Guillain-Barre Syndrome Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

The pathogenesis of GBS remains unclear. Guillain-Barré syndrome (GBS), or acute inflammatory demyelinating polyradiculoneuropathy (AIDP) It is an autoimmune disease, often triggered by a preceding viral or bacterial infection such as Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, or Mycoplasma pneumoniae. Vaccination against the flu, rabies, and meningitis are also documented precipitating factors. Guillain-Barré syndrome (GBS) can be described as a collection of clinical syndromes that manifests as an acute inflammatory polyradiculoneuropathy with resultant weakness and diminished reflexes. The pathogenesis of GBS remains unclear.

Guillain-Barré syndrome (GBS) Signs and symptoms Paresthesias generally begin in the toes and fingertips, progressing upward but generally not extending beyond the wrists or ankles. The classic weakness is ascending and symmetrical in nature. The LL are usually involved before the UL. Proximal muscles involved earlier than the more distal ones. Typical patient with GBS, presents 2-4 weeks following a relatively benign respiratory or gastrointestinal illness.  The weakness may progress over hours to days to involve the arms, truncal muscles, cranial nerves, and muscles of respiration. Most patients complain of paresthesias, numbness, or similar sensory changes.

Guillain-Barre Syndrome: Autonomic changes in GBS: Tachycardia Bradycardia Facial flushing Paroxysmal hypertension Orthostatic hypotension Anhidrosis and/or diaphoresis Urinary retention Typical respiratory complaints include: Dyspnea on exertion Shortness of breath Difficulty swallowing Slurred speech Ventilatory failure with required respiratory support occurs in up to one third of patients at some time during the course of their disease.

Nerve conduction studies Antiganglioside antibodies Type[3 Symptoms Nerve conduction studies Antiganglioside antibodies Acute inflammatory demyelinating polyneuropathy (AIDP) Sensory symptoms and muscle weakness, often with cranial nerve weakness and autonomic involvement Demyelinating polyneuropathy No clear association Acute motor axonal neuropathy (AMAN) Isolated muscle weakness without sensory symptoms in less than 10%; cranial nerve involvement uncommon Axonal polyneuropathy, normal sensory action potential GM1a/b, GD1a & GalNac-GD1a Acute motor and sensory axonal neuropathy (AMSAN) Severe muscle weakness similar to AMAN but with sensory loss Axonal polyneuropathy, reduced or absent sensory action potential GM1, GD1a Pharyngeal-cervical-brachial variant Weakness particularly of the throat muscles, face, neck and shoulder muscles Generally normal, sometimes axonal neuropathy in arms Mostly GT1a, occasionally GQ1b, rarely GD1a Miller Fisher syndrome Ataxia, eye muscle weakness, areflexia but usually no limb weakness Generally normal, sometimes discrete changes in sensory conduction or H-reflex  detected GQ1b, GT1a

Guillain-Barre Syndrome: Biochemical screening/ PFT/Cerebrospinal fluid analysis Cerebrospinal fluid studies: Most, but not all, patients with GBS have an elevated cerebrospinal fluid (CSF) protein level (>400 mg/L), with normal cell counts. Elevated or rising protein levels on serial LP’s and 10 or fewer mononuclear cells/mm3 strongly support the diagnosis (Albuminocytological dissociation). MRI and CT scanning excluding myelopathy Biochemical screening: Electrolyte levels Liver function tests (LFTs) Creatine phosphokinase (CPK) ESR Pulmonary function tests: To monitor respiratory status and the need for ventilatory assistance. Neurophyiological studies: EMG and NCS can be very helpful in the diagnosis.

Guillain-Barre Syndrome: Diagnostic Considerations Problems to consider in the differential diagnosis of Guillain-Barré syndrome (GBS) include : Acute myelopathy (e.g., from compression, transverse myelitis, vascular injury) Chronic inflammatory demyelinating polyneuropathy (CIDP) Vasculitic neuropathies Porphyria polyneuropathy Toxic neuropathies (e.g., arsenic, thallium, organophosphates, lead) Vitamin deficiency (e.g., vitamin B-12,thiamine) Neurotoxic fish or shellfish poisoning Paraneoplastic neuropathy Poliomyelitis

