Thrombolytic therapy Large hemispheric infarction Cerebellar infarction Basilar artery brai nstem stroke Fluctuating neurological de \201 cits Reduced conscious state Control of seiz ures Management of raised ICP Maintenance of CPP 371 CHAPTER 22.6 Ischaemic stroke of ICH outweighs the potential bene \201 ts of clot lysis). In the near future, however, n ew MRI techniques will be able to identify patients who might bene \201 t from treatment b eyond 3h. The patient must have a moderate to severe neurologi- cal de \201 cit without si gni \201 cant improvement. Absolute con- traindications include any blood on pre-treatment CT, established infarction on CT, severe hypertension, surgery or trauma within 14 days an d known coagulopathy. The NICE recommendations for administration are tPA infu- sion in a 0 .9mg/kg (max 90mg) continuous IV infusion over 60min, with 10% of total dose as a bolus at the start of the infusion (over 2 \200\2233min). These patients need careful moni- toring f or any neurological or cardiovascular decline, and should be managed in specialist units. F ollow-up CT scan should be performed after 24h, and aspirin should be com- menced if hemorr hage excluded. Other interventions The use of hyperventilation, steroids and mannitol to treat raised ICP and cerebral oedema in ischaemic stroke is widespread, although clinical trials do not demo nstrate improved survival or improved functional outcome Several potential neuroprotective agents have been studied, includ- ing calcium channel blockers, antioxidants and NMDA antag onists. Although trials have been completed, they are still of unproven clinical value. Res earch is currently ongo- ing into the potential bene \201 ts of therapeutic hypothermia. Other important stroke syndromes Cerebral venous sinus thrombosis Cerebral venous sinus thr ombosis should be considered as a cause of stroke in young women on the oral contracep- tiv e pill, during pregnancy and puerperium, in association with intracranial, ear or sinus inf ections, in patients with cancer and hematological disorders, and in patients with other ty pes of hypercoaguable states, such as in \202 ammatory bowel disease, phospholipid antibod y syndrome or severe dehydration. Headache and seizures are common, and should alert to the possible diagnosis. Papilloedema with focal neurology is not uncommon. MRI with MR venogra - phy or CT with CT venography are the investigations of choice to con \201 rm the diagnos is. Formal angiography may also be required, particularly in a patient with smaller vein oc clusions. Many centers recommend anticoagulation with heparin and then warfarin, although s upportive evidence from randomized trials is lacking. Causes of late deteriora- tion includ e extension of the thrombosis, raised ICP, seizures, systemic complications (pneumonia, PEs , sepsis) and complications of the associated hypercoaguable state. Intra-arterial tPA There are theoretical advantages to using intra-arterial tPA compared wi th systemic administration. Local tPA may be safer and more effective, as a higher concentr ation of tPA is attained directly at the thrombus site with potentially minor systemic side effects. However, intra-arterial throm- bolysis is limited to specialized centers. There a re only a few small randomized trials addressing this technique, but there is evidence for ef \201 cacy in acute basilar occlusion. Acute basilar occlusion accounts for up to 10% of large- vessel stroke, with the fatality rate being the highest for all ischaemic stroke su btypes, up to 90%, with rapid progres- sion to coma and death in many patients. Although no large randomized studies have been performed, there is evi- dence from small series that p atients who undergo suc- cessful recanalization of the basilar artery by intra-arterial thr ombolysis have lower mortality of 39%. There have also been some case reports of recanaliza tion by intra-arterial thrombolysis up to 18h after the onset of the basilar occlu- sion wi th improved outcome. Support groups The Stroke Association: www.stroke.org.uk American Stroke Association: www.s trokeassociation. org Decompressive surgery There are certain circumstances where neurosurgical intervention may be considered. Decompressive surgery involves the removal of a large part of the skull to a llow space for the expansion of swollen brain tissue, which thereby reduces ICP, prevents f atal brain herniation, increases perfusion pressure to the brain that is still salvageable, and preserves CBF. Patients with large supratentorial infarcts