Acute Inflammatory Demyelinating Polyneuropathy

1. Acute Inflammatory DemyelinatingPolyneuropathy Prepared by DR. PaawanWadhawan Moderator DR. Prabhakar

2. Introduction • Acute inflammatory demyelinatingpolyneuropathy (AIDP) is considered to be an immunological disorder with an acute, often fulminant evolution characterised by a syndrome of rapidly progressive flaccid paralysis, areflexia and albuminocytological dissociation in the cerebrospinal fluid. • It is popularly referred to as GB syndrome (GuillainBarre' syndrome) after the French army neurologists, who described this entity in 1916.

3. Introduction • With the decrease in incidence of poliomyelitis worldwide, AIDP has become the most common cause of acute flaccid paralysis. • Crude average annual incidence rates vary from 0.4-1.9 per 1 Lakh population in different countries of the world. Incidence increases with age and is highest in the 50-74 years age group.

4. Aetiopathogenesis • In 50-60% of cases there is a history of a preceding viral infection like • Cytomegalovirus • Epstein Barr virus • Hepatitis B and C • Mumps • Herpes virus • HIV • Other infections like Campylobacter jejuni, Borrelia burgdorferi, typhoid, Mycoplasma,andfilariasis .

5. Aetiopathogenesis • Gulliancamp me gayawahausneeinsteinkeB and C hips dabaye.uske bad gullian ne Heerkemammedabakarunkasizemegalokardiyaaur use HIV ho gaya. • GULLIAN KI HETEROSEXUAL KAHANI

6. Association with Campylobacter jejuni • Campylobacter jejuni probably causes more severe disease with axonal degeneration occurring either alone or in combination with demyelination and carries a correspondingly poor prognosis. • Outer membrane of C. jejuni shares an identical immunogenic region with the ganglioside GM-1 in the human peripheral nerves (molecular mimicry).

7. Other associations • Vaccination for rabies, smallpox, oral polio, tetanus toxoid. • Bee stings • Major surgery,myocardial infarction, idiopathic membranous glomerulonephritis and bone marrow transplantation have also been implicated. • Malignancies and systemic illnesses - Case reports document patients with AIDP associated with Hodgkin lymphoma, acute myelogenous lymphoma, Castleman disease, systemic lupus erythematosus, and hypothyroidism.

8. Association with swine flu vaccine • There were reports of GBS affecting some people who had received swine flu immunizations in the 1976 U.S. outbreak of swine flu. Overall, there were about 500 cases of GBS—25 of which resulted in death from severe pulmonary complications— which acc. to experts-were probably caused by an immunopathological reaction to the 1976 swine flu vaccine. Other influenza vaccines have not been linked to GBS, though caution is advised for certain individuals, particularly those with a history of GBS

10. The myelin sheath is the most susceptible element of the nerve fiber, for it may break down as part of a primary process involving the Schwann cells or of the myelin itself, or it may be damaged secondarily as a consequence of disease affecting its axon. Focal degeneration of the myelin sheath with sparing of the axon is called segmental demyelination. The characteristic change of segmental demyelination is the disappearance of the sheath over segments of variable length, bounded on each end by a preserved segment of myelin. This exposes long segments of the axon to the interstitial environment. Myelin may also degenerate from axonal disease in a general process that may occur either proximal or distal to the site of axonal interruption. Common to many lesions of the peripheral nerve is wallerian degeneration, a reaction of both the axon and myelin distal to  the site of disruption of an axon. Wallerian degeneration might be described as "dying forward," a process in which the nerve degenerates from the point of axonal damage outward. In contrast, when the axon degenerates as part of a "dying-back" phenomenon in a more generalized metabolically determined polyneuropathy, it is termed axonal degeneration. Here, the axon is affected progressively from the distal-most site to the proximal, with dissolution of myelin that occurs roughly in parallel with the axonal change. One possible explanation for this process is that the primary damage is to the neuronal cell body, which fails in its function of synthesizing proteins and delivering them to the distal parts of the axon. Certain toxic and metabolic processes affect axons uniformly along their length or impair anterograde axonal transport to the periphery; the functional impairment is then proportional to the size and length of the blocked axons.

