guillain-Barre

[3] Sipila JO, Soilu-Hanninen M. The incidence and triggers of adultonset Guillain-Barre syndrome in southwestern Finland 2004-2013. European Journal of Neurology. 2015;**22**(2):292-298 available from:

syndrome in ten steps. Nat.Rev.Neurol. 2019b;**15**(11):671-683 available from:

[4] Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study. Lancet. 2016;**387**(10027):1531-1539 available from: PM:26948433

[5] Cardona-Ospina, J.A., Henao-SanMartin, V., Acevedo-Mendoza, W.F., Nasner-Posso, K.M., Martinez-Pulgarin, D.F., Restrepo-Lopez, A., Valencia-Gallego, V., Collins, M.H., & Rodriguez-Morales, A.J. 2019. Fatal Zika virus infection in the Americas: A systematic review. Int.J.Infect.Dis., 88, 49-59 available from: PM:31499212

[6] Parra, B., Lizarazo, J., Jimenez-Arango, J.A., Zea-Vera, A.F., Gonzalez-Manrique, G., Vargas, J., Angarita, J.A., Zuniga, G., Lopez-Gonzalez, R., Beltran, C.L., Rizcala, K.H., Morales, M.T., Pacheco, O., Ospina, M.L., Kumar, A., Cornblath, D.R., Munoz, L.S., Osorio, L., Barreras, P., & Pardo, C.A. 2016. Guillain-Barre syndrome

from: PM:31746070

**References**

PM:31541214

PM:25196425

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

## **References**

*Current Concepts in Zika Research*

**110**

**Author details**

Thomas Harbo\* and Henning Andersen

provided the original work is properly cited.

\*Address all correspondence to: tharbo@dadlnet.dk

Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Leonhard SE, Conde RM, de Assis Aquino GF, Jacobs BC. Diagnosis and treatment of Guillain-Barre syndrome during the Zika virus epidemic in Brazil: A national survey study. J.Peripher.Nerv. Syst. 2019a;**24**(4):340-347 available from: PM:31746070

[2] Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira MLB, Cornblath DR, et al. Diagnosis and management of Guillain-Barre syndrome in ten steps. Nat.Rev.Neurol. 2019b;**15**(11):671-683 available from: PM:31541214

[3] Sipila JO, Soilu-Hanninen M. The incidence and triggers of adultonset Guillain-Barre syndrome in southwestern Finland 2004-2013. European Journal of Neurology. 2015;**22**(2):292-298 available from: PM:25196425

[4] Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre syndrome outbreak associated with Zika virus infection in French Polynesia: A case-control study. Lancet. 2016;**387**(10027):1531-1539 available from: PM:26948433

[5] Cardona-Ospina, J.A., Henao-SanMartin, V., Acevedo-Mendoza, W.F., Nasner-Posso, K.M., Martinez-Pulgarin, D.F., Restrepo-Lopez, A., Valencia-Gallego, V., Collins, M.H., & Rodriguez-Morales, A.J. 2019. Fatal Zika virus infection in the Americas: A systematic review. Int.J.Infect.Dis., 88, 49-59 available from: PM:31499212

[6] Parra, B., Lizarazo, J., Jimenez-Arango, J.A., Zea-Vera, A.F., Gonzalez-Manrique, G., Vargas, J., Angarita, J.A., Zuniga, G., Lopez-Gonzalez, R., Beltran, C.L., Rizcala, K.H., Morales, M.T., Pacheco, O., Ospina, M.L., Kumar, A., Cornblath, D.R., Munoz, L.S., Osorio, L., Barreras, P., & Pardo, C.A. 2016. Guillain-Barre syndrome

associated with Zika virus infection in Colombia. *N.Engl.J.Med.*, 375, (16) 1513- 1523 available from: PM:27705091

[7] Rodriguez-Morales AJ, Failoc-Rojas VE, Diaz-Velez C. Gastrointestinal, respiratory and/or arboviral infections? What is the cause of the Guillain-Barre syndrome epidemics in Peru? Current status - 2019. Travel.Med.Infect.Dis. 2019;**30**:114-116 available from: PM:31265907

[8] Villamil-Gomez WE, Sanchez-Herrera AR, Hernandez H, Hernandez-Iriarte J, Diaz-Ricardo K, Castellanos J, et al. Guillain-Barre syndrome during the Zika virus outbreak in Sucre, Colombia, 2016. Travel.Med.Infect.Dis. 2017;**16**:62-63 available from: PM:28347781

