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Treatment and Management of Autoimmune Neuropathies


Introduction

Autoimmune peripheral neuropathies (APNs) develop when immunologic tolerance to key antigenic sites on myelin, axon, nodes of Ranvier, or ganglionic neurons is lost ( , ). These conditions may manifest either acutely or in a more chronic manner; symptoms may include motor, sensory, and autonomic in isolation or in concert. The classic prototypical syndromes are the Guillain-Barré syndrome (GBS)—an acute postinfectious sensorimotor neuropathy—and chronic inflammatory demyelinating polyneuropathy (CIDP)—a subacute to chronic autoimmune sensorimotor neuropathy. There are multiple notable variants of each of these forms, as well as additional distinct conditions distinguished by specific antibodies, mechanism of action, concurrent systemic diseases, or sites of extraperipheral damage. The pathogenesis, diagnosis, and treatment vary among these conditions despite their overlapping symptomatology.

Acute Autoimmune Peripheral Neuropathies

GBS is an acute, monophasic, paralyzing illness, reaching its nadir within 4 weeks of onset. It is the most common and most severe acute paralytic neuropathy, with about 100,000 people developing the disorder every year worldwide. The annual incidence rate increases with age (0.6 per 100,000 per year in children and 2.7 per 100,000 per year in people aged 80 years and over), and the disease is slightly more frequent in males than in females ( ). GBS is a heterogeneous disorder with multiple variants ( Figs. 15.1 and 15.2 ), according to whether the main clinicopathologic involvement is centered on motor or sensory nerve fibers and whether it affects predominantly the myelin or the axon ( , ; ; ) ( Table 15.1 ). There is an antecedent infection with Campylobacter jejuni ( C. jejuni ) as the most frequently identified precipitant, followed by viruses (Cytomegalovirus, Epstein-Barr virus [EBV]) and other bacteria ( Haemophilus influenzae , Mycoplasma pneumoniae ) ( ). Zika virus has been reported to cause GBS and other parainfectious polyneuropathies ( ; ; ). During 2015 and early 2016, Zika GBS incident rate significantly increased in South and Central America ( ; ).

Fig. 15.1, Pattern of symptoms in variants of Guillain-Barré syndrome (GBS). Graphic representation of the pattern of symptoms typically observed in the different clinical variants of Guillain-Barré syndrome (GBS). Symptoms can be purely motor, purely sensory (rare), or a combination of motor and sensory. Ataxia can be present in patients with Miller Fisher syndrome, and both decreased consciousness and ataxia can be present in patients with Bickerstaff brainstem encephalitis. Symptoms can be localized to specific regions of the body, and the pattern of symptoms differs between variants of GBS. Although rare, bilateral facial palsy with paraesthesias, the pure sensory variant, and Miller Fisher syndrome are included in the GBS spectrum, they do not fulfill the diagnostic criteria for GBS.

Fig. 15.2, Major Guillain-Barré syndrome subtypes in which antibody-mediated effector pathways, including complement activation, cause glial or axonal membrane injury with consequent conduction failure

Table 15.1
Brighton Criteria for Diagnosis of Typical GBS
Diagnostic Criteria Level of Diagnostic Certainty
1 2 3 4
Bilateral and flaccid weakness of limbs + + + +/-
Decreased or absent deep tendon reflexes in weak limbs + + + +/-
Monophasic course and time between onset and nadir 12 hours to 28 days + + + +/-
CSF cell count <50/μL a + + - +/-
CSF protein concentration > normal value a + +/- - +/-
NCS findings consistent with one of the subtypes of GBS + +/- - +/-
Absence of alternative diagnosis for weakness + + + +
Brighton criteria account for the level of diagnostic certainty based on the combination of examination, history, laboratory, and electrodiagnostic findings in typical GBS. A level of 1 is most certain, while a level of 4 is least certain and reported as GBS, possibly due to insufficient data for further classification. + indicates present; -, absent; +/-, present or absent.
CSF , Cerebrospinal fluid; GBS , Guillain-Barre syndrome; NCS , nerve conduction study.

a If CSF is not collected or results are not available, nerve electrophysiology results must be consistent with the diagnosis GBS.