11. Pathpphysiology • All forms of Guillain-Barré syndrome are due to an immune response to foreign antigens (such as infectious agents) that are mistargeted at host nerve tissues instead. The targets of such immune attack are thought to be gangliosides, compounds naturally present in large quantities in human nerve tissues. The most common antecedent infection is the bacteria Campylobacter jejuni.However, 60% of cases do not have a known cause • There are three important features in the pathology of AIDP - • inflammation, • demyelination and • remyelination. • In a minority of patients, axonal damage and degeneration occur due to intense inflammatory response and such patients may not get complete recovery.

12. Pathpphysiology Damage to myelin sheath of peripheral nerves is mediated by synergistic and simultaneous action of macrophages, autoreactive T lymphocytes,and interferon gamma. Macrophage is the major effector of myelin disruption. It penetrates Schwann cell cytoplasm and phagocytose intact myelin lamellae. Damage to the myelin sheath leads to segmental demyelination. This results in decreased nerve conduction velocity and, at times, conduction block. The remaining Schwann cells divide and remyelinate the bare axons. As the regeneration occurs, nerve sprouting and increased scarring often results.

13. Diagram of probable cellular events in acute inflammatory polyneuropathy (Guillain-Barré syndrome). A. Lymphocytes attach to the walls of endoneurial vessels and migrate through the vessel wall, enlarging and transforming as they do so. At this stage no nerve damage has occurred. B. More lymphocytes have migrated into the surrounding tissue. The first effect on the nerve is breakdown of myelin, the axon being spared (segmental demyelination). This change appears to be mediated by the mononuclear exudate, but the mechanism is uncertain. C. The lesion is more intense, polymorphonuclear leukocytes being present as well as lymphocytes. There is interruption of the axon in addition to myelin sheath damage; as a result, the muscle undergoes denervation atrophy and the nerve cell body shows central chromatolysis. If the axonal damage is distal, the nerve cell body will survive, and regeneration and clinical recovery are likely. If, as in D, axonal interruption has occurred proximally because of a particularly intense root or proximal nerve lesion, the nerve cell body may die and undergo dissolution. In this situation, there is no regeneration, only the possibility of collateral reinnervation of muscle from surviving motor fibers. (From Asbury et al [1969], by permission.)

14. Mortality/Morbidity • Mortality rate ranges from 2-6%. • In general, death is due to complications of ventilation. Causes include cardiac arrest, pulmonary embolus, sepsis, bronchospasm, pneumothorax, adult respiratory distress syndrome (ARDS), and dysautonomia. • More than 75% of patients have complete or near-complete recovery with no deficit or only mild residual fatigue and distal weakness. • Other patients, almost all of whom required ventilation, report severe dysesthesias or moderately severe distal weakness as residual symptoms. About 15% of patients end up with significant neurological residuals.

15. History • Acute inflammatory demyelinating polyneuropathy typically manifests as an ascending paralysis. • Even in these cases, the clinical presentation and course vary. Additionally, many variants exist that differ markedly from classic AIDP in disease onset or course.

16. History –progressive weakness • The hallmark of classic AIDP is progressive weakness that usually begins in the feet before involving all 4 limbs. At presentation, 60% of patients have weakness in all 4 limbs. • Weakness plateaus at 2 weeks after onset in 50% of patients and by 4 weeks in over 90%. It is usually symmetric, although mild asymmetry is not uncommon early in the disease course. • In the arms, weakness may be worse proximally than distally. At presentation, half of patients have some facial weakness, although only 5% have varying degrees of ophthalmoplegia. • Oropharyngeal or respiratory weakness is a presenting symptom in 40% of patients. Improvement in strength usually begins 1-4 weeks after the plateau. About one third of patients require mechanical ventilation because of respiratory failure.

