Treatment guidelines for Guillain-Barré Syndrome

Introduction Guillain–Barré syndrome (GBS) is an acute onset, usually monophasic immune-mediated disorder of the peripheral nervous system. The term GBS is often considered to be synonymous with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), but with the increasing recognition of variants over the past few decades, the number of diseases that fall under the rubric GBS have grown to include axonal variants and more restricted variants, such as Miller Fisher syndrome (MFS) [Table 1].[1]Table 1: Guillain–Barré syndrome—clinical variantsEpidemiology The reported incidence rates for GBS are 1–2 per 100,000 population.[2–4] The lifetime likelihood of any individual acquiring GBS is 1:1000.[5] The subtypes of GBS have different incidence rates in different parts of the world. In Europe and North America AIDP is dominant contributing to 90% of the cases. In contrast in China and Japan AMAN being the most common subtype.[67] The picture is intermediate when we look at other population. In Indian series the incidence of AIDP and AMAN are virtually equal although AMAN is more common in younger patients.[8] There seems to be a slight preponderance of AIDP in studies by Gupta et al[9] and by Meena et al (unpublished data from NIMS, Hyderabad). Available Indian literature indicates a peak incidence between June–July and Sept–October.[10] In western countries, GBS is common in the 5th decade,[11] but in India it occurs more commonly at a younger age.[1012] GBS is equally common in men and women and can occur at any age. There is a male preponderance among the hospitalized population.[1012] Clinical Features Most often an unremarkable infection, such as upper respiratory infection, often predates the onset of GBS by 14 days.[25] Many antecedent infections have been identified, including Campylobacter jejuni, cytomegalovirus (CMV), Mycoplasma pneumonia, Epstein–Barr virus, influenza virus, JEV.[1314] Surgery, immunization, and parturition have also been associated with GBS. GBS usually begins abruptly with distal, relatively symmetrical onset of paraesthesias and quickly followed by progressive limb weakness. Progression is rapid, with 50% of patients reaching clinical nadir by 2 weeks and more than 90% by 4 weeks. The current diagnostic criteria include <4 weeks of progression to clinical nadir. Approximately 80%–90% of patients with GBS become nonambulatory during the illness.[1516] Pain is prominent in 50% of patients.[1617] Neurological examination is characterized by distal and often proximal, relatively symmetrical, weakness. Although GBS is essentially a motor neuropathy, sensory dysfunction is seen in a few patients. It is seen more in a demyelinating form of GBS.[1218] Sensory examination is often normal in the early phase of disease. Facial or pharyngeal weakness is commonly seen in GBS. Diaphragmatic weakness due to phrenic nerve involvement is also common. Approximately one third of hospitalized GBS patients require mechanical ventilation due to respiratory muscle or oropharyngeal weakness.[1819] Tachycardia is common but more serious autonomic nervous system dysfunction may occur, including life-threatening arrhythmias, hypotension, hypertension, and gastrointestinal dysmotility. The incidence is between 27% and 55% and is more common in demyelinating than axonal form.[1220] Pathogenesis Major advances have been made in understanding the mechanisms of some of the subtypes. The histological appearance of the AIDP subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain–Barré syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain–Barré syndrome have had a recent C. jejuni infection, and axonal forms of the disease are especially common in these people. The lipo-oligosaccharide from the C. jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles acute motor axonal neuropathy.[21–23] Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated in acute motor axonal neuropathy and, with the exception of GalNacGD1a, in acute motor and sensory axonal neuropathy. Diagnosis Progressive weakness in both upper and lower extremities within 4 weeks along with areflexia is essential requirement for the diagnosis. Supportive ancillary testing for GBS includes CSF analysis and electrodiagnostic testing, both of which may be normal in the early phase of GBS. The limitations of ancillary testing in the early phase combined with the importance of prompt treatment of GBS mandates that the clinician at times make the diagnosis based solely on history and examination. An elevated CSF protein concentration (with normal cell count) is only found on initial CSF analysis in 50% of patients; elevated CSF protein concentration occurs in more than 90% of patients at the peak of the disease. CSF pleocytosis is an important red flag, which raises the question of infectious (HIV, CMV, Lyme, sarcoid), carcinomatous, or lymphomatous polyradiculoneuropathy [Table 2].Table 2: Guillian–Barré syndrome—red fl ags raising other diagnostic possibilitiesElectrodiagnosis Electrodiagnostic (EDX) testing is performed to support the clinical impression. EDX testing of GBS patients often demonstrates features of demyelination, such as temporal dispersion, significantly slow conduction velocities, and prolonged distal and F-wave latencies.