Guillain-Barré Syndrome Subtypes

Acute inflammatory demyelinating polyneuropathy (AIDP): the prototype variant of GBS and accounts for 85% of cases ( ; ). Immune injury takes place at the myelin sheath and related Schwann cell components ( Fig. 15.3 ).

Fig. 15.3, (A) Proposed immune attack in acute inflammatory demyelinating polyneuropathy (AIDP). Autoantibodies are suspected to bind to myelin antigens and activate complement. The formation of a membrane attack complex ( MAC ) on the outer surface of Schwann cells leads to vesicular degeneration, with subsequent removal of myelin debris by macrophages. (B) shows a different pathogenesis proposed for acute motor axonal neuropathy (AMAN). Anti-GM1 or anti-GD1a antibodies are shown binding to the nodal axolemma. This may affect voltage-gated sodium (Nav) channels. Additional disruption of paranodal myelin may also contribute to conduction failure. Macrophages may subsequently invade the periaxonal space.

It is characterized by progressive ascending quadriparesis and often by prominent sensory symptoms ( ). Pain is a significant symptom. It can be muscle pain or radicular pain and can precede weakness in about a third of patients ( ; ; ). Exam shows hypotonic paraparesis and reduced or absent muscles reflexes ( ) or quadriparesis and cranial nerve involvement in severe cases resulting in facial, oculomotor, or bulbar weakness ( ; ; ). Autonomic dysfunction may lead to cardiac arrhythmia, excessive sweating, blood pressure instability, or ileus ( ). During the progressive phase, 20%–30% of patients develop respiratory failure and need ventilation at an intensive care unit (ICU) ( ).

Nerve conduction studies (NCSs) show multifocal demyelination. Demyelination and conduction block (CB) proximally at the level of the lumbar and cervical nerve roots explain the proximal weakness. CB along motor axons explains the bilateral ascending weakness ( ; ; ; ).

The cerebrospinal fluid (CSF) typically reveals a normal white blood cell count with moderate elevation of the protein content (albumino-cytologic dissociation). This is the likely consequence of a deficient blood-nerve barrier (BNB), particularly at the level of the spinal nerve roots. Currently, there are no specific antibody biomarkers ( ).

Patients are typically treated with either plasma exchange (PE) or intravenous immunoglobulins (IVIg) ( ; ; ; ). Neither treatment is better than the other, nor is the combination of IVIg and PE at the same time better than either treatment alone. Multiple clinical trials have failed to show any benefit for steroids ( ; ). Although the prognosis of GBS is generally favorable, there is still mortality in the range of 5% and disability beyond 1 year in approximately 20% of patients ( ).

Acute motor axonal neuropathy (AMAN): characterized by pure motor involvement and absence of evidence of demyelination on electrophysiological tests ( ). It is characterized by rapidly progressive weakness, often with respiratory involvement and usually good recovery.

AMAN accounts for 5%–10% of cases in the Western Hemisphere and 50% in Asia ( ). There is a strong association with preceding C. jejuni and Zika virus infection ( ; ). The primary immune attack is humoral and selectively acts on the motor axons and the axolemma at the nodes of Ranvier ( ; ). Reflexes can initially be normal ( ). The clinical course and prognosis are otherwise similar to classical AIDP ( ). GD1a, GM1, or GD3 ganglioside autoantibodies are found in roughly 50% of cases ( ; ). The antibodies fix complement, recruit macrophages, and deposit membrane attack complex (MAC) in the axolemmal membrane ( ), thus disrupting the axolemma at the nerve terminals and nodes of Ranvier with resulting disruption of nodal sodium channel clusters and detachment of paranodal myelin terminal loops ( ; ). Consequently, there is a nerve conduction blockade. This blockade is reversible and, pathophysiologically, initially predominates over axonal degeneration in AMAN ( ). This makes it the prototype of the newly described nodo-paranodopathies triggered by molecular mimicry ( ). Electrophysiologically, the reduction of distal compound muscle action potential (CMAP) amplitude may be seen in the absence of the other features of demyelination.

