NEUROMUSCULAR DISORDERS IN ICU

DR.KALADHAR.S FELLOWCRITICAL CARECARE HOSPITAL

INTRODUCTION

• Motor weakness in a patient in the ICU may be related to

1. pre existing neuromuscular disorder

2. new onset or previously undiagnosed neuromuscular disorder

3. complications of non neuromuscular critical illness

• Whatever the cause, ICU admission related to such conditions generally results from respiratory muscle weakness and difficulty in swallowing with consequent aspiration.

• Early recognition and intervention is crucial; death can result from ventilatory failure and aspiration pneumonia and the autonomic instability which complicates some conditions.

• Neuromuscular disorders can also complicate critical illness, increasing the duration of mechanical ventilation and of ICU and hospital stay and causing post discharge morbidity and mortality.

GUILLAIN BARRE SYNDROME

• Guillain–Barré syndrome (GBS) was described by Guillain, Barré, and Strohl in 1916 as an acute flaccid paralysis with areflexia and elevated spinal fluid protein without pleocytosis.

• GBS has been viewed as an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) affecting nerve roots and cranial and peripheral nerves of unknown cause that occurs at all ages.

• Over the years, it has become clear that the condition may be fatal because of respiratory failure and autonomic nervous system abnormalities.

• It is, therefore, recognized as a potential medical and neurologic emergency that may require the use of intensive care units (ICUs) experienced in handling the complications of the illness.

CLINICAL FEATURES IN AIDP

• GBS often occurs 2 to 4 weeks after a flu like or diarrheal illness caused by a variety of infectious agents, including cytomegalovirus, Epstein–Barr and herpes simplex viruses, mycoplasma, chlamydia, and Campylobacter jejuni.

• The major feature is weakness that evolves rapidly (usually over days) and classically has been described as ascending from legs to arms and, in severe cases, to respiratory and bulbar muscles.

• Frequently accompanied by tingling dysesthesias in the extremities

• Facial diparesis is present in 50% of affected individuals

• Deep tendon reflexes attenuate or disappear within the first few days of onset.

• Cutaneous sensory deficits (e.g., loss of pain and temperature sensation) are usually relatively mild, but functions subserved by large sensory fibers, such as deep tendon reflexes and proprioception, are more severely affected.

• Bladder dysfuncyion may occur in severe cases but is usually transient.

• If bladder dysfunction is a prominent feature and comes early in the course, diagnostic possibilities other than GBS should be considered, particularly spinal cord disease.

• The lower cranial nerves are also frequently involved, causing bulbar weakness with difficulty handling secretions and maintaining an airway; the diagnosis in these patients may initially be mistaken for brainstem ischemia.

• Most patients require hospitalization, and in different series up to 30% require ventilatory assistance at some time during the illness.

• The need for mechanical ventilation is associated with more severe weakness on admission, a rapid tempo of progression, and the presence of facial and/or bulbar weakness during the first week of symptoms.

• Autonomic involvement is common and may occur even in patients whose GBS is otherwise mild.

• The usual manifestations are loss of vasomotor control with wide fluctuation in blood pressure, postural hypotension, and cardiac dysrhythmias.

• These features require close monitoring and management and can be fatal.

• Pain is another common feature of GBS.

VARIANTS OF GBS

• Several subtypes of GBS are recognized, as determined primarily by electrodiagnostic (Edx) and pathologic distinctions.

• AIDP is the most common variant.

• Additionally, there are two axonal variants, which are often clinically severe—the acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) subtypes.

• In addition, a range of limited or regional GBS syndromes are also encountered.

• Notable among these is the Miller Fisher syndrome (MFS), which presents as rapidly evolving ataxia and areflexia of limbs without weakness, and ophthalmoplegia, often with pupillary paralysis

• The MFS variant accounts for 5% of all cases and is strongly associated with antibodies to the ganglioside GQ1b.

• Other regional variants of GBS include 1. pure sensory forms2. ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-

sensory GBS3. GBS with severe bulbar and facial paralysis, sometimes associated

with antecedent cytomegalovirus (CMV) infection and anti-GM2 antibodies

4. acute pandysautonomia

SUBTYPE FEATURESELECTRODIAGNOSIS

PATHOLOGY

Acute inflammatory demyelinating polyneuropathy (AIDP)

Adults affected more than children; 90% of cases in western world; recovery rapid; anti-GM1 antibodies (<50%)

Demyelinating

First attack on Schwann cell surface; widespread myelin damage, macrophage activation, and lymphocytic infiltration; variable secondary axonal damage

Acute motor axonal neuropathy (AMAN)

Children and young adults; prevalent in China and Mexico; may be seasonal; recovery rapid; anti-GD1a antibodies

Axonal

First attack at motor nodes of Ranvier; macrophage activation, few lymphocytes, frequent periaxonal macrophages; extent of axonal damage highly variable

SUBTYPES FEATURESELECTRODIAGNOSIS

PATHOLOGY

Acute motor sensory axonal neuropathy (AMSAN)

Mostly adults; uncommon; recovery slow, often incomplete; closely related to AMAN

Axonal

Same as AMAN, but also affects sensory nerves and roots; axonal damage usually severe

M. Fisher syndrome (MFS)

Adults and children; uncommon; ophthalmoplegia, ataxia, and areflexia; anti-GQ1b antibodies (90%)

DemyelinatingFew cases examined; resembles AIDP

DIAGNOSIS

• The most characteristic laboratory features of GBS are an abnormal CSF profile showing albuminocytologic dissociation (elevated protein without pleocytosis) and abnormal nerve conduction studies.