[9] Zambrano LI, Fuentes-Barahona IC, Soto-Fernandez RJ, Zuniga C, da Silva JC, Rodriguez-Morales AJ. Guillain-Barre syndrome associated with Zika virus infection in Honduras, 2016-2017. Int.J.Infect.Dis. 2019;**84**:136- 137 available from: PM:31096053

[10] Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barre syndrome. Lancet. 2016;**388**(10045):717-727 available from: PM:26948435

[11] Wakerley BR, Yuki N. Mimics and chameleons in Guillain-Barre and Miller fisher syndromes. Pract.Neurol. 2015;**15**(2):90-99 available from: PM:25239628

[12] Karam E, Giraldo J, Rodriguez F, Hernandez-Pereira CE, Rodriguez-Morales AJ, Blohm GM, et al. Ocular flutter following Zika virus infection. Journal of Neurovirology. 2017;**23**(6):932-934 available from: PM:29147884

[13] Hadden RD, Cornblath DR, Hughes RA, Zielasek J, Hartung HP, Toyka KV, et al. Electrophysiological classification of Guillain-Barre syndrome: Clinical associations and outcome. Plasma exchange/ Sandoglobulin Guillain-Barre syndrome trial group. Annals of Neurology. 1998;**44**(5):780-788 available from: PM:9818934

[14] Al-Hakem H, Sindrup SH, Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barre syndrome in Denmark: A populationbased study on epidemiology, diagnosis and clinical severity. J.Neurol. 2019;**266**(2):440-449 available from: PM:30536111

[15] van den Berg B, Storm EF, Garssen MJP, Blomkwist-Markens PH, Jacobs BC. Clinical outcome of Guillain-Barre syndrome after prolonged mechanical ventilation. Journal of Neurology, Neurosurgery, and Psychiatry. 2018;**89**(9):949-954 available from: PM:29627773

[16] Hughes RA, Wijdicks EF, Benson E, Cornblath DR, Hahn AF, Meythaler JM, et al. Supportive care for patients with Guillain-Barre syndrome. Archives of Neurology. 2005;**62**(8):1194-1198 available from: PM:16087757

[17] Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barre syndrome. Brain. 2018;**141**(10):2866-2877 available from: PM:30247567

[18] Chevret, S., Hughes, R.A., & Annane, D. 2017. Plasma exchange for Guillain-Barre syndrome. Cochrane. Database.Syst.Rev., 2, CD001798 available from: PM:28241090

[19] Hughes, R.A., Swan, A.V., & van Doorn, P.A. 2014. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane.Database.Syst. Rev., 9, CD002063 available from: PM:25238327

[20] Davidson AI, Halstead SK, Goodfellow JA, Chavada G, Mallik A, Overell J, et al. Inhibition of complement in Guillain-Barre syndrome: The ICA-GBS study. J.Peripher.Nerv.Syst. 2017;**22**(1):4-12 available from: PM:27801990

[21] Misawa S, Kuwabara S, Sato Y, Yamaguchi N, Nagashima K, Katayama K, et al. Safety and efficacy of eculizumab in Guillain-Barre syndrome: A multicentre, doubleblind, randomised phase 2 trial. Lancet Neurology. 2018;**17**(6):519-529 available from: PM:29685815

[22] Pritchard, J., Hughes, R.A., Hadden, R.D., & Brassington, R. 2016. Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain-Barre syndrome. Cochrane. Database.Syst.Rev., 11, CD008630 available from: PM:27846348

[23] Khan F, Amatya B. Rehabilitation interventions in patients with acute demyelinating inflammatory polyneuropathy: A systematic review. Eur.J.Phys.Rehabil.Med. 2012;**48**(3):507- 522 available from: PM:22820829

[24] Khan F, Pallant JF, Amatya B, Ng L, Gorelik A, Brand C. Outcomes of high- and low-intensity rehabilitation programme for persons in chronic phase after Guillain-Barre syndrome: A randomized controlled trial. J.Rehabil. Med. 2011;**43**(7):638-646 available from: PM:21667009

[25] Demir SO, Koseoglu F. Factors associated with health-related quality of life in patients with severe Guillain-Barre syndrome. Disabil.Rehabil. 2008;**30**(8):593-599 available from: PM:17852306