Pure motor GBS can occur in patients with AMAN or with AIDP ( ).

Acute motor-sensory axonal neuropathy (AMSAN): a rare variant of GBS, less than 10% of AMAN cases. It is associated with antecedent C. jejuni infection ( ). This disease shows some association with anti-GD1a. The presentation is with acute onset of distal weakness, loss of deep tendon reflexes, and sensory symptoms ( ). The primary pathology is in motor and sensory axons ( ). In AMAN and AMSAN, the pathologies are very similar ( ), where macrophages invade the space between the Schwann cell and axon, leaving the myelin sheath intact ( ). It shows a more serious clinical course and, owing to its axonal pathology, is associated with slow and incomplete recovery compared to the demyelinating variant ( ; ).

Miller Fisher syndrome (MFS): accounts for 5% of cases ( ) and is the second most common variant of GBS ( ). There is male predominance ( ) with median age in the fifth decade ( ). It is characterized by acute onset of ophthalmoplegia, gait ataxia, and areflexia ( , ; ; ). It is preceded by upper respiratory tract infection in 56%–76% of the patients, mostly C. jejuni ( ; ) and Haemophilus influenzae ( ). A diagnosis of MFS can be made with compatible clinical history and cardinal symptoms and the presence of albumino-cytologic dissociation in the CSF ( ). The disease then progresses until a clinical nadir is reached (range of 2–21 days) ( ). The immune attack takes place at the paranodal myelin epitopes strongly expressed in oculomotor nerves, dorsal root ganglia, muscle spindles, and neurons in the cerebellar molecular layer, a distribution that fits well with cardinal clinical manifestations ( ; ). MFS is strongly associated with serum antibodies to GQ1b in up to 85% of cases ( ; ; ; ), a ganglioside component of nerves that is disproportionately enriched in the extramedullary regions of the ocular motor nerves and some large neurons of dorsal root ganglia ( ; ; ; ; ). The antibodies also block acetylcholine release from the motor nerve terminals. Levels are proportionate to the disease activity and can be used as a diagnostic marker ( ). MFS is frequently accompanied by other cranial nerve involvement and can progress to weakness of the limbs (Miller Fisher-Guillain-Barre overlap syndrome) ( ).

While MFS is considered as a pure peripheral cranial polyneuropathy, in some patients concomitant central nervous system (CNS) involvement is suggested by magnetic resonance imaging (MRI) abnormalities of hyperintense lesions on T2-weighted and hypointense on T1-weighted images in the cerebral white matter, brainstem, and cerebellum ( ; ) and electroencephalography abnormalities ( ; ; ).

Incomplete forms with acute ophthalmoparesis without ataxia show strong association with anti-GQ1b antibodies ( ). Acute ataxic neuropathy without ophthalmoplegia frequently displays anti-GD1b reactivity ( ).

Bickerstaff brainstem encephalitis (BBE): a condition that presents similarly to MFS with ataxia, ophthalmoplegia, and areflexia but shows prominent CNS involvement, manifested in disturbances of consciousness and upper motor neuron signs. BBE shares many other features of MFS, including anti-GQ1b antibodies ( ).

Pharyngeal-brachial variant of GBS: associated with antibodies against GT1a and GQ1b gangliosides ( ). It is an unusual variant in which the paresis is restricted to the upper extremities but may progress to involve the lower extremities as shown by sensory signs, depressed or absent reflexes, or electrophysiological changes in these nerves ( ).

Acute pure sensory ataxic GBS: a variant that is thought to involve the dorsal roots and ganglia. Ataxia is typically a characteristic sensory ataxia, although rarely, a cerebellar-type ataxia may be present. Spinocerebellar 1a afferent fibers have been implicated in the ataxia in this condition, and cerebellar lesions have not been documented. Some of these patients also have immunoglobulin G (IgG) antibodies to GQ1b or GD1b ganglioside. This condition may represent overlap with the acute ataxic neuropathy without ophthalmoplegia variant of MFS, which is also noted for a sensory ataxia and dorsal root ganglia involvement ( , ; ; ).