• Although the CSF profile is usually normal during the first 48 hours after onset, by 1 week into the illness, the CSF protein is elevated in most patients, sometimes to levels as high as 1 g per dL.

• The cell count may be slightly increased but rarely exceeds 10 cells per μL; the cells are mononuclear in nature. When GBS occurs as a manifestation of HIV infection or Lyme disease, the CSF white cell count is generally increased (25 to 50 cells per μL).

• The CSF glucose is expected to be normal.

• Electrodiagnostic studies in AIDP typically disclose slowing (less than 80% of normal) of nerve conduction velocity, most often along proximal nerve segments, with increases in distal motor and sensory latencies.

• The amplitude of the evoked motor responses may be reduced because of axon loss or distal nerve conduction block, and the responses are frequently dispersed because of differential slowing along still conducting axons.

• Normal sural nerve and abnormal upper extremity sensory action potential, is characteristic of early GBS.

• Except for a mild increase in the erythrocyte sedimentation rate, hematologic studies are normal.

• Serum electrolytes may disclose hyponatremia, sometimes to a marked degree, because of inappropriate secretion of antidiuretic hormone caused by a disturbance of peripheral volume receptors.

• There may be evidence of previous viral or mycoplasma infection, such as lymphopenia or atypical lymphocytes. In some cases, evidence of recent viral infection may be sought by measuring antibody (Ig M) titers against specific infectious agents, especially cytomegalovirus, Epstein–Barr virus, and C. jejuni. In selected cases, screening for HIV infection should be undertaken.

Conditions That May Mimic Guillain–Barré Syndrome

Myasthenia gravis

Reflexes are sparedOcular weakness predominatesPositive response to edrophoniumEMG: decremental motor response

Botulism

Predominant bulbar involvementDescending pattern of paralysisAutonomic abnormalities (pupils)EMG: normal velocities, low amplitudes, incremental response (with high-frequency repetitive nerve stimulation)

Tick paralysisRapid progression (1–2 d)Tick present

Shellfish poisoningRapid onset (face, finger, toe numbness)Follows consumption of mussels/clams

Toxic neuropathies EMG: usually axon loss

Organophosphorus Acute cholinergic reaction toxicity

Porphyric NeuropathyMental disturbanceAbdominal pain

DiphthereticNeuropathy

Prior pharyngitisSlower evolutionPalatal/accommodation paralysisMyocarditis

PoliomyelitisWeakness, pain, and tendernessPreserved sensationCerebrospinal fluid: protein and cell count elevated

Periodic ParalysisReflexes normalCranial nerves and respiration sparedAbnormal serum potassium concentration

Critical IllnessNeuropathy

Sepsis and multiorgan failure > 2 wkEMG: axon loss

West Nile virus neuroinvasive disease

Associated fever, meningitis, or encephalitisAsymmetric weaknessCerebrospinal fluid: protein and cell count elevated

Acute myopathy of intensive care

Tetraparesis and areflexiaFollows prolonged treatment with neuromuscular-blocking agent and corticosteroidsTrauma, status asthmaticus, and organ transplantation associatedClinical and EMG features of myopathy

MANAGEMENT

• Monitor respiratory parameters: VC, arterial blood gas• Intubate if:• VC < 12–15 mL/kg• Oropharyngeal paresis with aspiration• Falling vital capacity over 4–6 h• Respiratory fatigue with VC 15 mL/kg• Use short-acting medications to control autonomic dysfunction• Nursing care: frequent turns to avoid pressure sores• Place pads at elbows and fibular head to avoid compression

neuropathies• Physical therapy• Subcutaneous heparin

PLASMAPHERESIS

• Exchange a total of 200 mL plasma/kg body weight over 7–14 d (40–50 mL/kg for 3–5 sessions)a

• Albumin is used as replacement solution, not fresh-frozen plasma

• During plasmapheresis, monitor BP and pulse every 30 min

• Obtain complete blood cell count (baseline and before each exchange to calculate plasma volume)

• Obtain immunoglobulin levels before first exchange and after last exchange; if immunoglobulin G < 200 mg/dL after last plasma exchange, infuse 400 mg/kg IVIG

IV IG

• IV IG - 2 g/kg divided over 5 consecutive days (0.4 g/kg/d for 5 days).