[24] Electrodiagnostic testing features of acquired demyelination (eg, conduction block, temporal dispersion, nonuniform slowing of conduction velocities) are particularly helpful because these findings are characteristic of immune-mediated demyelinating neuropathies. In early GBS, prolonged distal compound muscle action potential (CMAP) latencies and temporal dispersion are more commonly demonstrated than are slow motor conduction velocities and conduction block.[27] Another electrodiagnostic testing hallmark of GBS is the “sural sparing” pattern; that is, the finding of a normal sural sensory nerve response in the setting of abnormal upper extremity sensory nerve results.[27] This pattern is very unusual for neuropathies other than GBS. Sural sparing, a marker of demyelinating neuropathy, is more commonly seen in later than in early stages of AIDP. Other electrodiagnostic testing abnormalities are frequently encountered in early GBS but they are less specific to GBS. These include absent H-reflexes, low motor nerve CMAP amplitudes on distal stimulation, and prolonged F-wave responses.[25–27] It is reported that the H-reflex was absent in 97% of GBS patients within the first week of symptom onset. It should also be pointed out that motor electrodiagnostic testing findings are more often abnormal than sensory nerve results in early GBS. Blink reflex studies are often abnormal when there is facial nerve involvement.[26] Phrenic nerve conduction studies can be used to predict respiratory failure and the need for ventilation.[28] Reduced CMAP amplitudes of 0%–20% of the lower limit of normal carry a poor prognosis.[29] The diagnostic yield of various neurophysiological criteria may vary in different subforms of Guillain–Barré syndrome, whose prevalence varies in different geographical areas. In a recent study the diagnostic sensitivity of Albers et al,[30] Cornblath,[31] Ho et al,[32] Dutch GBS Study Group,[33] Italian GBS Study Group,[34] and Albers and Kelly criteria[35] were evaluated and correlated with clinical subtypes of GBS, duration, severity, and outcome.[36] The sensitivity of nerve conduction study in the diagnosis of GBS and in different clinical subtypes of GBS was highest using Albers criteria (88.2%) and lowest using Cornblath criteria (39.2%). As per Ho et al, patients could be categorized into AIDP (86.3%), AMAN (7.8%), and AMSAN (5.9%). Electrophysiological findings necessary to diagnose GBS is in Table 3.Table 3: Electrodiagnostic fi ndings in Guillain–Barré syndrome[32]Incidence of antiganglioside antibodies in GBS has varied widely in different published series.[3738] Its much more common in AMAN variant than AIDP. The incidence was found to be 58% in a study of 60 patients of GBS by Meena et al (Unpublished data from NIMS, Hyderabad). Although antiganglioside antibodies have been implicated in the pathogenesis of GBS, assaying antiganglioside values in a patient with GBS other than MFS at the present time has no diagnostic value in routine practice. Variants of Guillain–Barré syndrome Commonly recognized variants include those with axonal forms, variants based on particular fiber-type involvement (sensory or autonomic), and MFS. Variants with regional or a markedly asymmetric distribution also occur.[1] There are also differences in abruptness of onset and time to reach nadir, which can complicate diagnosis and decisions about treatment. For example, some patients have clinical features and disease course similar to GBS except for a slower progression (ie, progression that lasts longer than 4 weeks); this disease is sometimes referred to as subacute inflammatory demyelinating polyradiculoneuropathy (SIDP);[3940] however, in many respects SIDP is like GBS and often should be treated as such. AMSAN and AMAN are two variants characterized by immune attack directed at axons rather than Schwann cells and myelin.[41–44] AMAN occurs in large epidemics during summer in northern China and more sporadically elsewhere.[44] It mostly affects children and young people, usually from rural areas. Onset of motor weakness is abrupt. In addition to acute pure motor paralysis, many patients have transient neck and back stiffness early in the course with resolution within day. Recovery usually begins within 3 weeks and is often complete and may take longer. Mortality rate is roughly 3%–5%. Sensory nerve conduction studies are normal and motor nerve studies are remarkable for low or absent CMAP amplitudes with normal conduction velocities. Denervating potentials are seen on needle electromyography.[6] AMSAN shares many pathological features with acute motor axonal neuropathy but differs clinically from it in patient age of onset (usually adults rather than children), geographic distribution (can occur anywhere), time of onset (not only summertime), involvement of sensory nerves, course (protracted), and outcome (usually severe residual disability).[40–44] It has an abrupt onset and rapid progression with most patients requiring mechanical ventilation within a few days of symptom onset. Motor nerves are electrically inexcitable early in the disorder. Sensory nerve conduction studies are also abnormal. Widespread denervation is seen on needle examination. The course is protracted and outcome poor, with only 20% ambulating at 1 year. MFS: The more recognizable and distinct regional variant of GBS is MFS.