Acute pandysautonomic neuropathy: In this variant, the target antigen is in the sympathetic ganglionic neurons ( , ). Symptoms include orthostatic changes, gastrointestinal and urinary dysfunction, dry mouth or eyes, and photophobia due to mydriasis. There is a strong association with ganglionic (nicotinic) acetylcholine receptor antibodies, with up to half testing positive for Acetylcholine Receptor antibodies. Nerve biopsies have shown loss of unmyelinated fibers. There may be pain or dysesthesia without true sensory loss ( ).

Pathogenesis

GBS is a typical postinfectious disorder. Molecular mimicry occurs when glycoconjugate epitopes are shared between certain viral or bacterial proteins and myelin ( ; ) or nerve axolemma ( ; ; ) proteins ( Fig. 15.2 ). Thus, an antecedent infection can break tolerance and trigger an autoimmune attack ( ; ). GBS typically follows a rapidly progressive, monophasic course (<1 month) shortly after infection, usually without relapse. Two-thirds of adult patients report preceding symptoms of a respiratory or gastrointestinal tract infection within 4 weeks of onset of weakness ( ). Recent literature described cases of GBS following the use of tumor necrosis factor inhibitors (TNF inh) infliximab or adalimumab ( ). Potential mechanism may be explained by systemic TNF inh resulting in decreased apoptosis of autoreactive T cells, which may enhance autoimmune responses ( ). Another hypothesis is an increased susceptibility to infections. Treatment is by cessation of TNF inh therapy.

In AIDP, there is perivascular and endoneural inflammatory infiltrates throughout the nerves, roots, or plexuses along with segmental demyelination mediated by macrophages ( , ; ; ). The macrophages break through the basement membrane of healthy Schwann cells and make direct contact with the outermost myelin lamellae, leading to destruction of the superficial myelin sheath ( , ; ; ; ). Released cytokines and chemokines facilitate ongoing T-cell activation ( ). There are deposits of complement-fixing antibodies, IgG, IgM, and MAC against myelinated fibers and against glycolipids that contain carbohydrate (glycocongugate) epitopes ( ; ; ) on peripheral nerves. The glycolipids bear one or more sialic acid molecules (such as ganglioside GM1, GD1a, GT1a, GQ1b), exposed at the extracellular surface ( , ; ; ).

Viruses, such as cytomegalovirus, EBV, herpes, hepatitis A and E, or HIV, and bacteria, such as Haemophilus influenzae , Mycoplasma pneumoniae , and C. jejuni ( ; ), are most commonly implicated. In endemic areas of infection, dengue virus and Zika virus have been associated with the development of GBS, which is usually of the AIDP variety. Most of the antibodies associated with GBS are of the IgG subclass.

Infection by C. jejuni carrying GM1-like or GD1a-like lipo-oligosaccharide induces IgG or IgM antibodies to GM1 or GD1a expressed in motor nerves, resulting clinically in AMAN in 80% of patients ( ; ; ; ). IgM anti-GQ1b antibodies are also found in some patients with chronic IgM paraproteinemic polyneuropathies ( , ; ; ; ). Hemophilus influenzae carries GM1 and GQ1b epitopes and may cross-react with the corresponding myelin antigens. Mycoplasma pneumoniae stimulates antibodies against peripheral nerve galactocerebroside ( ; , ; ). GBS triggered by CMV infection has been also associated with the presence of IgM anti-GM2 antibodies ( , ). Although probably relevant, genetic and environmental factors that affect an individual’s susceptibility to develop the disease are unknown ( ).

