Guillain-Barre Syndrome

Introduction

Guillain-Barre syndrome (GBS) is an acute autonomic disorder characterized by rapid-onset areflexic muscle paralysis with characteristic albuminocytologic dissociation in cerebrospinal fluid (CSF). Landry defined the illness approximately 150 years ago as a quickly ascending progressive paralysis (Landry’s paralysis). In 1916, Guillain, Barre and Strohl described the clinical features as motor weakness, areflexia, paraesthesia with slight sensory loss, and increased protein in the cerebrospinal fluid without pleocytosis.¹

GBS is noted all over the world in patients of all ages and both sexes. It forms the most common cause of acute flaccid paralysis, which may develop suddenly or gradually in a matter of days. The global incidence is approximately 1-2 cases per 100,000 persons annually.

Recently, the Public Health Department of Maharashtra has reported 180 suspected cases of GBS, of which 146 cases were confirmed positive, with 6 deaths by 9th February 2025, 22 patients are on ventilator support. 121 stool samples have been tested, of them, 28 have tested positive for Norovirus and 5 for Campylobacter jujuni. Preceding bacterial and viral infections weaken the patients’ immunity, leading to the development of GBS. The Pune outbreak could be one of the largest in the World.²

A severe case of GBS has been reported from Siddipet in Telangana. A 25-year-old female has presented with severe manifestations necessitating ventilator support. A case of GB syndrome in a 17-year-old female has been reported from Assam, and was on ventilator support.

Definition

Guillain-Barre syndrome is an acute immune-mediated polyneuropathy where the body's immune system attacks peripheral nerves by mistake. The condition presents clinically with acute onset of symmetric limb weakness, areflexia, and pathologically with demyelination and/or axonal degeneration of peripheral nerves.

Aetiopathogenesis

The condition was considered for an extended period as an acute inflammatory demyelinating polyradiculoneuropathy. Recent experimental studies have shown axonal degeneration, which may be primary or secondary.^3,4 The former situation has been proved based on clinical, electrophysiologic, and pathologic studies. Hence, Guillain-Barre syndrome is appropriately considered an acute motor and sensory axonal neuropathy.

The cause and pathogenesis of GBS remain undetermined. Symptoms of respiratory tract infection or diarrhoea precede the neuropathic symptoms in nearly two-thirds of cases. C. jejuni has been recognized as a common antecedent of Guillain-Barre Syndrome. The patients with preceding C. jejuni infection are more likely to have acute axonal neuro-pathy or axonal degeneration.⁵ The condition occurs due to an acute immune response to C. jejuni rather than as a direct effect of the organism or one of its toxins. The nature of the immune response is undetermined. Other viruses such as Cytomegalovirus, Epstein-Barr virus, (HIV), Varicella-zoster virus, Zika virus, and Mycoplasma pneumoniae may infrequently precipitate poly-randiculoneuropathies.^5,6 The administration of certain vaccines, such as Influenza, has been linked to the development of GBS.

Guillain-Barré syndrome is the most common post-infectious inflammatory peripheral neuropathy. Datta and colleagues investigated the role of infectious agents in triggering GBS. 119 out of 150 patients with GBS showed serological evidence of antecedent infection. Chikungunya was the most ordinary antecedent infection, followed by C. jejuni.⁷

A cell-mediated inflammatory response is directed at the spinal roots' myelin protein in the peripheral and extra-axial cranial nerves. The inflammatory cytokines released, block nerve conduction. In severe cases, it is followed by a complement-mediated destruction of the myelin sheath and the associated axons.

The pathological abnormalities in acute inflammatory demyelinating polyneuropathy are the presence of inflammatory infiltrates, essentially of T cells and macrophages, and areas of segmental demyelination, often associated with secondary axonal degeneration.

GBS has been considered an acquired, acute, inflam-matory, immune-mediated disorder of the peripheral nervous system usually triggered by infectious or other immunogenic stimuli.⁸ Though auto-antigens have not been conclusively recognized, auto-antibodies appear to bind to myelin antigens and activate the complement pathway. It leads to the development of a membrane attack complex (MAC) on the outer surface of Schwann cells and initiates vesicular degeneration. Macrophages infiltrate the region and remove myelin debris.⁹ There appears to be a molecular mimicry between the bacterial C. jejuni and peripheral nerve components to elicit auto-antibodies.