[14546] Like GBS, the onset of MFS often follows an infection, for example C. jejuni.[47] MFS patients classically present with external ophthalmoparesis, areflexia, and ataxia,[2] although MFS patients often present with fewer components of the classical clinical triad[1464849] or with additional clinical features (facial weakness, oropharyngeal weakness, internal ophthalmoparesis, central nervous system involvement). Bickerstaffs brainstem encephalitis (BBE) is a related syndrome in which alteration of consciousness or conticospinal tract signs are seen in addition to ophthalmoparesis and ataxia. Many patients with MFS or BBE also have “overlapping GBS” with flaccid quadriparesis.[4650] Anti-GQ1b antibodies are present in 95% of patients with acute MFS[51] and in approximately two-thirds of patients with BBE. The recognition of various clinical presentations and the high sensitivity and specificity of anti-GQ1b antibody testing suggest rubric name of “anti-GQ1b antibody syndrome.” Anti-GT1a antibody without anti-GQ1b reactivity is found in patients presenting with the pharyngeal–cervical–brachial (PCB) variant of GBS.[5253] More than half of MFS patients will have cytoalbuminological dissociation on CSF analysis performed within the first 3 weeks of disease onset.[54] In MFS, motor nerve conduction studies in the limbs are usually normal or only mildly abnormal with slight reductions in compound muscle action potential amplitudes and conduction velocities.[55] Conduction block and temporal dispersion are not a feature of MFS. Sensory nerve action potential amplitudes are usually moderately to severely reduced, more so in the upper extremity sensory nerves (eg, median) than the sural nerve. Blink reflex R1 delayed or absent. MRI of the brain frequently demonstrates cranial nerve enhancement (eg, occulomotor nerves) in MFS[56] and high-intensity abnormalities in the posterior fossa, white matter, or thalami in patients with BBE.[50] MFS is generally a benign, self-limiting conduction. Almost all treated and untreated patients return to normal activities within 6 months of disease onset, usually with resolution of ophthalmoplegia within 1–2 months and ataxia within 3–4 months.[57] Other regional variants of GBS are those that affect other specific areas of the body, such as only the face or the afferent sensory and autonomic systems.[58] Management Patients with GBS who are symptomatic but are able to walk unaided for more than 5 m and who are stable can be managed conservatively at peripheral centers. However, they should be observed for progression of the disease, especially if they are still within the first week of the onset of the disease. Blood pressure and heart rate fluctuations, clinical signs of respiratory failure should be carefully and meticulously monitored. Clinical signs of ileus should be watched. If any of these signs are detected they should be immediately shifted to specialized centers for further management. In the acute phase in bed-bound adult patients require both supportive therapy and immunotherapy can be used taking into consideration the cost factors and the clinical status (staging, complications, and other comorbid conditions) of individual patients. Supportive Care Immunotherapy therapy has not reduced the mortality in GBS. Mortality is due to disease-related issues or secondary in due to prolonged disease and of these patients are essential in the Supportive have been Management of respiratory failure GBS is the most common peripheral neuropathy respiratory advances in respiratory and mortality from GBS is as high as 20% for patients. ventilation is usually by one third of the Clinical signs like of and and a pressure respiratory from onset to of less than 1 facial weakness, and neck weakness are other factors associated with respiratory which with than phrenic nerve conduction studies is a of respiratory failure (Unpublished data by Meena et al from NIMS, Hyderabad). may be over by less of and a In it weeks to out of may be performed 2 weeks and should be based on status of an It is and but is associated at times with life-threatening and If is it may be to 1 more week to at from Management of is a of in patients with GBS. and as hypertension, hypotension, and occur in a of GBS This is due to over and under occurs usually in severe at the peak of the Tachycardia is most usually in the of which not require treatment. to a for serious or has varied widely because of the that exists in such at the by different However, the of in reduced normal heart rate and first of severe the for of may or and this can be reduced by is seen in one third of patients with GBS and can be or be followed by If is severe pressure than approximately and specific therapy may be with or should be or should be used with especially if of with can be managed by and using Patients with a of should not be in a or and should for other such as and or of or pressure occur in of severely GBS patients. is associated with other features of and can be managed by of and or is the common in GBS and is due to of the and The treatment is different for require