17. History-Sensory symptoms • Mild to moderately severe paresthesias in thedistallimbs are common and often precede the onset of weakness by 1 or more days. • Proximal sensory changes are uncommon but may occur in more severe cases of AIDP.

18. History-Autonomic dysfunction • About two thirds of patients have one or more autonomic abnormalities. Sustained sinus tachycardia is the most common dysfunction. Postural hypotension leading to presyncope or syncope can occur. • Sweating dysfunction is common but rarely noted by patients. Urinary retention and constipation are more likely to occur later in the course of AIDP. Autonomic dysfunction is more common in intubated patients. Pain • Mild lower back and/or hip pain is very common and occasionally precedes the onset of weakness. • The pain is severe in about 15% of patients.

19. Clinical variants • Acute inflammatory demyelinatingpolyneuropathy(AIDP) is the most common form of GBS, and the term is often used synonymously with GBS. It is caused by an auto-immune response directed against Schwann cell membranes. • Miller–Fisher syndrome (MFS) is a rare variant of GBS and manifests as a descending paralysis, proceeding in the reverse order of the more common form of GBS. It usually affects the eye muscles first and presents with the triad of ophthalmoplegia, ataxia, and areflexia(OAtAr). Anti-GQ1b antibodies are present in 90% of cases and this antibody is specifically associated with ophthalmoplegia.

20. Clinical variants • Acute motor axonal neuropathy (AMAN), a.k.a. Chinese Paralytic Syndrome, attacks motor nodes of Ranvier and is prevalent in China and Mexico. It is likely due to an auto-immune response directed against the axoplasm of peripheral nerves. The disease may be seasonal and recovery can be rapid. Anti-GD1a and Anti-GD3(more common) antibodies are present. • Acute motor sensory axonal neuropathy (AMSAN) is similar to AMAN but also affects sensory nerves with severe axonal damage. Like AMAN, it is likely due to an auto-immune response directed against the axoplasm of peripheral nerves. Recovery is slow and often incomplete. • So aman has good prognosis while amsan has bad prognosis.

21. Clinical variants • Acute panautonomic neuropathy is the most rare variant of GBS, sometimes accompanied by encephalopathy. It is associated with a high mortality rate, due to cardiovascular involvement, and associated dysrhythmias. Impaired sweating, lack of tear formation, photophobia, dryness of nasal and oral mucosa, itching and peeling of skin, nausea, dysphagia, constipation unrelieved by laxatives or alternating with diarrhea occur frequently in this patient group. The most common symptoms at onset are related to orthostatic intolerance, as well as gastrointestinal and sudomotor (sweat gland)dysfunction.

22. Clinical variants • Regional variants of Guillain-Barré syndrome, such as pharyngeal-cervical-brachial weakness or only leg weakness, are rare and resemble AIDP in time course. • Hyperacute axonal polyradiculoneuropathyhas a hyperacute course with onset to respiratory failure within 48 hours.These patients have a high mortality rate. Recovery when it occurs, is delayed, very prolonged, and characteristically quite incomplete. • Critical illness polyneuropathyhas an uncertain relationship to the acute inflammatory neuropathies. • Sensory Guillain-Barré syndrome, where sensory symptoms occur in isolation, are rare.

23. Clinical variants • Acute inflammatory demyelinatingpolyneuropathy(AIDP) • Hyperacute axonal polyradiculoneuropathy • Critical illness polyneuropathy • Acute motor axonal neuropathy (AMAN), • Acute motor sensory axonal neuropathy (AMSAN) • Sensory Guillain-Barré syndrome • Miller–Fisher syndrome (MFS) • Acute panautonomic neuropathy • pharyngeal-cervical-brachial weakness

24. Physical examination • A detailed physical examination can help support the diagnosis of acute inflammatory demyelinating polyneuropathy and/or exclude disorders in the differential diagnosis.Weakness • Although patients often report only weakness in the legs, careful examination usually demonstrates arm weakness (proximally and distally). • Some patients with Miller-Fisher or other regional variants may have weakness of cranial muscles only. • Deep tendon reflexes • Hyporeflexia or areflexia is seen in 70% of patients at presentation and eventually in all patients. • A progressive decrease in reflexes is a useful finding that may precede electromyographic (EMG) changes.