[26] Gupta, A., Taly, A.B., Srivastava, A., & Murali, T. 2010. Guillain-Barre Syndrome–rehabilitation outcome, residual deficits and requirement of

**113**

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika…*

in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. J.Rehabil.Med. 2007;**39**(2):121-125 available from:

[34] Garssen MP, Bussmann JB,

Schmitz PI, Zandbergen A, Welter TG, Merkies IS, et al. Physical training and fatigue, fitness, and quality of life in Guillain-Barre syndrome and CIDP. Neurology. 2004;**63**(12):2393-2395 available from: PM:15623709

[35] Griffiths RD, Palmer TE, Helliwell T, MacLennan P, MacMillan RR. Effect of passive stretching on the wasting of muscle in the critically ill. Nutrition. 1995;**11**(5):428-432 available from:

[36] Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance

2004;**23**(2):273-280 available from:

electrical stimulation for muscle weakness in adults with advanced disease. Cochrane.Database.Syst. Rev. (1) CD009419 available from:

[38] Maffiuletti, N.A., Roig, M., Karatzanos, E., & Nanas, S. 2013. Neuromuscular electrical stimulation for preventing skeletal-muscle weakness and wasting in critically ill patients: A systematic review. BMC.Med., 11, 137

available from: PM:23701811

[39] Harbo T, Markvardsen LK, Hellfritzsch MB, Severinsen K,

electrical stimulation in early rehabilitation of Guillain-Barre syndrome: A pilot study. Muscle & Nerve. 2019;**59**(4):481-484 available

from: PM:30549053

Nielsen JF, Andersen H. Neuromuscular

[40] El ML, Calmels P, Camdessanche JP,

Gautheron V, Feasson L. Muscle

[37] Maddocks, M., Gao, W., Higginson, I.J., & Wilcock, A. 2013. Neuromuscular

in critical illness. Clin.Nutr.

PM:17351693

PM:8748193

PM:15030968

PM:23440837

*DOI: http://dx.doi.org/10.5772/intechopen.93930*

lower limb orthosis for locomotion at 1 year follow-up. Disabil.Rehabil., 32, (23) 1897-1902 available from:

[27] Meythaler JM, DeVivo MJ,

[28] Nicholas R, Playford ED,

[29] Prada V, Massa F, Salerno A, Fregosi D, Beronio A, Serrati C, et al. Importance of intensive and prolonged rehabilitative treatment on the Guillain-Barre syndrome long-term outcome: A retrospective study. Neurol.Sci. 2019

available from: PM:31586288

[30] Medical Research Council. Aids to examination of the peripheral nervous system. London: HMSO. Memorandum

[31] Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial prednisolone in acute polyneuropathy. Lancet. 1978;**2**(8093):750-753 available

[32] Simatos AN, Vincent PO, Yu BH, Bastien R, Sweeney A. Influence of exercise on patients with Guillain-Barre syndrome: A systematic review. Physiotherapy Canada. 2016;**68**(4):367- 376 available from: PM:27904236

[33] Bussmann JB, Garssen MP, van Doorn PA, Stam HJ. Analysing the favourable effects of physical exercise: Relationships between physical fitness, fatigue and functioning

Braswell WC. Rehabilitation outcomes of patients who have developed Guillain-Barre syndrome. American Journal of Physical Medicine & Rehabilitation. 1997;**76**(5):411-419 available from: PM:9354496

Thompson AJ. A retrospective analysis of outcome in severe Guillain-Barre syndrome following combined neurological and rehabilitation management. Disabil.Rehabil. 2000;**22**(10):451-455 available from:

PM:20331413

PM:10950498

No. 1976;**45**

from: PM:80682

*Neuromuscular Effects and Rehabilitation in Guillain-Barré Syndrome Associated with Zika… DOI: http://dx.doi.org/10.5772/intechopen.93930*

lower limb orthosis for locomotion at 1 year follow-up. Disabil.Rehabil., 32, (23) 1897-1902 available from: PM:20331413

*Current Concepts in Zika Research*

[14] Al-Hakem H, Sindrup SH,

and clinical severity. J.Neurol. 2019;**266**(2):440-449 available from:

[15] van den Berg B, Storm EF,

Jacobs BC. Clinical outcome of Guillain-Barre syndrome after prolonged mechanical ventilation. Journal of Neurology, Neurosurgery, and Psychiatry. 2018;**89**(9):949-954 available from: PM:29627773

available from: PM:16087757

PM:30247567

[17] Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barre syndrome. Brain. 2018;**141**(10):2866-2877 available from:

