Guillain-Barré syndrome: History, pathogenesis, treatment, and future directions.

BACKGROUND AND PURPOSE: Since its description by Guillain, Barré, and Strohl in 1916, Guillain-Barré syndrome (GBS) has attracted a large literature. The author reviews the history of research into its pathogenesis and treatment to highlight promising avenues for future research. METHODS: This is a nonsystematic personal review. RESULTS: Since the early 1900s, the clinical picture of GBS has been illustrated in multiple series culminating in the ongoing International Guillain-Barré Syndrome study of 2000 patients. In the 1950s and 1960s, the inflammatory nature of the commonest form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms, acute motor-sensory axonal neuropathy and acute motor axonal neuropathy, were recognized. In the 1990s and early 2000s, these forms were shown to be due to antibodies against Campylobacter jejuni glycans cross-reacting with glycolipids on axonal membranes. The pathogenesis of AIDP remains unknown, but T-cell responses to the compact myelin proteins, P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells are important. Randomized controlled trials in the 1970s and 1980s showed no benefit from corticosteroids. Trials in the 1980s showed benefit from plasma exchange and in the 1990s from intravenous immunoglobulin. CONCLUSIONS: Future research should seek biomarkers to identify subgroups with different treatment responses, define the true natural history of the disease with population-based epidemiological studies, study the pathology in autopsies early in the disease, seek causative antibodies and confirm autoimmune T-cell responses in AIDP, and expand treatment trials to include anti-T-cell agents.

Jean-Charles Chatelin (1884-1948), counted among the "Righteous", but forgotten as a neurologist who studied under Pierre Marie.

Charles Chatelin (1884-1948) studied under Pierre Marie (1853-1940) at hôpital La Salpêtrière and went on to a career profoundly affected by World War I. He wrote a remarkable thesis on the clinical aspects and radiography of hereditary craniofacial dysostosis, which had been recently described by Octave Crouzon (1874-1938). A few days after the publication of Georges Guillain (1876-1961) and Alexandre Barré (1880-1967), Chatelin published a comprehensive study of the eponymous syndrome. His study was prepared before that of Guillain and Barré, but only their names are remembered. After examining patients with spinal injuries, Chatelin and Pierre Marie gave the first description of what would become, in 1924, "Lhermitte's sign." The eponym was first used after this sensory symptom was added by Lhermitte to the clinical picture of multiple sclerosis. In 1915, Chatelin and Pierre Marie used a technique based on radiographic overlays to localize intracranial projectiles. They coupled this with precise examinations of the visual field of wounded soldiers, in order to map out the intra-cerebral visual pathways with accuracy. During World War II, Chatelin and his wife demonstrated their empathy by hiding a Jewish family in their home until Paris was liberated.

The Legacy of the Seminal Publication by Guillain, Barré, and Strohl: The History Behind the Eponym.

The report, "On a syndrome of radiculoneuritis with hyperalbuminosis of the cerebrospinal fluid without a cellular reaction. Remarks on the clinical characteristics and tracings of the tendon reflexes," published in 1916, included superb longitudinal clinical observations of progressive areflexic paralysis in 2 French soldiers, unique laboratory findings from the still new at that time technique of lumbar puncture, and electrophysiological studies. The classic observation of the albumino-cytologic dissociation in the spinal fluid, even over 100 years later, is still one of the most important laboratory findings used by clinicians to confirm the suspected diagnosis of the Acute Inflammatory Demyelinating Polyneuropathy, typically eponymously referred to as Guillain Barré Syndrome (GBS). The contribution of André Strohl, who reported the electrophysiological abnormalities observed in their patients with novel myographic studies of tendon reflexes, led to eventual widespread use of electrodiagnostic techniques in bedside diagnosis of neuromuscular conditions. Since 1916, the clinicopathological spectrum of GBS has expanded continuously, with better understanding of the etiology, pathology, and electrodiagnostic findings. However, most of the seminal observations and conclusions presented by Guillain, Barré, and Strohl have withstood the test of time. Their landmark publication has become a standard of excellence in the history of clinical neurology. Deservedly, "GBS" is one of the most recognized medical eponyms around the world.

Guillain-Barré syndrome: What have we learnt during one century? A personal historical perspective.

We are approaching the centenary of the first description of Guillain-Barré syndrome. The past 30 years had witnessed an amazing progress in the understanding of the immunological and pathological mechanisms of this disorder. We now recognize that Guillain-Barré syndrome is remarkably heterogeneous and under this umbrella term are several variants and subtypes with distinct clinical, electrophysiological and immunopathological features. This review is a historical journey, through a personal perspective, following the milestones that led to the current substantial knowledge of Guillain-Barré syndrome.

Guillain-Barré syndrome: 100 years on.

The Guillain-Barré syndrome is associated with acute polyradiculoneuritis for almost one century. Its spectrum has considerably been enlarged since its first description. It now includes pure motor or sensory syndromes, focal forms, demyelinating and axonal neurophysiological features that characterise excitability dysfunctions, and immunological differentiations. We can hope that this improved classification will facilitate development of treatment innovations for a condition that is still a life-threatening condition with a severe functional prognosis in a significant proportion of cases.