Guillain-Barre Syndrome: Differential diagnosis Botulism Cauda Equina and Conus Medullaris Syndromes Chronic Inflammatory Demyelinating (CIDP) Polyradiculoneuropathy Multifocal motor neuropathy Heavy Metal Toxicity Lyme Disease Metabolic Myopathies Multiple Sclerosis Nutritional Neuropathy Vasculitic Neuropathy

Guillain-Barre Syndrome: Treatment & Management Pre-hospital and Emergency Department Care Pre-hospital care of patients with GBS requires careful attention to ABCs. Administration of: Oxygen Assisted ventilation may be indicated, along with Establishment of I/V access. Emergency medical services personnel should monitor for cardiac arrhythmias and transport expeditiously. In the emergency department, continuation of ABCs, intravenous treatment, oxygen, and assisted ventilation may be indicated Intubation should be performed on patients who develop any degree of respiratory failure.

Guillain-Barre Syndrome: Management Intensive care unit Admission to the intensive care unit (ICU) should be considered for all with Labile dysautonomia FVC of less than 20 mL/kg Severe bulbar palsy.  Any patients exhibiting clinical signs of respiratory compromise to any degree also should be admitted to an ICU. S/C un-fractionated heparin or LMWH o prevent DVT. Respiratory therapy 1/3rd of patients with GBS require ventilatory support and require: Serial assessment of ventilatory status Measurements of vital capacity Pulse oximetry monitoring. Tracheotomy is required in a patient with prolonged respiratory failure, especially if mechanical ventilation is required for more than 2 weeks

Guillain-Barre Syndrome: Management Cardiac monitoring Close monitoring of heart rate, blood pressure, and cardiac arrhythmias allows early detection of life-threatening situations. Antihypertensive and vasoactive drugs should be used with caution in patients with autonomic instability. Immunomodulation Immunomodulatory treatment in GBS has been used to hasten recovery. IVIG and plasma exchange have proved equally effective. IVIG treatment is easier to implement and potentially safer than plasma exchange. Additionally, IVIG is the preferential treatment in hemodynamically unstable patients and in those unable to ambulate independently.

Guillain-Barre Syndrome: Nutrition/ Prevention of infection Enteral or parenteral feedings are required for patients on mechanical ventilation to ensure that adequate caloric needs are met when the metabolic demand is high. Prevention of infection The risk of infection can be decreased by the use of Minimal sedation Frequent physiotherapy Mechanical ventilation with positive end-expiratory pressure where appropriate. Prevention of thromboses/pressure sores Subcutaneous unfractionated or LMWH and thromboguards are often used to prevent lower-extremity DVT and PE. Prevention of pressure sores and contractures entails careful positioning, frequent postural changes, and daily range-of-motion (ROM) exercises.

Guillain-Barre Syndrome: Physical Therapy/Occupational Therapy The goals of the therapy programs are to reduce functional deficits and to target impairments and disabilities resulting from GBS. Occupational therapy early in the rehabilitation program to promote upper body strengthening, and activities that aid functional self care. Restorative and compensatory strategies can be used to promote functional improvements. Energy conservation techniques and work simplification also may be helpful, especially if the patient demonstrates poor strength and endurance. Recreational therapy assists in the patient's adjustment to disability and improves integration into the community.

Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria Level of diagnostic accuracy Diagnostic criteria 1 2 3 4 Bilateral and flaccid weakness of limbs + +/- Decreased or absent tendon reflex in weak limbs Monophasic course and time between onset-nider 12 h 28 days CSF cell count < 50/µl CSF protein content >normal value NCS findings consistent with one the subtypes of GBS Absence of alternative diagnosis for weakness

Miller-Fisher Syndrome Symptoms Miller Fisher syndrome (MFS) is a post-infectious, immune mediated neuropathy characterized in typical cases by the clinical triad of Ophthalmoplegia, Ataxia Areflexia. MFS is considered to be a variant of the Guillain-Barré syndrome (GBS). The clinical symptoms usually develop within days and improve spontaneously or after treatment within weeks.

Miller-Fisher Syndrome Symptoms More than 90% of MFS patients have serum antibodies to the gangliosides GQ1b and GT1a. These antibodies likely arise during antecedent infection by molecular mimicry and are pathogenic for peripheral nerves in animal bioassays. Patients with severe MFS, may develop bulbar weakness or may progress to GBS. These patients may benefit from treatment with intravenous immunoglobulin or plasma exchange. Generally, recovery begins a few weeks after symptom onset and is usually complete by 6 months.  