may deteriorate due to mass ive cerebral oedema, usually developing between 2 and 5 days. Recent pooled data from three ran- domized trials has demonstrated that in patients with malignant MCA infarction, decom pressive surgery under- taken within 48h of stroke onset reduces mortality and increases th e number of patients with a favorable func- tional outcome, particularly if the non-dominan t hemi- sphere is involved. The decision to perform decompressive surgery should, however, be made on an individual basis in every patient Large cerebellar infarctions may be associa ted with oedema, which can cause compression of the 4th ventricle, obstructive hydrocephalu s, herniation and death. Therefore, cerebellar infarction associated with a declining level of consciousness constitutes a potential neurosurgical emergency. Surgical decompression o f the posterior fossa or shunting may be required. As the level of consciousness is the mos t powerful predictor for outcome, patients with large cerebellar infarction should be obser ved on a stroke unit or ICU. Further reading Chen, ZM, Sandercock P, Pan HC, et al. on behalf of the CAST and IST Collab orative Groups. Indications for early aspirin use in acute ischaemic stroke: a combined ana lysis of 40,000 randomized patients from the Chinese Acute Stroke Trial and the Internation al Stroke Trial. Stroke 2000; 31: 1240 \200\2239. Gubitz G, Counsell C, Sandercock P, et al. Antiplatelet agents for acute ischaemic stroke. In: The Cochrane Library. Oxford: Update Software, 2000a. Gubitz G, Counsell C, Sandercock P, et al. Anticoagulants for acute ischaemic stroke. In: T he Cochrane Library. Oxford: Update Software, 2000b. Kollmar R, Schwab S. Ischaemic stroke: acute management, inten- sive care, and future persp ectives. Br J Anaesth 2007; 99: 95 \200\223101 National Institute for Health and Clinical E xcellence. Final appraisal determination: alteplase for the treatment of acute ischaemic st roke. Issue date April 2007, www.nice.org.uk Singh V. Critical care assessment and management of acute ischae- mic stroke. J Vascul Intervent Radiol 2004; 15: S21 \200\2237. Smith WS. Intra-arterial thrombolytic therapy for acute basilar occlusion. Stroke 2007; 28: 701 \200\2233. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarcti on of the middle cerebral artery: a pooled analysis of three randomized controlled trials. Lancet Neurol 2007; 6: 215 \200\22322. Wardlaw JM, del Zoppo G, Yamaguchi T, et al. Thrombolysis for acute ischaemic stroke. Cochr ane Database Syst Rev 2003; (3): CD000213. Warlow CP, Dennis MS, van Gijn J, et al. Stroke: a practical guide to management, 2nd edn, Oxford: Blackwell Science, 2001. 372 M SMITH & C PRITCHARD Guillain \200\223Barre syndrome Clinical features GBS is preceded by a \200\230 \202 u-like illness or gastroenteritis in 66% of cases. A symmetrical weakness evolves over a few days, usually after the antecedent symptoms have settled. Sensory symptoms and pain may pre-date the onset of weakness. The w eakness reaches a peak within 2 \200\2234 weeks and, following a plateau phase lasting 3 \200\2234 weeks, resolves over a variable period. Guillan \200\223Barre syndrome (GBS) is an acute peripheral neu- ropathy with at least four subtypes. Acute in \202 ammatory demyelinating polyneuropathy (AIDP) is the most common s ubtype, characterized by ascending and symmetrical weakness, areflexia and sensor y and aut onomic disturbances. Acute motor axonal neuropathy (AMAN) describes a purely motor de \201 cit, and when sensory \201 bres are also involved the subtype is designated acute motor sensory axonal neuropathy (AMSAN). The Miller \200\223Fisher variant of GBS is characterize d by ataxia, opthalmoplegia and are \202 exia with little limb weakness. Symptoms and signs GBS is characterized by a progressive, ascending symmetri- cal limb weak ness that evolves over a few days and may be heralded by distal paraesthesia, pain and numb ness. In severe cases, the weakness may progress to quadriplegia. Re \202 exes are diminis hed or absent. Involvement of respira- tory muscles may result in hypoventilation and dyspn oea, and 30% patients require mechanical ventilation. Facial nerve weakness is a frequent \201 nding, but bulbar weakness is less common, although serious. Autonomic involve- ment results in sinus tachycardia, cardiac arrhythmias, postural hypotension, severe sweating, i leus and urinary retention. Epidemiology \200 \200 \200 1.5 times more common in males than females Subtypes have different geographical variations Most cases