• Need for a ventilator cannot be reliably predicted on the basis of extent of weakness; however, patients who are highly likely to require mechanical ventilation are those with rapid disease progression, bulbar weakness, autonomic dysfunction, and bilateral facial weakness.

• Patients must be followed carefully with measurements of maximum inspiratory pressure and forced vital capacity until weakness has stopped progressing so the respiratory insufficiency can be anticipated and managed appropriately.

• Ropper and Kehne suggest intubation if any one of the following criteria is met: mechanical ventilatory failure with reduced expiratory VC of 12 to 15 mL per kg, oropharyngeal paresis with aspiration, falling VC over 4 to 6 hours, or clinical signs of respiratory fatigue at a VC of 15 mL per kg.

• Lawn et al. found the following respiratory factors to be highly associated with progression to respiratory failure: VC less than 20 mL per kg, maximal inspiratory pressure (MIP) less than 30 cm H2O, maximal expiratory pressure (MEP) less than 40 cm H2O, or a reduction of more than 30% of VC, MIP, or MEP in 24 hours.

• Elective intubation may be considered in these patients at particularly high risk for progression to respiratory failure.

• Plasmapheresis, in general, is recommended for patients who are unable to walk unaided, who require intubation or demonstrate a falling VC, and who have weakness of the bulbar musculature leading to dysphagia and aspiration.

• Treatment of patients with mild GBS (i.e., those who are still ambulatory) is beneficial; two plasma exchanges were more beneficial than none in time to onset of motor recovery in patients with mild GBS.

• Patients with moderate (not ambulatory) or severe (mechanically ventilated) GBS benefited from four exchanges; those with severe GBS did not benefit any further with the addition of two more exchanges.

• Because of its potential for inducing hypotension, patients who have compromise of their cardiovascular system or autonomic dysfunction may not tolerate this procedure.

• Plasmapheresis is safe in pregnant women and children.

• Plasmapheresis is generally not used in patients who are no longer progressing 21 days or more after the onset of GBS.

• IVIG is as effective as plasmapheresis.

• It is preferred because of its ease of administration.

• In 3% to 12% of patients given IVIG, side effects may occur that range from minor reactions such as flulike symptoms, headache, nausea, and malaise to more severe side effects, including anaphylactic reactions in IgA-deficient persons, transmission of hepatitis C, aseptic meningitis, and acute renal failure in those with renal insufficiency.

• Absolute contraindications to IVIG are unusual. For example, patients with IgA deficiency may be given an IgA-poor preparation with precautions, whereas those with renal insufficiency may be given an IVIG sucrose-poor preparation with close monitoring of their renal status.

• Treatment is beneficial if given within 4 wks of onset of neuropathic symptoms for plasmapheresis and within 2 wks of onset for IVIG.

• Treatment with plasmapheresis followed by IVIG is not recommended.

• Although retreatment with the same therapy is commonly practiced, generally with half the initial dose used, evidence-based literature is lacking regarding the efficacy of repeat treatment.

• Oral corticosteroids delayed recovery while IV methylprednisolone alone was not beneficial or harmful.

• Although the combination of IVIG and IV methylprednisolone (500 mg per day for 5 days) showed no significant difference over IVIG alone unless adjusted for various factors, there is a trend toward shortened time to independent ambulation with combination treatment.

• Corticosteroids are not recommended in the treatment of GBS.

MYASTHENIA GRAVIS

INTRODUCTION

• Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles.

• The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack.

• Myasthenia gravis is not rare; its prevalence in Western populations is approximately 1 in 20,000.

• Female to Male ratio is approximately 3:2, although there are two distinct incidence peaks, with the incidence among women peaking in the third decade and that among men in the fifth to sixth decades.

• A mild familial predisposition has been noted

CLASSIFICATION

• Subtypes of MG are classified as1) early onset MG;<50yrs. thymic hyperplasia and females2) late onset MG; >50yrs. thymic atrophy and mainly males3) thymoma associated MG4) MG with anti MuSK Abs5) ocular MG; symptoms only affecting EOM6) MG with no detectable AChR and MuSK Abs

CLLINICAL CLASSIFICATION

• The Myasthenia Gravis Foundation of America clinical classification divides MG into 5 main classes and several subclasses.

• It is designed to identify subgroups of pts of MG who share distinct clinical features or severity of disease that may indicate different prognoses or response to therapy.

• It should not be used to measure outcome.