[18] Chevret, S., Hughes, R.A., & Annane, D. 2017. Plasma exchange for Guillain-Barre syndrome. Cochrane. Database.Syst.Rev., 2, CD001798 available from: PM:28241090

[19] Hughes, R.A., Swan, A.V., & van Doorn, P.A. 2014. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane.Database.Syst. Rev., 9, CD002063 available from:

Garssen MJP, Blomkwist-Markens PH,

[16] Hughes RA, Wijdicks EF, Benson E, Cornblath DR, Hahn AF, Meythaler JM, et al. Supportive care for patients with Guillain-Barre syndrome. Archives of Neurology. 2005;**62**(8):1194-1198

PM:9818934

PM:30536111

Toyka KV, et al. Electrophysiological classification of Guillain-Barre syndrome: Clinical associations and outcome. Plasma exchange/

[20] Davidson AI, Halstead SK, Goodfellow JA, Chavada G,

available from: PM:27801990

[21] Misawa S, Kuwabara S,

from: PM:29685815

Mallik A, Overell J, et al. Inhibition of complement in Guillain-Barre syndrome: The ICA-GBS study. J.Peripher.Nerv.Syst. 2017;**22**(1):4-12

Sato Y, Yamaguchi N, Nagashima K, Katayama K, et al. Safety and efficacy of eculizumab in Guillain-Barre syndrome: A multicentre, doubleblind, randomised phase 2 trial. Lancet Neurology. 2018;**17**(6):519-529 available

[22] Pritchard, J., Hughes, R.A., Hadden, R.D., & Brassington, R. 2016. Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain-Barre syndrome. Cochrane. Database.Syst.Rev., 11, CD008630 available from: PM:27846348

[23] Khan F, Amatya B. Rehabilitation

interventions in patients with acute demyelinating inflammatory polyneuropathy: A systematic review. Eur.J.Phys.Rehabil.Med. 2012;**48**(3):507-

522 available from: PM:22820829

[24] Khan F, Pallant JF, Amatya B, Ng L, Gorelik A, Brand C. Outcomes of high- and low-intensity rehabilitation programme for persons in chronic phase after Guillain-Barre syndrome: A randomized controlled trial. J.Rehabil. Med. 2011;**43**(7):638-646 available

[25] Demir SO, Koseoglu F. Factors associated with health-related quality of life in patients with severe Guillain-Barre syndrome. Disabil.Rehabil. 2008;**30**(8):593-599 available from:

[26] Gupta, A., Taly, A.B., Srivastava, A., & Murali, T. 2010. Guillain-Barre Syndrome–rehabilitation outcome, residual deficits and requirement of

from: PM:21667009

PM:17852306

Sandoglobulin Guillain-Barre syndrome trial group. Annals of Neurology. 1998;**44**(5):780-788 available from:

Andersen H, de la Cour CD, Lassen LL, van den Berg B, et al. Guillain-Barre syndrome in Denmark: A populationbased study on epidemiology, diagnosis

**112**

PM:25238327

[27] Meythaler JM, DeVivo MJ, Braswell WC. Rehabilitation outcomes of patients who have developed Guillain-Barre syndrome. American Journal of Physical Medicine & Rehabilitation. 1997;**76**(5):411-419 available from: PM:9354496

[28] Nicholas R, Playford ED, Thompson AJ. A retrospective analysis of outcome in severe Guillain-Barre syndrome following combined neurological and rehabilitation management. Disabil.Rehabil. 2000;**22**(10):451-455 available from: PM:10950498

[29] Prada V, Massa F, Salerno A, Fregosi D, Beronio A, Serrati C, et al. Importance of intensive and prolonged rehabilitative treatment on the Guillain-Barre syndrome long-term outcome: A retrospective study. Neurol.Sci. 2019 available from: PM:31586288

[30] Medical Research Council. Aids to examination of the peripheral nervous system. London: HMSO. Memorandum No. 1976;**45**

[31] Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial prednisolone in acute polyneuropathy. Lancet. 1978;**2**(8093):750-753 available from: PM:80682

[32] Simatos AN, Vincent PO, Yu BH, Bastien R, Sweeney A. Influence of exercise on patients with Guillain-Barre syndrome: A systematic review. Physiotherapy Canada. 2016;**68**(4):367- 376 available from: PM:27904236