Gangliosides form the main component of the peripheral nerves. They consist of a ceramide attached to one or more hexoses and contain sialic acid (N-acetylneuraminic acid) linked to an oligosaccharide core. Four gangliosides have been recognized as GM1, GD1a, GT1a, and GQ1b, and they represent mono (M), di-(D), tri-(T), and quadric- (Q) sialosyl groups. There is a marked expression of GM1 and GD1a at the nodes of Ranvier. IgG anti-GMI or anti-GD1a autoantibodies bind to the nodal axolemma and result in the formation of MAC. The presence of IgG autoantibodies against GMI and GD1a are strongly associated with acute motor axonal neuropathy, acute motor-sensory axonal neuropathy, and acute motor neuropathy. IgG anti-GQ1b antibodies are strongly associated with Miller-Fisher syndrome.⁸ Anti-ganglioside antibodies, though, are beneficial for atypical cases; they are not routinely used in sensory-motor GBS due to low sensitivity.

Disease spectrum

Guillain-Barre syndrome was considered a demyelin-ating polyneuropathy referred to as acute inflammatory demyelinating polyneuropathy (AIDP). Now, the spectrum of the peripheral nerve disorder has been widened with several clinical variants and classified according to the fibre type involved (sensory, motor, sensory and motor, and cranial) and the predominant type of injury as demyelinating and axonal subtypes.¹⁰

a) Acute inflammatory demyelinating polyneuropathy (AIDP): AIDP is the most typical pattern of the disease manifestation. Males exhibit a higher risk than females. It presents a subacute progression of symmetric weakness. Weakness is noted in distal parts of the lower extremities, associated with foot drop and unsteadiness in gait. It may progress to cause paralysis, facial diplegia, and diaphragmatic paralysis. Lower cranial nerves may be involved, causing bulbar weakness. There is motor weakness, areflexia, minimal sensory disturbances, and autonomic disturbances. There may be tingling dysesthesia in the extremities and, later, pain in the neck, shoulder, and back. The condition is not associated with fever or constitutional symptoms at onset. The cutaneous sensory deficits are mild, and there are no bladder disturbances. Autonomic involvement causes loss of vasomotor control with wide fluctuation in blood pressure and postural hypotension. There is axonal injury due to an immune attack against myelin. The condition is essentially demyelinating.

b) Acute motor-sensory axonal neuropathy (AMSAN): Acute motor and sensory axonal neuropathy show progressive sensory loss and motor weakness. The occurrence of respiratory failure is rapid, necessitating ventilatory support. There is marked sensory involvement at the time of onset. The motor and sensory nerves are not excitable early on in EMG/NCS studies and in nearly 50% of cases, anti-CD1b. However, the condition exhibits minimal inflammation and demyelination. The injury is axonal.

c) Acute motor axonal neuropathy (AMAN): Acute motor axonal neuropathy makes an abrupt onset of motor weakness without any sensory loss. Often, the condition is preceded by upper respiratory infection or C. jejuni infection. EMG/NCP studies demonstrate diminished compound motor action potential amplitude and standard sensory potentials. The presence of anti-GM1 and anti-GD1a antibodies can be demonstrated in 50% of cases. The condition has been reported in rural China. Hence, the name Chinese paralytic illness is used to describe the condition. The condition results from axonal injury.

d) Miller-Fisher syndrome (MFS): Following Campy-lobacter infection, there can be limited or regional GBS with manifestations of rapidly evolving external ophthalmoplegia (paralysis of ocular muscles), ataxia, and areflexia, and the condition is named Miller-Fisher syndrome. It was reported in 1956 as a likely variant of GBS.¹¹ The condition may present with facial diplegia. There is no weakness in the extremities. Incomplete forms of the condition include acute ophthalmoparesis without ataxia or acute ataxia neuropathy without ophthalmoplegia. Antibodies to the ganglioside GQ1b are present, and the demonstration of their presence is helpful for the diagnosis. The condition is demyelinating. There can be an alteration of consciousness. The condition also exhibits albuminocytologic dissociation in the cerebrospinal fluid. The raised level of IgG against GQ1 is particular. The condition has a good prognosis.

e) Localized forms of GBS: Localized forms of the GBS involve certain muscle groups or nerves.⁹ There are two examples. In a localized form of demyelinating GBS, there is the presence of facial diplegia with paraesthesia, and in a localized form of the axonal GBS, there is a pharyngeal-cervical-brachial weakness that manifests with weakness of oropharyngeal, shoulder, and neck muscles.