Class 11. any ocular muscle weakness2. may have weakness of eye closure3. all other muscle strengths are normal

Class 21. mild weakness affecting muscles other than ocular muscles2. may also have ocular muscle weakness of any severity

Class 2a MG1. predominantly affecting limb, axial muscles or both2. may also have lesser involvement of oropharyngeal muscles

Class 2b MG predominantly affecting oropharyngeal, respiratory muscles or both may also have lesser or equal involvement of limb, axial muscles or

both

Class 31. moderate weakness affecting muscles other than oular muscles2. may also have ocular muscle weaness of any severity

Class 3a MG predominantly affecting limb, axial muscles or both may also have lesser involvement of oropharyngeal muscles

Class 3b MG predominantly affecting oropharyngeal, respiratory muscles or both may also have lesser or equal involvement of limb, axial muscles or

both

Class 41. severe weakness affecting muscles other than ocular muscles2. may also have ocular muscle weaness of any severity

Class 4a MG predominantly affecting limb, axial muscles or both may also have lesser involvement of oropharyngeal muscles

Class 4b MG predominantly affecting oropharyngeal, respiratory muscles or both may also have lesser or equal involvement of limb, axial muscles or

both

• Class 51. intubation with or without mechanical ventilation, except when

employed during postoperative management2. the use feeding tube without intubation places the pt in class 5b

Ab binding to the AChR activates the complement cascade, resulting in the formation of membraneattack complex (MAC) and localized destruction of the postsynaptic NMJ membrane. This ultimately leads to a simplified, altered morphology of thepostsynaptic membrane of the NMJ of MG patients, which lacks the normal deep folds and has a relatively flat surface.

• Abs crosslink AChR molecules on the NMJ postsynaptic membrane, causing endocytosis of the cross linked AChR molecules and their degradation.

• This ultimately leads to reduced number of AChR molecules on the postsynaptic membrane.

• Ab binding the ACh binding sites of the AChR causes functional block of the AChR by interfering with binding of ACh released at the NMJ. this results in failure of neuromuscular transmission.

CLINICAL FEATURES

• The cardinal features are weakness and fatigability of muscles.

• The weakness increases during repeated use (fatigue) or late in the day, and may improve following rest or sleep.

• The distribution of muscle weakness often has a characteristic pattern.

• The cranial muscles, particularly the lids and extraocular muscles, are typically involved early in the course of MG; diplopia and ptosis are common initial complaints.

• Facial weakness produces a "snarling" expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat.

• Speech may have a nasal timbre caused by weakness of the palate, or a dysarthric "mushy" quality due to tongue weakness.

• Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food.

• Bulbar weakness is especially prominent in MuSK antibody–positive MG.

• In 85% of patients, the weakness becomes generalized, affecting the limb muscles as well. If weakness remains restricted to the extraocular muscles for 3 years, it is likely that it will not become generalized, and these patients are said to have ocular MG.

• The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved.

• If weakness of respiration becomes so severe as to require respiratory assistance, the patient is said to be in crisis.

• Crisis refers to threatened or actual respiratory compromise in a myasthenic patient.

• It may reflect respiratory muscle insufficiency or inability to handle secretions and oral intake, but it is typically a combination of both.

• With currently available treatments, myasthenic crisis is not common.

• An occasional patient presents with fulminating disease; crisis management then coincides with initial evaluation and institution of therapy. Otherwise, crisis may be precipitated by other illnesses, such as influenza or other infections, or by surgery.

• Intercurrent infection is often associated with increased weakness in the myasthenic pt.

• Any infections should be treated aggressively.

• Both hypothyroid and hyperthyroid states are often associated with increased weakness. Again, there is an increased association between thyrotoxicosis and myasthenia gravis.

• The manifestations of electrolyte imbalance may be enhanced in myasthenics.

• Special consideration must be given to respiratory care of the myasthenic.

• Incentive spirometry should be avoided, because muscular fatigue outweighs any potential benefit, even in the postoperative patient.

• Careful attention to respiratory toilet is key and can be complicated by cholinesterase inhibitors, which increase respiratory secretions. Atropine may be used to minimize this effect.

• The diagnosis of myasthenia gravis is clinically suggested in patients who present with chronic ocular, bulbar, or appendicular weakness, variable over time, with preservation of normal sensation and reflexes.

• Myasthenia gravis should always be considered in the differential diagnosis of isolated ocular or bulbar weakness.

• Again, prominent muscular fatigability and temporal fluctuation are key features of the disease.

• Normal pupils, normal sensation, and normal reflexes are to be expected and are helpful in diagnosing MG when coincident with an acute or subacute paralytic illness.

EDROPHONIUM TEST

• Edrophonium hydrochloride (Enlon; formerly “Tensilon”) is a fast, short-acting parenteral cholinesterase inhibitor.

• Myasthenic weakness typically improves transiently after administration of 4 to 10 mg (0.4 to 1.0 mL).

• The edrophonium test may be blinded, with drug or normal saline being injected. Whether drug or placebo, a 0.2-mL test dose is given to screen for excessive cholinergic side effects, such as cardiac arrhythmia, gastrointestinal hyperactivity, or diaphoresis.

• The remaining 0.8 mL is given after 1 minute.• Interpretation of the test depends on identifying and observing an

unequivocal baseline muscular deficit that can be improved following the injection of edrophonium.

• Ptosis and ophthalmoparesis, if present, are semiquantifiable and well suited; if respiratory compromise is present, monitoring maximum inspiratory pressure (MIP) or vital capacity is useful.