Electrophysiology

NCSs can support the diagnosis, differentiate between axonal and demyelinating subtypes ( ), and provide prognostic insight. Early on, the nerves are so severely affected that they are inexcitable. Abnormalities are most pronounced 2 to 4 weeks after the start of weakness ( ). F-wave prolonged latency or absent response is used in GBS diagnosis. The H-reflex stimulates directly the Ia fibers, bypassing the muscle spindle organs, and is absent in GBS. NCSs in AIDP show features of demyelination that include increased distal motor latencies, decreased nerve conduction velocities, absence or decreased persistence of F-waves and H-reflexes, increased temporal dispersion, and CBs. The sural sensory potential is often preserved ( ), and this electrophysiological feature helps to distinguish GBS from other varieties of polyneuropathy. Features of axonal GBS (AMAN or AMSAN) are decreased sensory nerve action potential (SNAP) amplitudes, decreased CMAP amplitudes, or both. Reversible conduction failure or transient CB may be secondary to inflammatory injury of either glial or axonal membranes (or both simultaneously), caused by antiganglioside antibodies ( ; ) at the node of Ranvier. Nodal CB can arise quickly, but functionality can be restored in equally short time. Most often, nodal CB occurs in the AMAN variant of GBS ( ; ).

AMAN can either improve very slowly and incompletely or recover rapidly, probably because of restoration of transient CBs. GBS with features of demyelination and secondary axonal loss seen as low CMAP are predictive of poor outcome. Severe demyelination reflects a more diffuse neurological injury or an impaired process of nerve recovery that may affect phrenic nerves as well ( ).

Diagnosis

GBS is a clinical diagnosis. Examination of the CSF usually shows albumino-cytological dissociation, which is defined as the combination of a normal cell count and increased protein level. A normal protein level (especially in the first week) does not rule out the diagnosis ( ). Additionally, 15% of patients with the disease have a mild increase in CSF cell count (5–50 cells per μL) ( ) ( Fig. 15.4 )

Fig. 15.4, World Health Organization ( WHO ) guideline for Guillain-Barré syndrome ( GBS ) diagnosis/surveillance. LP , Lumbar puncture.

Differential Diagnosis

The differential diagnosis can be broad with all the variants of GBS ( Table 15.2 ). Vasculitic neuropathy is characterized by painful asymmetric weakness that is progressive over months. The etiologies include cryoglobulinemia, hepatitis, HIV and Lyme, cancers (lymphomas), and connective tissue diseases ( ). Diphtheria is a rapidly progressive demyelinating polyneuropathy that can also affect the cranial nerves ( ). Polio is purely motor ( ; ). West Nile virus can cause mild sensory polyneuropathy, weakness, and encephalitis ( ). Botulism causes descending weakness that starts as cranial neuropathies, similar to Miller Fisher, and is complicated by severe autonomic symptoms. HIV infection increases the incidence of GBS. Lumbar puncture shows increased nucleated cells. Acute intermittent porphyria causes multifocal neuropathy with motor much worse than sensory involvement with autonomic dysfunction ( ; ). Tick paralysis causes paresthesias, followed rapidly by gait ataxia, cranial neuropathy leading to blurry and double vision, dysarthria, and respiratory failure ( ). Lead and mercury cause slowly progressive weakness ( ). Arsenic neuropathy begins after weeks of exposure with paresthesias followed by progressive weakness, sensory loss, ataxia, and autonomic dysfunction. Glue Sniffer neuropathy caused by hexacarbons leads to initial paresthesias, followed by progressive weakness secondary to sensory and motor axonal neuropathies ( ). Amiodarone causes chronic sensorimotor demyelinating polyneuropathy and, rarely, acute polyneuropathy, virtually indistinguishable from AIDP ( ; ). Nitrous oxide in the setting of B 12 deficiency can lead to acute neuropathy and subacute combined degeneration. Cytosine arabinoside rarely causes acute progressive demyelinating polynuropathy. Increased CSF protein is apparent ( ; ). Critical illness myopathy is typically a generalized, more proximal weakness, including neck and facial strength. The time course and progression of illness and facial weakness may help differentiate from GBS ( ). Subacute or acute cervical myelopathy has a similar appearance to GBS ( ). CIDP is separated from GBS by the timing and course of illness ( ; ; ).