Taking a Strohl Through History: Putting Strohl Back in Guillain-Barré-Strohl Syndrome.

Guillain-Barré Syndrome is a popular eponym that comes from a 1916 paper by Drs. Guillain, Barré, and Strohl. These physicians described two soldiers in the French Sixth Army during World War I who developed acute progressive motor weakness. Although Drs. Guillain and Barré have continued to be included in the syndrome's eponym, Dr. Strohl has been forgotten despite having strongly contributed to the original paper. The reasons previously mentioned for Dr. Strohl's absence appear trivial in contemporary practice and thus, his name deserves to be reintroduced to Guillain-Barré-Strohl Syndrome.

History of acute polyradiculoneuropathy (part 2): From 1916 to 2019.

First reported by Guillain, Barré, and Strohl during the Great War, the concept of "Guillain-Barré syndrome" (GBS) progressively emerged as a clinical entity in its own right. Despite many debates about its clinical and pathophysiologic characteristics, GBS is now recognized as a disease throughout the world. We describe here the main steps of the rich history of GBS, from 1916 to the present.

History of acute polyradiculoneuropathy (part 1): The prehistory of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy described in 1916 by Guillain, Barré, and Strohl. However, many similar cases had been reported earlier under various terms, with less detail and with various explanations about its pathophysiologic origin. Based on the analysis of old articles, we propose an overview of the history of acute inflammatory polyradiculoneuropathy before the official description of GBS.

The mysterious death of Georges Cuvier (1832): An early case of severe Guillain-Barré syndrome?

Although Guillain-Barré syndrome was officially described in 1916, other cases had been reported earlier, such as some cases of Landry's paralysis. This year is the 250th anniversary of the birth of Georges Cuvier (1769-1832), one of the fathers of comparative anatomy and palaeontology: he died at age 63 from an unknown disease. By reading medical reports about his last days and hours, we conclude Cuvier died from a severe form of Guillain-Barré syndrome. Moreover, we think this observation could be the first complete report of acute polyradiculoneuropathy with pharyngeal-cervical-brachial onset.

Guillain, Barraquer and I.

The year 2016 was the centennial anniversary of the recognition of the Guillain-Barré syndrome, which was first described by George Guillain, Jean-Alexandre Barré and André Strohl. In celebration of the centennial, this historical review describes aspects of the contributions of Guillain and the Spanish neurologist, Barraquer-Bordas and a brief account of the Fourth International Neurological Congress, which brought together Guillain and Barraquer-Bordas. There were many outstanding Brazilian physicians at that meeting. Finally, the author describes his interaction with Barraquer-Bordas and provides an account of his influence in shaping a generation of Brazilian neurologists, including himself.

World leaders surviving serious illness: Franklin D. Roosevelt and Pope John Paul II.

The quality of medical care and the degree of transparency communicated to the world whilst President Franklin D. Roosevelt and Pope John Paul II were seriously ill, as well as the global consequences of critical decisions they made during this time, were examined from published studies and through personal communications. Franklin D. Roosevelt, in his last years, was secretive about his health and, with one exception, was probably given indifferent medical advice, arguably hung on to office too long which, at least for Europe, contributed to some negative outcomes. Pope John Paul II, when quite ill, was open and communicative about his illness, had high-quality medical and surgical care and, together with his spirited will, greatly contributed to favourable European political outcomes, and to European and world stability.

Guillain-Barré syndrome: celebrating a century.

A hundred years ago, Guillain, Barré and Strohl described a syndrome with a predominant motor acute or subacute polyneuritis, albumin-cytologic dissociation in the cerebrospinal fluid, and a benign course. Before them, many other authors, such as Landry, Duménil, Osler, and Grainger Stewart had described similar cases although they had not performed lumbar punctures. In this work, we outline certain features of the beginning of this famous syndrome.

What's in the Literature?

In this edition, we provide a detailed summary of an informative book, "GBS100: Celebrating a Century of Progress in Guillain-Barré Syndrome" developed by the Peripheral Nerve Society to honor the centenary of the original paper on Guillain-Barré Syndrome. We also review various studies in myasthenia gravis including: management with rituximab; the efficacy of early fast-acting treatment with corticosteroids; and various dosing strategies for tacrolimus. Finally, we review new studies including: the potential pathogenesis, risk factors, and functional decline of patients with inclusion body myositis; MxA immunoreactivity in dermatomyositis; diagnostic approaches for evaluating patients with myalgia, fatigue, and exercise intolerance; MRI patterns in genetic muscle disease; and MRI as an outcome measure in facioscapulohumeral muscular dystrophy.

Did Jules Dejerine describe AMAN at the end of the 19th century?