• If there is any doubt about the positivity of the test, it should be considered negative.

• False-positive edrophonium tests are quite rare; false negatives are common.

• In children, the appropriate test dose is 0.03 mg per kg, one-fifth of which may be given as a test dose.

• Neostigmine is a longer-acting parenteral cholinesterase inhibitor that sometimes affects a more obvious clinical response. It is also typically associated with more obvious autonomic side effects.

• The 1.5-mg test dose (0.04 mg per kg in children) should therefore be preceded by 0.5 mg of atropine; both may be given subcutaneously.

SEROLOGICAL TESTING

• Approximately 85% of myasthenics have detectable serum antibodies, which bind to acetylcholine receptors.

• A normal test does not exclude the diagnosis, especially in the patient presenting with predominantly ocular symptoms and signs.

• Among seronegative myasthenic patients, from 30% to 70% may be found to have antibodies directed against muscle-specific tyrosine kinase [MuSK], an enzyme that catalyzes acetylcholine receptor aggregation in the formation of neuromuscular junctions.

• Patients who have antibodies to MuSK are often young women (onset of symptoms before 40 years of age) with prominent bulbar involvement and neck or respiratory muscle weakness.

• They tend to have more severe disease requiring aggressive immunosuppressive treatment and have a higher frequency of respiratory crisis compared to seronegative or AChR-positive myasthenics.

• Unlike patients with antibodies to AChR, there appears to be a correlation between MuSK antibody levels and disease severity, with antibody levels often decreasing after various immunosuppressive treatments except thymectomy.

• Striated muscle antibodies that react with muscle proteins titin and ryanodine receptor have also been found, mainly in patients with thymoma and in those with late onset myasthenia (onset of symptoms > 50 years of age).

• Thus, they may be helpful in the detection or recurrence of thymoma. In addition, they tend to be associated with more severe disease, and therefore may aid in prognosis.

• Myasthenics also have an increased incidence of other autoantibodies, including antithyroid antibodies, antiparietal cell antibodies, and antinuclear antibodies, although routine screening for these is not part of the diagnostic evaluation for suspected myasthenia gravis.

ELECTROMYOGRAPHIC STUDIES

• The electromyographic hallmark of myasthenia gravis is a decrement in the amplitude of the muscle potential seen after exercise or slow repetitive nerve stimulation. The decrement should be at least 10% and preferably 15% or more.

• Routine motor and sensory conduction studies are normal.

• The more severely affected patient is more likely to show a decremental response; responses are most consistently elicited from facial and proximal muscles.

• If a significant decrement is observed, exercising the muscle briefly for 10 seconds transiently reverses the decrement.

• Single-fiber electromyography is relatively sensitive, documenting increased jitter variability in the temporal coupling of single fibers within the same motor unit. Increased jitter, however, is far from specific; most peripheral neurogenic diseases also lead to increased jitter.

• Muscle biopsy has no role in the evaluation of myasthenia, unless there is a strong consideration of neurogenic or inflammatory weakness.

GENERAL MEASURES• When the weakening myasthenic reaches a point at which increased

respiratory effort is required, fatigue often prevents the effective use of secondary muscles, and respiratory failure rapidly ensues.

• FVC and MIP are better indices and should be serially charted.

• The FVC should be assessed with the patient both sitting and supine, because diaphragmatic paresis may be accentuated in the supine position.

• An FVC less than 20 mL per kg or an MIP greater than (i.e., not as negative as) -40 cm H2O suggests impending failure and usually warrants intubation.

• If a downward trend is noted (greater than 30% decrease), elective intubation should be considered even sooner, unless there is a realistic expectation of rapid reversal.

• The possibility of cholinergic crisis in patients receiving anticholinesterase drugs (e.g., pyridostigmine), although no longer common, should not be overlooked. The presence of fasciculations, diaphoresis, or diarrhea should alert the clinician to this possibility.

• There are four basic therapies used to treat MG:(i) symptomatic treatment with acetylcholinesterase inhibitors,(ii) rapid short-term immunomodulating treatment with plasmapheresis

and intravenous immunoglobulin,(iii) chronic long-term immunomodulating treatment with glucocorticoids

and other immunosuppressive drugs,(iv) surgical treatment.

ACETYLCHOLINESTERASE INHIBITORS

• Acetylcholinesterase inhibitors are used as a symptomatic therapy and act by increasing the amount of available acetylcholine at the NMJ.

• They do not alter disease progression or outcome.

• Pyridostigmine is the most commonly used drug.

• It has a rapid onset of action within 15 to 30minutes reaching peak activity in about two hours.

• The effect lasts for about three to four hours.

• The initial oral dose is 15–30 mg every 4–6 hours and is titrated upwards depending on the patient’s response.

• Adverse side effects of Pyridostigmine are mostly due to the cholinergic properties of the drug such as abdominal cramping, diarrhea, increased salivation and bronchial secretions, nausea, sweating, and bradycardia.