of but need and in of The to these two is by central patients should be or and support they are able to walk to If a prolonged is and a has been treatment with Pain and sensory are reported in of patients with GBS and should be treated with and may become a Other such as and also can be or should be early and and high protein have been so has to muscle and respiratory seems to be than in these patients. for infections with or more and and may be but the of these should be by clinical Immunotherapy and are for adult and patients with GBS if during the first few weeks of disease. In a of 6 to supportive for adults with GBS, it was found that reduced the of respiratory Patients treated with significantly in the secondary outcome to without of patients requiring of muscle 1 and severe 1 year. to onset of motor in mildly patients was significantly in the However, the cost of has been to be by the of The of and the number of has not been and it varies in different but many the of North in which a of was over days all over the There is evidence that the number of in GBS should be to disease and that also patients with from In GBS, two of are to In GBS, 4 are to In severe GBS, 6 are no than In with these et al reported that at 2 are to significantly the In cost is the may be In India was used by et al with used to be the progression of the disease or This is still performed in various centers in with of is to The not affect the outcome of to the Study Although was found to be to as the to outcome was demonstrated with in Study when with North Study This is due to the that treatment was within 2 weeks in the study and within 4 weeks in the is more when within days disease onset rather than but was still in patients treated to days disease onset. should be patients with and severe GBS from treatment. Patients who need for who are and those who are and should be The value of in children younger than is not in that in patients who treatment within 4 weeks of onset, and of patients with GBS who are within 2 weeks. is usually as one on 5 over 1–2 more were observed in than the of include hypotension, pneumonia, abnormal and Major infection, and are to therapy is an to This form of therapy from the without the need for with or because of of that there is no in between patients treated with and or In a of 6 with patients it has been that therapy is for The first on the of was published in and that is as as the of these in a of for 5 has as the treatment in many because of its and The on the of in GBS 4 additional was found between and with to the in 4 the of mechanical or residual The of followed by was not significantly than or The of and was not more than although there be a of this combined treatment when a is made for In in patients with dysfunction the rate of should be to half of the normal of treatment Most have only patients who are treated within the first 2 weeks from onset of weakness and who are to walk without If these criteria are there is no that patients with GBS should be treated with or The question remains as to to in patients with progressive limb weakness or but who are still able to Although not it seems to these patients with of mildly patients These patients are able to walk with some support or no study that these patients often have residual that have the of have not the in mildly patients. It should be in that no have the of or in these mildly patients with GBS. Miller Fisher syndrome have the of or in patients with studies have that the outcome in patients with MFS is generally In a large the of ophthalmoplegia and ataxia. The that and not the outcome of patients with MFS, because of Patients with or MFS may be treated Patients with more severe or antibody syndrome, an GBS, should of patients who in of therapy patients with GBS to or a course of In these the is these patients need they have been treated with has not been but the of followed by is no than or is also not because out the study in a series of patients the of a course of in severe patients with This study that a course of could be About of patients with GBS initial or Although no have the of a in this it is common to a course in These patients are to have a prolonged immune response that nerve that treatment for a longer of longer between onset and treatment and longer time to nadir may be associated with a of of and in GBS with in especially in of any treatment a in treatment This is very in GBS in which the treatment has equal There are a few cost analysis studies this and the results are However, in of may the cost when to the to or be based on The limitations for of be of the and of of and fewer with may of as the first of GBS has a serious on the and the onset of Recovery can be slow and take is seen in of adult patients but is less common in is a of GBS in two of adult patients. In an of it was not to weeks had on and GBS is a monophasic immune-mediated neuropathy characterized by acute onset of predominantly motor weakness and is a common of respiratory There are many variants with different and in the diagnosis. Immunotherapy a in the of GBS patients and both and are equally may be because of its low and of However, can be used with equal due to cost supportive treatment is equally important in the and mortality in GBS.