[33] Bussmann JB, Garssen MP, van Doorn PA, Stam HJ. Analysing the favourable effects of physical exercise: Relationships between physical fitness, fatigue and functioning

in Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. J.Rehabil.Med. 2007;**39**(2):121-125 available from: PM:17351693

[34] Garssen MP, Bussmann JB, Schmitz PI, Zandbergen A, Welter TG, Merkies IS, et al. Physical training and fatigue, fitness, and quality of life in Guillain-Barre syndrome and CIDP. Neurology. 2004;**63**(12):2393-2395 available from: PM:15623709

[35] Griffiths RD, Palmer TE, Helliwell T, MacLennan P, MacMillan RR. Effect of passive stretching on the wasting of muscle in the critically ill. Nutrition. 1995;**11**(5):428-432 available from: PM:8748193

[36] Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance in critical illness. Clin.Nutr. 2004;**23**(2):273-280 available from: PM:15030968

[37] Maddocks, M., Gao, W., Higginson, I.J., & Wilcock, A. 2013. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane.Database.Syst. Rev. (1) CD009419 available from: PM:23440837

[38] Maffiuletti, N.A., Roig, M., Karatzanos, E., & Nanas, S. 2013. Neuromuscular electrical stimulation for preventing skeletal-muscle weakness and wasting in critically ill patients: A systematic review. BMC.Med., 11, 137 available from: PM:23701811

[39] Harbo T, Markvardsen LK, Hellfritzsch MB, Severinsen K, Nielsen JF, Andersen H. Neuromuscular electrical stimulation in early rehabilitation of Guillain-Barre syndrome: A pilot study. Muscle & Nerve. 2019;**59**(4):481-484 available from: PM:30549053

[40] El ML, Calmels P, Camdessanche JP, Gautheron V, Feasson L. Muscle

#### *Current Concepts in Zika Research*

strength recovery in treated Guillain-Barre syndrome: A prospective study for the first 18 months after onset. American Journal of Physical Medicine & Rehabilitation. 2007;**86**(9):716-724 available from: PM:17709995

[41] Albiol-Perez S, Forcano-Garcia M, Munoz-Tomas MT, Manzano-Fernandez P, Solsona-Hernandez S, Mashat MA, et al. A novel virtual motor rehabilitation system for Guillain-Barre syndrome. Two single case studies. Methods Inf. Med. 2015;**54**(2):127-134 available from: PM:25609504

[42] Harbo T, Brincks J, Andersen H. Maximal isokinetic and isometric muscle strength of major muscle groups related to age, body mass, height, and sex in 178 healthy subjects. Eur.J.Appl. Physiol. 2012;**112**(1):267-275 available from: PM:21537927

*Current Concepts in Zika Research*

available from: PM:17709995

PM:25609504

from: PM:21537927

strength recovery in treated Guillain-Barre syndrome: A prospective study for the first 18 months after onset. American Journal of Physical Medicine & Rehabilitation. 2007;**86**(9):716-724

[41] Albiol-Perez S, Forcano-Garcia M, Munoz-Tomas MT, Manzano-Fernandez P, Solsona-Hernandez S, Mashat MA, et al. A novel virtual motor rehabilitation system for Guillain-Barre syndrome. Two single case studies. Methods Inf. Med. 2015;**54**(2):127-134 available from:

[42] Harbo T, Brincks J, Andersen H. Maximal isokinetic and isometric muscle strength of major muscle groups related to age, body mass, height, and sex in 178 healthy subjects. Eur.J.Appl. Physiol. 2012;**112**(1):267-275 available

**114**

## *Edited by Alfonso J. Rodriguez-Morales*

Zika is an arboviral disease that has caused a significant impact, especially in the Americas after the epidemics in 2015 and 2016. The World Health Organization (WHO) declared it as a Public Health Emergency of International Concern (PHEIC) in 2016, linking it with the Guillain-Barré syndrome and especially the microcephaly and the Congenital Zika Syndrome. The multiple consequences, especially in the central and peripheral nervous system in the short and long term, are still to be better defined. Therefore research on Zika is crucial. This book presents an update of the significant epidemiological and clinical research of Zika over the last years in many aspects and from a multinational perspective.

Published in London, UK © 2021 IntechOpen © Racksuz / iStock

Current Concepts in Zika Research

Current Concepts

in Zika Research

*Edited by Alfonso J. Rodriguez-Morales*