Table 15.2
Differential Diagnosis of Guillain-Barré Syndrome
Central nervous system conditions Brainstem: stroke (asymmetric limb paresis), infection. Spinal cord: compression (asymmetric), poliomyelitis (purely motor disorder with meningitis), transverse myelitis (abrupt bilateral leg weakness, ascending sensory).
Muscle conditions Metabolic: hypokalemia, hypophosphatemia (irritable, apprehensive, hyperventilation, normal cerebrospinal fluid). Myopathy: infectious, inflammatory polymyositis (chronic, affects proximal limb muscles), toxic. Rhabdomyolysis, periodic paralysis.
Neuromuscular junction conditions Myasthenia gravis (weakness and fatigue that improves with rest), toxins.
Polyneuropathies CIDP. Critical illness. infection (Lyme disease, HIV). Metabolic: diabetes mellitus, porphyria, uremia. Vasculitic neuropathies (mononeuropathy). Toxicity: diphtheria, botulism (descending paralysis), heavy metals (arsenic) (slowly progressive confusion, psychosis, organic brain syndrome), substance abuse (n-hexane exposure from glue sniffing).
Diagnosis of GBS, Miller Fisher syndrome, and their subtypes can be challenging in early disease, but many differentials can be excluded based on history and examination alone.
CIDP , Chronic inflammatory demyelinating polyneuropathy; GBS , Guillain-Barré syndrome.

Treatment

GBS is a potentially life-threatening disease ( ; ; ). The severity and duration can range from mild weakness that recovers spontaneously to quadriplegia and ventilation dependence or severe, permanent disability.

Supportive care is necessary and encompasses monitoring respiratory function by frequent measurement of forced vital capacity or negative inspiratory force. The Erasmus GBS Respiratory Insufficiency Score determines the chance a patient will need artificial ventilation ( ). Cardiac and hemodynamic monitoring for autonomic dysfunction and timely transfer to ICU when needed are crucial ( ; ). Additional and important management issues include prophylaxis for deep vein thrombosis, management of possible bladder and bowel dysfunction, early initiation of physiotherapy and rehabilitation, and psychosocial support.

IVIg (0.4gm/kg body weight daily for 5 days) and large volume PE (200–250mL plasma/kg body weight in five sessions) are equally effective treatments for GBS ( ; ; ). IVIg is no better than PE, and the combination of both treatments is no better than one treatment alone. IVIg is usually the treatment of choice as it is easier to administer and more available ( ; ). Randomized controlled trials (RCTs) on the efficacy of corticosteroids showed no significant benefit; oral corticosteroids in fact have been shown to have a negative effect on outcome ( ; ). An RCT of the humanized monoclonal antibody eculizumab ( ; ) is being performed ( ; ).

Pain that is moderate to severe is a common symptom in GBS. It may present during the acute stage or may be reported a year after GBS onset. Pain intensity was shown to be associated with the level of weakness, fatigue, and functional disability during the later stages of GBS ( ). Multiple types of pain (back and sciatic pain, meningeal signs, dysaesthesia and paraesthesia, muscle pain, arthralgia, visceral pain, etc.) suggest nociceptive and neuropathic origin ( ). Radicular pain, linked to inflammation of nerve roots ( ), and muscle pain are the most common types during the acute phase ( ). Carbamazepine ( ) and gabapentin ( ), as well as opioids ( ), are used as pain management in patients with GBS.

MFS is a self-limiting condition with gradual spontaneous improvement of symptoms and eventual recovery. Ataxia and ophthalmoplegia typically resolve within 1 to 3 months after onset, and near-complete recovery is expected within 6 months ( ). Immunomodulatory therapies including IVIg and PE are used to hasten recovery and decrease the likelihood of progression to a more severe GBS ( ).

The severity of the disease course of BBE justifies treatment with IVIg or PE, although evidence of efficacy is limited ( ; ). Neither IVIg nor PE is contraindicated during pregnancy. IVIg might be preferred due to convenience of administration ( ; ).

Treatment-related fluctuation: occurs within the first 8 weeks of treatment with IVIg or PE in about 10% of patients ( ; ). It is explained by prolonged and sustained nerve damage or functional blockade ( ) and implies that progression might have been worse without therapy ( ; ; ). Repeating treatment was shown to have no effect on the outcome ( ; ). When there is a new deterioration after 8 weeks, the diagnosis of CIDP should be suspected and occurs in about 5% of patients ( ; ; ).