Manifestations

Acute inflammatory demyelinating polyneuropathy appears 1-4 weeks following upper respiratory infection or diarrhoea especially caused by C. jejuni. Such a history may not be available in nearly 30 percent of patients.

The spectrum of C. jejuni induced Guillain-Barre Syndrome ranges from mild cases of demyelinating neuropathy to rapidly progressive axonal neuropathy with prolonged recovery and severe residual disability.⁵ These patients appear to have ‘hyperacute’ onset following gastroenteritis.¹¹ Initially, the condition presents with numbness, distal parasthesia, weakness, and pain in the limbs. It is followed by rapidly ascending lower and upper extremities muscle weak-ness. Weakness ascends from lower limbs proximally over hours to several days. Weakness is more marked proximally than distally. The condition progresses over days to 4 weeks.¹¹ There is relative symmetry of the manifestations. Most patients cannot walk independently when maximum weakness is reached. There is generalized hypo or areflexia with flaccid paralysis. Unusually, some patients may exhibit normal or brisk reflexes during the illness.

Sensory symptoms are mild. It may be limited frequently to distal impairment of vibration sense. There may be cranial nerve involvement, especially facial nerve, that exhibits bifacial paralysis. Nearly 20 percent of patients may develop respiratory weakness, necessitating ventilatory support. There may be autono-mic dysfunctions such as orthostatic hypotension, anid-rosis, dry eyes and mouth, fixed pupils, urinary retention or hypertension, tachycardia, episodic diaphoresis or  bradycardia, and heart block.¹² Recovery begins 2 to 4 weeks after progression ceases. A variant, Miller- Fisher syndrome, may present with ophthalmoplegia, diplopia, ataxia, rapid onset symmetric cranial palsy, and areflexia.¹³

GBS has caused multiple epidemics in Peru. In the 2019 outbreak of GBS in Peru, of the 683 patients, 287 (42%) showed descending muscle weakness, and 446 (65.3%) exhibited ascending weakness. In 530 patients, there was preceding respiratory and gastrointestinal infection in 219 (41.3%) patients. The infection had been seen 4 weeks before neurological manifestations. 195(36.8%) patients had a history of preceding respiratory illness, and only 3 (0.6%) patients had a history of an antecedent gastrointestinal infection. 113 (21.3%) patients did not have any preceding infection.¹⁴

Diagnosis

In the initial stages of the illness, no laboratory or electrophysiologic abnormalities were evident. The diagnosis is made based on a detailed history and detailed neurologic examination. It localizes the disease to the peripheral nerves. The key is the presence of an ascending weakness beginning in the distal lower extremities. The distribution of weakness may exhibit variability, and may progress quickly, resulting in severe weakness in all extremities. It may even lead to respiratory failure due to respiratory muscle weakness, necessitating ventilatory assistance.

The diagnosis of Guillain-Barre Syndrome must be made quickly and accurately. Diagnostic procedures include cerebrospinal fluid examination, nerve condu-ction velocity (NCV) studies, and electromyography (EMG). The CSF examination, at the peak of weakness, characteristically shows albuminocytologic dissocia-tion. There is elevated protein concentration and regular or sometimes a mild increase in cell count. Some patients may even show pleocytosis. Even protein concentration may be expected during the first week of illness.

Nerve conduction velocity studies using surface or needle electrodes are carried out to record action poten-tials from nerves that lie close to the skin's surface. It helps to identify the damage to the peripheral nerves. It also helps to determine whether the pathological process is focal or diffuse and whether the damage is axonal or demyelinated. The compound motor action potentials (CMAPs) resulting from the stimulation of individual nerve trunks show an amplitude of 5-30 microvolts. It becomes small if there is a reduction in the number of functioning axons. The conduction block and multifocal motor are slowing. Very early in the course of the disease, the only abnormality may be the delay of a late response, the F-wave. F-wave response evaluates the proximal portion of the motor nerve.¹⁵

Electromyography, in the initial phase of illness, may show a reduction in the ability to generate motor units. After a week, abnormalities make their presence with abnormal spontaneous activity. It implies that there is a loss in contact of the muscle fibre to the motor unit, thus causing denervation. Anti-Ganglioside Antibodies (GM1, GQ1b) with ELISA are utilised to detect GBS variants. GMI is associated with AMAN and GQ1b with Miller-Fisher syndrome.¹⁶