25. Physical examination Autonomic dysfunction • Fluctuations in heart rate, specifically a sustained sinus tachycardia, are seen often. • Some intubated patients also may have bradycardia, especially after vagal stimulation with Valsalva and/or tracheal suctioning maneuvers. • Orthostatic hypotension can occur and is likely due to dysfunction of the baroreceptor reflex. • At times, the labile blood pressure is observed with severe hypertension that may be due to dysfunction of the afferent limb of the baroreceptor reflex. • Urinary retention is common, especially in intubated patients. The rare patient may even develop an ileus.

26. Diagnostic Criteria of AIDP

27. Diagnostic Criteria of AIDP –cont.

29. Differential Diagnosis • Acute myelopathieswith chronic back pain and sphincter dysfunction • Botulism with early loss of pupillary reactivity • Diphtheria Weakness may follow the pharyngeal infection by 2-3 weeks, beginning with palatal paralysis (??descending paralysis)and, often, paralysis of accommodation. Limb weakness is not common. • Lyme disease polyradiculitis(caused by the spirochete Borreliaburgdorferiwhich is transmitted by Ixodid tick species--Erythemamigrans helps in differentiating) and other tick-borne paralyses • Porphyriapositive family history, presence of recurrent abdominal pain, constipation, hypertension, mental changes and precipitation after infection, surgery or drugs. The patient may also give a history that the urine develops a port-wine colour on standing. • Vasculitis neuropathy The erythrocyte sedimentation rate may be elevated, but other tests for systemic disease are negative. • Poliomyelitis with fever and meningeal signs

30. Differential Diagnosis 8. CMV polyradiculitisin immunocompromised patients 9. Critical illness neuropathy Weakness is more common in the setting of sepsis and/or multiorgan failure. Pt will be having sepsis . 10. Myasthenia gravis reflexes preserved,no sensory loss .The mandibular muscles remain relatively strong in GBS, whereas the exercised jaw hangs open in myasthenia. 11. Poisonings with organophosphate (TOCP), thallium loss of hair, or arsenic (rain drop pigmentation) 12 . Periodic paralyses, usually hypokalemiccharacterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and are more episodic than periodic. 13. Carcinomatous meningitis -An irregular distribution of weakness between proximal and distal parts, the absence of facial weakness and the appearance of symptoms sequentially in one limb after another

31. Differential Diagnosis 14) Hypophosphatemia: An acute areflexic paralysis may follow hypophosphatemia in the setting of total parenteral nutrition, alcohol abuse, or rapid refeeding after starvation. The weakness rapidly responds to phosphate replacement. 15) Buckthorn shrub poisoning: This plant is found in the southwestern United States and Central America and bears a fruit that causes paralysis by an unknown mechanism. The CSF is usually normal. 16) Malingering and conversion reaction: Bizarre or nonphysiologic abnormalities may be seen on neurologic examination.

32. Mnemonics • Descending areflexic paralysis----miller BDP • Miller fisher syndrome,botulism,diptheria,polio • Grading of GBS –gullianki 6 din kikillaskillaskimaut • Miller fisher ekmachuarathajojhukke (descending paralysis) machlipakadtatha,useeknayab current marnevalimachli fans gayi ,jaise hi miller ne use chua use areflexia ho gaya,vo ataxia se girgaya or uskiaankheinghumneylagin(opthalmoplegia),vosambhlaaurusne us machlikoek ANTIG1Qb naamkeheerekebadlebechdiyaaurvohkhusikhusiraha.