• Nicotinic side effects are also frequent and include muscle fasciculation and cramping. High doses of pyridostigmine exceeding 450 mg daily, administered to patients with renal failure, have been reported to cause worsening of muscle weakness.

• Response to treatment varies from marked improvement in some patients to little or no improvement in others.

SHORT TERM IMMUNOMODULATING THERAPIES• Plasma exchange and intravenous immunoglobulin have rapid

onset of action with improvement within days, but this is a transient effect.

• They are used in certain situations such as myasthenic crisis and preoperatively before thymectomy or other surgical procedures.

• They can be used intermittently to maintain remission in patients with MG who are not well controlled despite the use of chronic immunomodulating drugs.

PLASMAPHERESIS

• It improves strength in most patients with MG by directly removing AChRAbs from the circulation.

• Typically one exchange is done every other day for a total of four to six times.

• Adverse effects of plasmapheresis include hypotension, paresthesias, infections, thrombotic complications related to venous access, and bleeding tendencies due to decreased coagulation factors

IV IG

• It involves isolating immunoglobulins isolated from pooled human plasma by ethanol cryoprecipitation and is administered for 5 days at a dose of 0.4 g/kg/day, fewer infusions at higher doses are also used.The mechanism of action of IVIg is complex.

• Factors include inhibition of cytokines competition with autoantibodies, and inhibition of complement deposition.

• Interference with the binding of Fc receptor on macrophages, Ig receptor on B cells, and interference with antigen recognition by sensitized T cells are other mechanisms.

• IVIg is considered to be safe but rare cases of complications do occur such as thrombosis due to increased blood viscosity and other complications related to large volumes of the infused preparation.

• More specific techniques to remove pathogenic anti-AChR antibodies utilizing immunoadsorption have been developed recently, which offer a more targeted approach to MG treatment.

• Clinical trials showed significant reduction of blocking antibodies with concomitant clinical improvement in patients treated with immunoadsorption techniques.

• Compared to plasma exchange, IVIg is similar in terms of efficacy mortality, and complications.

• However, plasma exchange has considerable cost advantages over IVIg with a cost benefit ratio of 2 : 1 for treatment of myasthenia gravis.

CORTICOSTEROIDS

• Corticosteroids were the first and most commonly used immunosuppressant medications in MG.

• Prednisone is generally used when symptoms of MG.

• Temporary exacerbation can occur after starting high doses of prednisone within the first 7–10 days which can last for several days.

• In cases known to have severe exacerbations, plasma exchange or IVIg can be given before prednisone therapy to prevent or reduce the severity of corticosteroid-induced weakness and to induce a more rapid response.

• Oral prednisone might be more effective than anticholinesterase drugs in oMG and should therefore be considered in all patients with oMG.

NONSTEROIDAL IMMUNOSUPPRESSIVE AGENTS• Azathioprine, a purine analog, reduces nucleic acid synthesis,

thereby interfering with T-and B-cell proliferation.

• It usually takes up to 15 months to detect clinical response.

• When used in combination with prednisone, it might be more effective and better tolerated than prednisone alone.

• Adverse side effects include hepatotoxicity and leukopenia.

• Mycophenolate mofetil selectively blocks purine synthesis, thereby suppressing both T-cell and B-cell proliferation.

• The standard dose used in MG is 1000 mg twice daily, but doses up to 3000 mg daily can be used.

• Higher doses are associated with myelosuppression, and complete blood counts should be monitored at least once monthly.

• The drug is contraindicated in pregnancy and should be used with caution in renal diseases, GI diseases, bone marrow suppression, and elderly patients.

• Cyclophosphamide administered intravenously and orally is an effective treatment forMG.

• More than half of the patients become asymptomatic within 1 year of treatment.

• Undesirable side effects include hair loss, nausea, vomiting, anorexia, and skin discoloration, which limit its use to the management of patients who do not respond to other immunosuppressive treatments.

• Cyclosporine blocks the synthesis of IL-2 cytokine receptors and other proteins critical to the function of CD4+ T cells.

• Cyclosporin is used mainly in patients who do not tolerate or respond to azathioprine.

• Large retrospective studies have supported its use as a steroid-sparing agent.

• Tacrolimus has been used successfully to treat MG at low doses.

• It has the theoretical advantage of less nephrotoxicity than cyclosporine.

• However, there are more controlled trial data supporting the use of cyclosporine.Tacrolimus also has the potential for severe side effects.

• MG patients resistant to therapy have been successfully treated with cyclophosphamide in combination with bone marrow transplant or with rituximab, a monoclonal antibody against the B cell surface marker CD20.

• Etanercept, a soluble and a recombinant TNF receptor blocker, has also been shown to have steroid-sparing effects in studies on small groups of patients.

THYMECTOMY

• Surgical treatment is strongly recommended for patients with thymoma.