Predictors of outcome: The Erasmus GBS Outcome Scale is based on age, worse at 40 years and over, preceding diarrheal infection in the past 4 weeks, and high disability at nadir with greater weakness, facial/bulbar weakness, and mechanical ventilation, to predict the ability to walk at 6 months ( ). Electrodiagnostically, demyelination and low CMAP amplitudes are associated with a worse prognosis. Low serum albumin (<3.5 g/dL) at baseline, but especially 2 weeks after IVIg treatment, is associated with a worse outcome ( ).

GBS as a neurologic complication of SARS-CoV-2, COVID-19:

A systematic review aimed to identify predominant clinical, laboratory, and neurophysiological patterns of neurologic complications in association with COVID-19 infection showed that neurological symptoms arise with a median latency of 14 days. A higher prevalence of GBS in patients with COVID-19 was seen in males compared to females [ ] with a worse clinical outcome compared to the females [ , ] and Pediatric cases have been increasingly reported in the literature [ , , , ]. Similar to classic GBS risk factors for unfavorable outcome in COVID-19 associated GBS include older age, preceding diarrhea and past or concurrent COVID-19 pneumonia [ , ). Nevertheless, GBS may also develop in the context of a paucisymptomatic or asymptomatic COVID-19 ( )

The pathophysiologic basis is that abnormal immune-mediated response of cytokine overproduction e.g., CRP, IL-6, TNF-α, IL-1, etc. leads to systemic inflammatory storm that manifest as myelitis, encephalitis, GBS or hypercoagulable state and cerebrovascular events [ , ]. A postinfectious mechanism for GBS is that of molecular mimicry between the viral protein associated gangliosides, the angiotensin-converting enzyme 2 and the gangliosides containing sialic acid residues including the GalNAc residue of GM1, and peripheral nerve gangliosides.54–56 thus resulting in delayed immune-mediated damage to peripheral nerve ( ). This is supported by absence of SARS-CoV-2 RNA in CSF and the response to IVIG.

Clinical manifestation of GBS in patients with COVID-19 is symmetrical and generalized weakness and sensory disturbances. Weakness in the limbs and acute flaccid quadriparesis were observed in most cases ( ) All of the major GBS electrodiagnostic patterns have been reported in association with COVID-19. As in classic GBS, the demyelinating pattern, acute inflammatory demyelinating polyneuropathy (AIDP) was the most common pattern ( ), and to a lesser extent AMSAN and AMAN [ ]. In analogy to classic GBS, approximately one-fifth of COVID-19-associated GBS subjects required mechanical ventilation during hospitalization [ ]. The workup frequently reveals negative nasopharyngeal swab at GBS onset [ , , , ]. CSF from COVID-19 associated GBS patients, similar to classic GBS, shows elevated protein levels, normal cell counts and absent the anti-ganglioside antibodies. CSF has been negative for SARS-CoV-2 by RT-PCR. Post-mortem brain tissues from COVID-19 patients did not show evidence for viral infection by immunohistochemical analysis ( ).

COVID-19- induced cytokine storm associated with GBS responds well to IVIG therapy, based on direct removal of cytokines and the shift towards a more favorable anti-inflammatory cellular and cytokine profile ( ). Plasma exchange is not preferred to treat COVID-19 associated GBS at present, as it challenges the tenuous hemodynamic state of critically ill patients and exposes more health care workers for longer periods of time to infected patients ( ). The potential GBS risk from the vaccine should be weighed against the considerable morbidity and mortality of the infection ( ).

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Chronic Autoimmune Peripheral Neuropathies

CIDP typically presents with motor and sensory symptoms leading to relatively symmetrical, proximal, and distal weakness. By definition, CIDP should progress or relapse for a period greater than 8 weeks. CIDP is the most common acquired autoimmune-mediated neuropathy, with a prevalence of 8–9/100,000 ( , ; ). The mean age of onset is around 50 years, with a slightly lower prevalence in children and women ( ). There are variable clinical phenotypes with variable clinical course and differing responses to immunotherapy ( ; ; ; ).

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