33. Vascular Vasculitis neuropathy • Haemat • Cvs • Infdiptheria,polio,cmv,lyme,Critical illness neuropathy • Trauma • Cvd/autoimmune Myasthenia gravis • Age • Liver/kidney • Brain/spinal cord Acute myelopathies • Intestine • El/endocrine/Glucose-k↓,p↓,porphyria • Lungs • Inflamation • Tumors Carcinomatous meningitis • Nutrition • Genetic channelopathies of k • Unique tick • Psychiatric Malingering and conversion reaction: • Drugs • Skin • Obg/paed • Musculoskeletal • Poisoinars,th,tocp, Buckthorn shrub poisoning, Botulism • alcohol

34. Workup • Cerebrospinal fluid • Increased CSF protein without an increased WBC count (albuminocytologicdissociation) is observed classically in AIDP. However, this finding is not specific to AIDP. • About two thirds of patients have this CSF finding during the first week of symptoms and 82% have it by 2 weeks after symptom onset. • Although protein values can be elevated by 10-fold or more, no association exists between protein level and clinical severity. • Some patients have oligoclonal banding of the CSF. • Myelin basic protein also is increased in some patients

35. Cerebrospinal fluid –cont. • More than 90% of patients have fewer than 10 WBC/µL, with a mean of 3 WBC/µL. If more than 50 WBC/µL are present, an alternative diagnosis should be considered, including HIV, Lyme disease, polio, or other infections. Patients with HIV-associated AIDP often have >50 WBC/µL (mean, 23 WBC/µL). • In non-HIV cases, the cells are overwhelmingly lymphocytes, whereas a nonlymphocyticpleocytosis is seen in patients with HIV. • Both tau and 14-3-3 protein levels are reported to be elevated early (during the first few days of symptoms) in some cases of GBS. • Tau increases in CSF may reflect axonal damage and predict a residual deficit.

36. Blood tests • Blood tests have little role in the diagnosis of AIDP but may help to exclude other conditions and to serially monitor patients with AIDP in the hospital (especially those who are critically ill). • Recently, an association has been found between acute axonal motor variants and immunoglobulin G (IgG) directed against ganglioside GM1 and/or GD1a. • Most patients with the Miller-Fisher variant of AIDP have antibodies directed against ganglioside GQ1b. Some patients with pure sensory variants have antiganglioside GD1b antibodies. • Several case reports have suggested a close association of IgG anti-GD1b antibodies with ataxia in Guillain-Barré syndrome. • These tests are seldom beneficial in classic AIDP, but can help when patients present with variants.

37. Blood tests • Although not necessary for diagnosis, measurement of antiviral or antibacterial antibodies may confirm an association • Measurement of potassium, phosphate, and porphyrinmetabolism products may help exclude alternative diagnoses in atypical cases. • Some critically ill patients with AIDP develop the syndrome of inappropriate antidiuretic hormone (SIADH) with associated hyponatremia and reduced serum osmolarity. • Additionally, liver enzymes sometimes are elevated in AIDP. • If intravenous immunoglobulin (IVIg) therapy is anticipated in noncritical cases, immunoglobulin A (IgA) levels should be drawn before treatment.

38. Other tests • Urine tests to exclude heavy metal intoxication may be necessary in some patients. • Stool cultures may confirm C jejuni enteritis. Patients with this condition may have a more aggressive course and a slightly worse prognosis.

39. Imaging Studies • Imaging is seldom necessary for diagnosing acute inflammatory demyelinating polyneuropathy, but it may be necessary to exclude alternative diagnoses and to monitor critically ill patients. • MRI of the spine is sometimes necessary to rule out spinal cord and/or nerve root processes that mimic AIDP. • Nerve root, caudaequina, or cranial nerve enhancement is observed sometimes on T1-weighted, gadolinium-contrasted scans. This can help diagnose some atypical cases. • Cytomegalovirus radiculitis, meningealcarcinomatosis, lymphomatosis, and sarcoidosis may have similar MRI findings.