• Thymectomy is advised as soon as the patient’s degree of weakness is sufficiently controlled to permit surgery.

• Patients undergoing surgery are usually pretreated with low-dose glucocorticoids and IVIg.

• Thymectomy may not be a viable therapeutic approach for anti-MuSK antibody-positive patients because their thymi lack the germinal centers and infiltrates of lymphocytes that characterize thymi in patients who have anti-AChR antibodies.

• This supports a different pathologic mechanism in anti-MuSK Ab-positive and anti-AChR Abpositive MG.

• Most experts consider thymectomy to be a therapeutic option in anti-AChR Ab-positive gMG with disease onset before the age of 50 years.

REHABILITATION

• A rehabilitation program in combination with other forms of medical treatment can help relieve symptoms and improve function in MG.

• Physical therapy is beneficial for long-term restoration of muscle strength.

• Graded strengthening exercises help the individual remain as functional as possible.

• Occupational therapy helps the individual adapt to new ways of performing daily living tasks using energy conservation and compensatory techniques.

NEUROMUSCULAR WEAKNESS ACQUIRED IN THE ICU

• It is a major cause of morbidity for survivors of critical illness.

• Although reversible, ICU-acquired muscle weakness often markedly prolongs the total duration of hospitalization and subsequent care.

• Three basic causes of acquired neuromuscular weakness in the ICU have been identified:

(1) a sensorimotor polyneuropathy,( 2) an acute myopathy, and(3) persistent blockade of the neuromuscular junction

• Residual blockade of the neuromuscular junction after discontinuation of a neuromuscular blocking agent (NMBA) is rarely responsible for persistent neuromuscular weakness in the ICU.

• Recovery from paralysis almost always occurs within hours of discontinuing the commonly used NMBAs, with the exception of vecuronium administration in renal failure.

• Therefore, ICU–acquired muscle weakness is nearly always caused by a sensorimotor polyneuropathy or by acute myopathy.

• CIM is probably the major contributor to severe ICU-acquired weakness, while CIPN affects 70% to 80% of patients with severe sepsis and multiorgan failure.

CIM - RISK FACTORS

• IV corticosteroids and neuromuscular blocking agents are considered major risk factors.

• Occasionally, the myopathy develops in patients who have received high-dose corticosteroids alone, without neuromuscular blocking agents, or in patients who have received neither corticosteroids nor neuromuscular blocking agents, but the latter group typically has severe systemic illness with multiorgan failure and sepsis.

DIAGNOSIS

• The hallmark of critical illness myopathy is weakness that is typically diffuse in distribution, affecting both limb and neck muscles.

• As is typical of most myopathic disorders, weakness tends to have a proximal predominance in the limbs, but it may also involve distal muscles profoundly.

• Tendon reflexes tend to be depressed but present, and on occasion, may be absent, possibly due to a generalized reduction in membrane excitability that occurs in sepsis.

• There may be facial muscle involvement, and rarely, extraocular muscles are affected; other muscles supplied by cranial nerves are usually spared.

• An elevated CK level helps to support the diagnosis of a myopathic cause of weakness in an ICU patient, but in the myopathy of intensive care, the CK rise, which is found in about 50% of affected patients, only occurs early in the course of the illness, peaks within a few days of onset, and then declines back into the normal range.

• With nerve conduction studies, motor responses are typically low-amplitude or absent, while sensory responses are relatively preserved, with amplitudes that are > 80% of normal in two or more nerves (sensory responses may be reduced, however, when ICU polyneuropathy coexists;).

• An interesting observation made of patients with CIM, and demonstrated by direct muscle stimulation, is that the condition leads to electrical inexcitability of the muscle membrane so that the ratio of nerve-evoked muscle action potential to direct stimulation of muscle is close to 1.

• In contrast, when weakness stems from severe neuropathy, the ratio of nerve-evoked response to muscle-stimulation–evoked response is less than 1 (and close to 0).

• Needle electrode examination shows fibrillation potential activity in resting muscle in some patients.

• Biopsy shows muscle fiber atrophy, especially involving the type II fibers; a variable degree of muscle fiber necrosis, the absence of any inflammatory cells; and the hallmark of the disorder: features of a disrupted intramyofibrillar network that manifests as patchy or complete reduction in myosin–adenosine triphosphatase reactivity in nonnecrotic fibers due to a loss of myosin that may be confirmed immunocytochemically or by electron microscopy.

• With a fairly stereotypic clinical presentation, and EMG results typical of a myopathy—often with fibrillation potential activity—the muscle biopsy is usually not necessary to establish the diagnosis of ICU myopathy.

PATHOPHYSIOLOGY

• Myosin loss and muscle fiber necrosis probably contribute to persisting weakness. Myosin loss is characteristic of critical illness myopathy, and is essentially pathognomonic of the disorder.

• Corticosteroids may cause the loss of myosin, but other factors trigger the process, such as an abnormal neuromuscular junction caused by pharmacologic blockade in ICU patients.