Guillain-Barré syndrome (GBS) is a heterogeneous group of acute immune-mediated neuropathies, including acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). AMAN is an axonal subtype of GBS that has been known since the 1990s; this term was first used to describe a summer epidemic of acute ascending paralysis observed in children in northern China (and Mexico). It is pathologically characterized by noninflammatory axonal degeneration of the motor nerves (with little or no demyelination). The French neurologist Jules Dejerine (1849-1917) conducted a clinical and pathologic description of AMAN in the late 19th century. We describe his observations, which provide us with valuable information on the course of pathologic lesions in this disease.

Spinal nerve involvement in early Guillain-Barré syndrome: The Haymaker and Kernohan's legacy.

Pathological studies of early Guillain-Barré syndrome (GBS), defined as of 10days of disease onset, are scanty making it difficult to interpret the physiopathology of clinical and electrophysiological features. In 1949, Webb Haymaker and James Kernohan reported 50 clinico-pathological studies of fatal GBS cases, 32 of them having died between days 2 and 10 after onset. They established that the brunt of initial lesions, consisting of endoneurial oedema interpreted as degenerative, relied on spinal nerves. That this oedema was inflammatory was soon thereafter recognized. Two decades later, however, the pathogenic role of endoneurial oedema was disputed. In experimental allergic neuritis, considered an animal model of GBS, the initial lesion appearing on day 4 post-inoculation is marked inflammatory oedema in the sciatic nerve and lumbosacral nerve roots. Additional detailed clinico-pathological studies corroborated that the appearance of epi-perineurium at the subarachnoid angle, where anterior and posterior roots join to form the spinal nerve, is a pathological hotspot in early GBS, there developing inflammatory oedema, incipient demyelination and endoneurial ischemic zones with axonal degeneration. Furthermore, nerve ultrasonography has demonstrated predominant spinal nerve changes in early GBS, either demyelinating or axonal. Other outstanding Haymaker and Kernohan's contributions were to clarify the complex nosology of the syndrome bringing under the same rubric Landry's paralysis, acute febrile polyneuritis and GBS, and critically analyzing GBS exclusion criteria by then prevailing. It is concluded that the authors' legacy remains as relevant as ever.

Guillain-Barré Syndrome.

Guillain-Barré syndrome is an acute inflammatory immune-mediated polyradiculoneuropathy presenting typically with tingling, progressive weakness, and pain. Variants and formes frustes may complicate recognition. The best known variant is the sensory ataxic form of Miller Fisher syndrome, which also affects the oculomotor nerves and the brain stem. Divergent pathologic mechanisms lead to demyelinating, axonal, or mixed demyelinating-axonal damage. In the demyelinating form, yet to be identified antigens are inferred by complement activation, myelin destruction, and macrophage-activated cleanup. In the axonal and Miller Fisher variants, gangliosides (GM1, GD1a, GQ1b) are targeted by immunoglobulins and share antigenic epitopes with some bacterial and viral antigens. Campylobacter jejuni infection is associated with an axonal-onset variant; affected patients commonly experience more rapid deterioration. Many other antecedent infectious agents have been recognized including the most recently identified, Zika virus. Supportive care remains the mainstay of therapy. Plasma exchange or intravenous immunoglobin hastens recovery. Combination immunotherapy is not more effective, and the efficacy of prolonged immunotherapy is unproven. One in 3 patients will have deterioration severe enough to require prolonged intensive care monitoring or mechanical ventilation. Full recovery is often seen; most patients regain ambulation, even in severe cases, but disability remains in up to 10% and perhaps more. Numerous challenges remain including early identification and control of infectious triggers, improved access of modern neurointensive care worldwide, and translating our understanding of pathogenesis into meaningful preventive or assistive therapies. This review provides a historical perspective at the centenary of the first description of the syndrome, insights into its pathogenesis, triage, initial immunotherapy, and management in the intensive care unit.

Franklin Delano Roosevelt's (FDR's) (1882-1945) 1921 neurological disease revisited; the most likely diagnosis remains Guillain-Barré syndrome.

In 2003, we published evidence that the most likely cause of FDR's 1921 neurological disease was Guillain-Barré syndrome. Afterwards, several historians and neurologists stated in their publications that FDR had paralytic poliomyelitis. However, significant criticism of our article or new support for that diagnosis was not revealed. One critic claimed that FDR's cerebrospinal fluid indicated poliomyelitis, but we did not find evidence that a lumbar puncture was performed. The diagnosis of FDR's neurological disease still depends upon documented clinical abnormalities. His age, prolonged symmetric ascending paralysis, transient numbness, protracted dysaesthesia (pain on slight touch), facial paralysis, bladder and bowel dysfunction, and absence of meningismus are typical of Guillain-Barré syndrome and are inconsistent with paralytic poliomyelitis. FDR's prolonged fever was atypical for both diseases. Finally, permanent paralysis, though commoner in paralytic poliomyelitis, is frequent in Guillain-Barré syndrome. Thus, the clinical findings indicate the most likely diagnosis in FDR's case remains Guillain-Barré syndrome.