Brighton criteria

The Brighton criteria developed by the Brighton Collaboration are a set of diagnostic criteria utilised to recognise GB syndrome all over the world.¹⁷ The criteria include:

1. Sudden onset of symmetric, flaccid limb weakness.

2. Decreased or absent deep tendon reflexes in the affected limbs.

3. Monophasic illness pattern with the peak of illness within 12 to 28 days followed by improvement or death.

4. Cerebrospinal fluid showing albuminocytological disassociation.

5. Electrophysiological abnormalities.

6. Absence of other diagnosis to explain the symptoms.

In a study at Puducherry, Mateen and colleagues tried to validate the Brighton criteria in India. They found that among 79 cases of GBS, 86% fulfilled Brighton level 3, 84% level 2, and 62% level 3 diagnostic certainties. They concluded that the diagnosis of GBS can be made using Brighton Working Group criteria with moderate-to-high sensitivity.¹⁸

Autonomic neuropathies (ANs)

Autonomic neuropathies are rare peripheral nerve disorders with immune-mediated pathogenesis. There are antibodies targeting peripheral nerve structures. The autonomic neuropathies are classified based on the onset, clinical features, and electrophysiology. The onset is acute (<4 weeks) in GBS. It is called subacute when the period of progression varies from 4 to 8 weeks. It is chronic when it is >8 weeks, and such a condition is encountered in Chronic inflammatory demyelinating polyneuropathy (CIDP). The symptoms may be sensory, motor, or both. Electrophysiology exhibits demyelinating injury due to axonal neuropathy. When the condition involves the node of Ranvier, it leads to reversible conduction failure or axonal degeneration, which is referred to as node paranodopathy.

Prognosis

Generally, GBS follows a monophasic course and typically does not recur. It is difficult to visualize the course of the disease. Some patients exhibit very mild manifestations, requiring no treatment. Nearly 80 percent of patients recover completely in 3 to 6 months. Others suffer from neurological disability. Nearly 30 percent of patients may show rapid deterioration with respiratory failure, necessitating ventilatory support. The Erasmus GBS Respiratory Insufficiency Score (EGRIS) has to be used within the first week to assess the severity and risk of respiratory failure. Old age hurts the prognosis. Regular monitoring of respiratory functions, especially vital capacity and arterial blood gases, should be done. It must be noted that respiratory failure may develop without warning. Preceding gastrointestinal illness, prior infection with C. jejuni, severe acute illness, and evidence of axonal degeneration as found in electromyography and nerve conduction studies are other risk factors. Electrocardiographic monitoring is necessary, and dysautonomia is common. The persistent presence of GMI antibodies for more than 6 months indicates a poor prognosis.

Prolonged ventilatory support, presence of raised levels of anti-GM1 IgG and IgM antibodies, delayed initiation of treatment with IVIg, and severe initial manifestation of the disease make the prognosis worse.¹⁹

An assessment of GBS carried out in Bangladesh from 2010-13 showed a high mortality rate of 12% (50/407) among the affected population. 48 % (24/50) of patients required mechanical ventilation, with a median time of 18 days from the onset of symptoms to death.²⁰

Treatment

Treatment is essentially supportive. Though many developments have taken place in the management of GBS, it remains unsatisfactory. The benefits of treatment are incomplete.

Corticosteroids: Corticosteroids have been tried in Guillain-Barre Syndrome over three decades. Earlier reports showed the beneficial effects of steroids on the course and outcome of Guillain-Barre Syndrome.²¹ The use of corticosteroids was stressed as it reduced the total duration of illness and resulted in a quick recovery.²² Subsequent studies have raised doubts regarding the benefit of corticosteroids, though they are administered in the hope of hastening recovery and preventing complications. Singh and Gupta, in a prospective study at Varanasi found no benefit from corticosteroids to patients.²³ The Guillain-Barre Syndrome steroid trial Group, in a follow-up of cases up to 48 weeks, did not find any significant difference in outcome between the group that received intravenous methylprednisolone 500 mg daily for 5 days or the group that received placebo and concluded that the use of corticosteroids in Guillain-Barre Syndrome is unwarranted.²⁴