40. Electrodiagnostic testing • Electrodiagnostic testing is always necessary to confirm the diagnosis of acute inflammatory demyelinating polyneuropathy • Nerve conduction studies (NCS) can document demyelination, the hallmark of acute inflammatory demyelinatingpolyneuropathy. • Early on, findings of NCS studies are often normal. However, 90% are abnormal within 3 weeks of symptom onset. • Patients who meet 3 of the 4 NCS criteria have a clear primary demyelinating neuropathy, although patients who meet fewer than 3 criteria still may have AIDP.

41. Patients who meet 3 of the 4 NCS criteria have a clear primary demyelinating neuropathy, although patients who meet fewer than 3 criteria still may have AIDP. NCS Criteria • Reduced conduction velocity • Conduction block or abnormal dispersion • Prolonged distal latencies • Prolonged F-waves • Needle EMG can document the extent of denervation. • Autonomic tests such as sympathetic skin responses and cardiovagal testing may be indicated in patients with autonomic failure.

42. Pulmonary function tests • Pulmonary function tests, useful in determining the timing of intensive care unit (ICU) transfers and elective intubation, should be performed in all patients. • Transfer to an ICU generally is indicated when forced vital capacity (FVC) is less than 20 mL/kg. • Intubation is usually warranted when FVC drops to 15 mL/kg or negative inspiratory pressure drops to less than -25 cm H2 O.

43. Treatment Ideally all patients of AIDP should be hospitalised and benefited with ICU care, in the early stage for observation, and in the advanced stage for management of respiratory paralysis as well as for definitive therapy. Careful observation of cardiorespiratory function, prevention of complication due to prolonged immobilisation and analgesia are other aspects to be taken care of.

44. Specific Treatment • It includes , plasma exchange (PE), intravenous immunoglobulin (IVIg), combination therapy and liquorpheresis. Plasmapheresis • Plasmapheresis (PP) is a technique that permits selective removal of plasma from circulation and separation is achieved either by a centrifugal cell separator or filtration across a semipermeable membrane. • Plasmapheresis and plasma exchange (PE) are the two terms often used interchangeably but there is a difference: PP means separation of whole blood into plasma and cellular components and PE means the same process with the replacement by fluids.

45. Plasmapheresis • Several factors like antimyelin antibodies, cytokines, complement components and other inflammatory mediators, which are potentially pathogenic soluble factors, are removed by PE from the circulation. • Four or five exchanges of 200-250 ml of plasma per kg body weight done on alternate day produce a dramatic improvement in weakness and outcome. • Plasma exchange hastens recovery, decreases the chances of becoming ventilator-dependent and shortens the time spent on ventilator. • Maximum benefit of PE is obtained when initiated within 1 week of illness. • Liquorpheresis (CSF filtration) is a new technique developed to purify CSF from pathological factors (probably responsible for manifestation of GBS).

46. Intravenous Immunoglobulin (IVIg) • IVIg, originally developed as replacement therapy for hypogammaglobulinemia, contains normal polyvalent immunoglobulin G derived from a large number of blood donors. • Beneficial effects of IVIg were initially noted in patients of CIDP, and later in other neuroimmunological disorders including GBS. • The indications of IVIg therapy in GBS is acute GBS with inability to walk 10 metres independently presenting within two weeks of disease onset. • There is yet no consensus as to whether IVIg should be given to patients who do not fulfil these criteria. • IVIg is often the initial therapy chosen because of its ease of administration and good safety record. • The dose recommended is 0.4 gm/kg/day for 5 days or 0.5 gm /kg/day for 4 days (total of 2.0 gm/kg body weight) and the drug is administered intravenously.

47. Possible mechanism of action of (IvIg)

48. Possible mechanism of action of (IvIg) • Mnemonic is toaffect all components of immunity • ↓B cell activation/antibody production • Produce antiidiotypic antibodies • Blocks Fc receptor on macrophages/interfere with ADCC • ↓action of cytokines by producing anticytokines antibodies • Neutralisecomplement mediated effects • ↑ T Supressor cells

49. COMPLICATIONS OF PLASMA EXCHANGE

50. COMPLICATIONS OF PLASMA EXCHANGE