• Some patients who are not exposed to administered corticosteroids or neuromuscular blocking agents, but who are systemically ill, often with metabolic acidosis, can also develop the myopathy of intensive care.

• Acidosis may stimulate glucocorticoid production, lead to an increase in muscle protein degradation, and trigger thick filament loss.

• Paralysis appears to be due to abnormal inactivation of sodium channels, which suggests that the myopathy of intensive care may be, in part, an acquired disease of ion channel gating.

TREATMENT

• Essentially symptomatic

• Treat the underlying systemic illness

• Discontinue or minimise the use of corticosteroids and NMBA.

• There is emerging evidence that intensive insulin therapy might have a role in reducing the incidence of both critical illness myopathy and critical illness polyneuropathy.

CIPN - DIAGNOSIS

• Patients with critical illness polyneuropathy develop a sensorimotor axon-loss polyneuropathy.

• Although distal muscles may be affected to a greater extent than proximal muscles, more commonly there is generalized flaccid weakness with depressed or absent reflexes.

• There is usually distal sensory loss, but pain and paresthesias are not typical features.

• The cranial nerves are generally spared.

• Many patients with critical illness polyneuropathy have a concomitant encephalopathy stemming from their underlying multiorgan system failure or sepsis, or both.

• The most important diagnostic test is the EMG.

• Nerve conduction velocities are normal or only mildly reduced, but the amplitudes of sensory and motor responses are reduced, or even absent.

• This pattern is typical for axon-loss polyneuropathies rather than demyelinating neuropathies and is helpful in distinguishing CIPN from the Guillain–Barré syndrome.

• On needle electrode examination, there are typically features of acute denervation—fibrillation potentials and positive sharp wave activity—and reduced recruitment of motor unit potentials; as in many axon-loss polyneuropathies, there may be more pronounced changes seen in distal compared to more proximal muscles.

PATHOPHYSIOLOGY

• The polyneuropathy appears to be a complication of the systemic inflammatory response syndrome (SIRS) triggered by sepsis, severe trauma, or burns.

• It may be induced by impaired microcirculation leading to reduced nerve perfusion and endoneurial edema which leads in turn to nerve hypoxia; the neuropathy may also result to a degree from the deleterious effects of cytokines produced by activated leukocytes.

• There is also evidence that the acute polyneuropathy in critically ill patients stems in part from an abnormality in nerve excitability, caused by increased sodium channel inactivation (similar to what is found in the myopathy of intensive care), without actual nerve damage.

TREATMENT

• Essentially symptomatic and supportive.

• Stabilising the underlying illness.

• IIT may have a role.

• Recovery of sensory and motor function occurs over weeks to months, depending on the severity of the neuropathy.

• In some of the instances of very slow recovery over months, long-term ventilatory support may be required, even after the underlying critical illness has resolved.

DISTINGUISHING CIM FROM CIPN

• Favoring the diagnosis of myopathy would be severe generalized weakness, with failure to wean from mechanical ventilation (the latter more likely to be associated with ICU myopathy rather than neuropathy, preservation of reflexes and sensation, a transient rise in CK, and an EMG picture of relatively preserved sensory responses with low or absent motor responses and early recruitment of small, polyphasic motor unit potentials, often with fibrillation potential activity.

• Favoring a polyneuropathy would be the clinical findings of demonstrable sensory loss and areflexia, and the EMG findings of absent or low motor amplitudes in the company of absent or low sensory responses, along with fibrillation potentials and reduced recruitment of motor unit potentials. Clinically, a polyneuropathy might easily be missed because, in many patients, careful sensory examination is impossible in the ICU setting, especially if there is a coexisting encephalopathy.

• It may be difficult to distinguish one disorder from another in an individual case.

• ICU-related myopathy and polyneuropathy arise in a common setting, share the clinical features of severe generalized weakness with areflexia, may have a similar underlying acquired sodium channelopathy, and cannot always be reliably differentiated by EMG testing.

• It is likely that in many patients both disorders are present in varying degrees and in fact have a combined syndrome of critical illness myopathy and polyneuropathy and may be considered to have critical illness polyneuromyopathy.

SIGNS AND SYMPTOMS OF RESPIRATORY FAILUREGeneralised warning signs Increasing generalised weakness Dysphagia Dysphonia Dyspnea on exertion and at rest

Subjective Assessment Rapid shallow breathing Weak cough Tachycardia Staccato speech Accessory muscle use

Abdominal paradox Orthopnea Weakness of trapezius and neck muscles Single breath count Cough after swallowing

Objective Assessment VC <15ml/kg or <1L or 50% drop in VC MIP > -30 cm H2O MEP < 40 cm H2O Nocturnal desaturation

• A successful approach to these disorders requires the physician to recognize the nature of the clinical situation prompting neurologic consultation or admission to the ICU.

• An analysis of types of neurologic clinical situations being encountered often guides the physician initially in diagnosis and management.

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