Peters et al., from Vellore have reported the results of a retrospective cohort study of Guillain-Barre Syndrome with or without steroids and have found no significant benefit from steroids.²⁵ They did not find neuropathies with slow conduction due to myelin damage. Impaired conduction occurs from axonal improvement in the disability scores at discharge. Thus, corticosteroids have not shown any benefit to patients with acute Guillain- Barre Syndrome. Now, it has been found that steroids have no role in the management.²⁶

Plasma exchange: Among other modes of therapy, the benefit of plasmapheresis or plasma exchange (PE) has been established in a controlled multi-center study. Plasma exchange is effective in hastening recovery in patients with GBS. Therapeutic plasma exchange is undertaken to remove antibodies and complement from the bloodstream and replace it with either albumin or fresh frozen plasma. The plasma is separated from the cells and the cells are subsequently re-infused along with either fresh frozen plasma or albumin. Often, albumin is selected. Plasmapheresis is useful only when it is started within 2 weeks of the onset of symptoms.²⁷ Plasma exchange has been shown to shorten the recovery time. Patients with moderate-to-severe weakness have benefited when the therapy is begun within 2 weeks of onset. A series of 5 exchanges (40-50 ml/kg) on alternate days using saline and albumin as replacement fluid with a continuous flow machine has shown to be beneficial.²⁶ Generally, PE is well tolerated, but there are risks of cardiac arrhythmias, hypotension, infection, and blood coagulation. After an analysis of 649 patients with GBS patients, a Cochrane systematic review has concluded that the therapy accelerates motor recovery and decreases the need for mechanical ventilation.²⁶ The Initiation of plasmapheresis at an early stage of the disease exhibits a rapid improvement.²⁷

Intravenous immunoglobulin: Plasma exchange and human immunoglobulin have shown promising results in hastening recovery.²⁸ Intravenous immunoglobulin (IVIg) is a cornerstone in the management of GBS, and it is initiated within 2 weeks after the onset of the disease. Immediate immunotherapy is indicated in acute neuropathy. Immune globulin is likely to neutralize pathogenic antibodies and inhibit autoantibody-mediated complement activation. Intravenous immunoglobulin in a dose of 0.4 mg/kg/day for a total dose of 2 g/kg body weight is administered over five consecutive days. It effectively reduces the severity and duration of GBS when given in the first 2 weeks of the disease.²⁹ However there is no advantage of combining the two treatment regimens. There is no significant difference in the beneficial response to therapy over the other. Often IVIg is preferred to plasma exchange because of ease of administration and availability. IVIg is purified from the plasma pooled from many donors. IVIg modulates the response through three different mechanisms, such as neutralization of pathogenic antibodies, inhibition of complement activation, and modulation of Fc events with IVIg, which are infrequent^.30,31 Rarely there are risks of infection or anaphylaxis. IVIg plays a pivotal role in the management of GBS, offering a favourable balance of efficacy and safety. Its timely administration is vital.

Ventilatory support: Patients with severe Guillain- Barre Syndrome exhibiting respiratory failure require close ventilatory monitoring. Their vital capacity and arterial blood gases are to be regularly estimated. Intubation and ventilator support must be undertaken if the patient exhibits at least one major criterion or two minor criteria, even in the absence of clinical respiratory distress. The primary criteria are an exhibition of hypercarbia (partial pressure of arterial carbon dioxide, PaCO₂ above 48 mm Hg), hypoxaemia (partial pressure of arterial oxygen, PaO₂ while breathing ambient air, below 56 mm Hg), and a vital capacity of less than 15 ml/ kg body weight. The minor criteria are inefficient cough, impaired swallowing, and atelectasis.³² Those who develop complete quadriplegia or those who show evidence of axonal damage by nerve conduction studies may have residual distal weakness, and others recover completely with proper management. The majority of them can recover their previous level of function. The requirement for mechanical ventilation and cardiac autonomic dysfunction was higher among the elderly.³³

Atropine is to be used in patients exhibiting brady-yarrhythmias, fluid administration is necessary in profound orthostatic hypotension. Antihypertensives are needed in the management of paroxysmal hypertension. Since the patients are bedridden, administration of subcutaneous heparin and the use of compressive stockings are necessary to prevent the occurrence of deep-vein thrombosis.³⁴ The presence of impaired swallowing may lead to the risk of aspiration and it necessitates the introduction of a nasogastric tube. An early and active individualized rehabilitation program should be started to hasten recovery.

Conflicts of Interest

Nil