CHRONIC INFLAMMATORY DEMYELINATING NEUROPATHY Dr. M. Sofi MD; FRCP (London); FRCPEdin; FRCSEdin

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder with cyto-albuminologic dissociation. It can be considered the chronic equivalent of acute inflammatory demyelinating polyradiculoneuropathy, the most common form of Guillain-Barré syndrome. CIDP typically starts insidiously and evolves slowly, in either a slowly progressive or a relapsing manner, with partial or complete recovery between recurrences. Periods of worsening and improvement usually last weeks or months. Most experts consider the necessary duration of symptoms to be greater than 8 weeks for the diagnosis of CIDP to be made.

Signs and symptoms of CIDP Initial limb weakness, both proximal and distal Sensory symptoms (e.g., tingling and numbness of hands and feet) Motor symptoms (usually predominant) In about 16% of patients, a relatively acute or subacute onset of symptoms Symptoms of autonomic system dysfunction (e.g., orthostatic dizziness) Signs Signs of cranial nerve (CN) involvement (facial muscle paralysis or diplopia) Gait abnormalities Motor deficits (symmetric weakness of both proximal and distal muscles in upper and lower extremities) Diminished or absent deep tendon reflexes Sensory deficits (typically in stocking-glove type) Impaired coordination

Diagnosis: Laboratory studies that may be helpful include: Electrodiagnostics: In CIDP, the NCS demyelination findings are: Reduction in nerve conduction velocities Presence of conduction block or abnormal temporal dispersion in at least one motor nerve Prolonged distal latencies in at least two nerves; Absent F waves/ prolonged minimum F wave latencies in at least two motor nerves. Cerebrospinal fluid analysis: Elevated protein levels (80% of patients); 10% of patients also have mild lymphocytic pleocytosis and increased gamma globulin Complete blood count (CBC), (ESR), antinuclear antibody (ANA) level, biochemistry profile, and serum and urine Immunoelectrophoresis Serum test to exclude other autoimmune diseases.

Sural nerve biopsy is done when the diagnosis is not completely clear, when other causes of neuropathy (e.g., vasculitic hereditary,) cannot be excluded, or when profound axonal involvement is observed on EMG. Electron micrograph Note "onion bulb" formation in the myelin sheath of the nerve fibers due to continuous demyelination and re-myelination. Electron micrograph of the peripheral nerve

Diagnostic Criteria For CIDP: EFNS/PNS Guidelines Nerve biopsy Electrodiagnosis MRI Spinal roots, brachial plexus, Cerebrospinal fluid analysis Laboratory studies Evaluation inherited neuropathies CIDP Atypical CIDP Atypical Chronically progressive , stepwise, or recurrent symmetrical proximal and distal weakness and sensory dysfunction Predominantly distal DADS Asymmetric (Multifocal acquired demyelinating sensory motor neuropathy) Developing over at least 2 months Lewis-Sumner syndrome Absent or reduced tendon reflexes in all extremities Focal (Brachial or lumbosacral plexus

Differential Diagnoses Acute Inflammatory Demyelinating Polyradiculoneuropathy Acute and Chronic Inflammatory Demyelinating Polyneuropathy in HIV Amyotrophic Lateral Sclerosis CNS Lupus Cauda Equina and Conus Medullaris Syndromes Diabetic Neuropathy Multifocal Motor Neuropathy Neurosarcoidosis Nutritional Neuropathy Polyarteritis Nodosa Progressive Polyradiculopathy in HIV Syringomyelia Toxic Neuropathy Tropical Myeloneuropathies Uremic Neuropathy Vasculitic Neuropathy Wegener Granulomatosis Neuropathy

Immunomodulatory/immunosuppressive agents Their use is based on the proposed pathogenesis of CIDP as an immune-mediated condition: I/V immunoglobulin (IVIg), plasma exchange (PE) Recent controlled studies show subcutaneous immunoglobin (SCIG) appears to be as effective for CIDP treatment as IVIG in most patients, and with fewer systemic side effect Prednisolone in combination with IVIg Immunosuppressive drugs are often of the cytotoxic chemotherapy class including rituximab which targets B cells Cyclophosphamide, a drug which reduces the function of the immune system. Other immunosuppressive drugs include: Azathioprine Methotrexate Mycophenolate Cyclosporine

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