are sporadic Incidence \200 \200 1 \200\2234 cases per 100 000 of the population Increases with age Causes GBS has an immune basis. In AIDP, antibodies generated in response to an infectious agent cross-react with myelin proteins and result in the characteristic inflammatory demyel ination. Often the causative agent is not identi \201 ed, but Campylobacter jejuni (40%), Mycoplasma pneumoniae (5%), CMV (15%), EBV and HIV have all been implicated. Some vaccines (in \202 uenza, rabies) and major surgery have also been associated with the development o f GBS. In 10% of cases the axon itself is damaged by antibodies to ganglio- sides on the ax olemma (AMAN and AMSAN subtypes). Investigations Vital capacity (VC) \200 4 hourly VC routinely, with more frequent assessment if clinical deterioration Transfer to ITU when VC is <20ml/kg Intubation if VC is <15ml/kg \200 Cerebrospinal \202 uid analysis \200 \200 CSF protein elevated in 80% patients after 1 week WCC usually normal. Diagnosis Diagnostic criteria have been established and are based on clinical features, ele vated CSF protein concentration and nerve conduction studies. In the acute phase, the symp- toms can be mistaken for a psychological problem, and a high index of suspicion of GBS mus t be present in all patients presenting with acute weakness. Neurophysiology \200 Nerve conduction studies are abnormal in 85% of cases within 1 week of onset of symptoms Ne rve conduction studies can differentiate between demyelination (decreased conduction veloci ty) and axonal damage (decreased amplitude) Microbiology and immunology \200 Differential diagnosis The differential diagnosis of GBS is wide. Antibodies for C. jejuni, CMV, EBV, HSV, HIV, M. pneumo- niae and atypical pneumonia stool for C. jejuni and poliovirus Serology \200\224hepatitis A, B, C and atypical pneumonia Anti ganglioside autoantibodies to delineate GBS subtypes Acute polyneuropathy \200 \200 \200 \200 \200 \200 \200 Acute intermittent porphyria Heavy metal poisoning Poliomyelitis Diphtheria Lyme disease Neuroimaging \200 MRI brain and spinal cord cord compression brainstem lesions \200 Disorders of the neuromuscular junction \200 \200 \200 \200 Myasthenia gravis Botulism Diphtheria Poisoning \200\224organophosphates, lead, shell \201 sh Other investigations \200 B12 and folate \200 Thyroid function tests \200 Urinary por phyrins \200 Paraprotein bands \200 Drug and toxin screen Miscellaneous \200 \200 \200 \200 \200 Critical illness polyneuropathy Transverse myelitis Brainstem lesions Carcinomatosis Muscle disorders \200\224rhabdomyolysis, periodic paralysis Autonomic tests Cardiac monitoring and others as indicated. 373 CHAPTER 22.7 Guillain \200\223Barre syndrome Management The treatment of GBS consists of general supportive care and speci \201 c treat ment. Many patients require ICU admission. muscle strength and shortens the recovery period. Bene \201 t is greatest when started wit hin 7 days of disease onset. Total plasma exchange for a treatment episode is 400ml/kg. Th e risks include hypotension, coagulopathy and hypocalcaemia, as well as catheter-related th rombo- sis and sepsis. Patients with dysautonomia or severe car- diovascular disease may no t tolerate plasma exchange. IVIG is a pooled blood product of puri \201 ed IgG adminis- te red at a dose of 400mg/kg daily for 5 days. It is more expensive than plasma exchange but i s usually the favored treatment option because of its ease of admin- istration and fewer si de effects, particularly line-associated infection. There is a small risk of thrombosis dur ing treatment with IVIG, so patients should be well hydrated prior to treatment. Corticoste roids are ineffective treatment for GBS and increase mortality. Indications for admission to ICU \200 \200 \200 \200 Respiratory failure Bulbar weakness Autonomic instability Management of complications Intubation and mechanical ventilation \200 ARF occurs because of hypoventilation, inadequate airway protection and poor cough. Intubat ion indicated when clinical evidence of fatigue, pulmonary aspiration or VC <15ml/kg. Early intubation is indicated when bulbar and respiratory muscle weaknesses co-exist. Care shoul d be taken during intubation to avoid brady- cardia and large swings in blood pressure rela ted to autonomic instability. Succinylcholine is avoided because of the risk of fatal hyper kalaemia. NIV is of limited value, and is contraindicated in the presence of bulbar palsy. Early tracheostomy is recommended in those who respond poorly to treatment or who are dif \201 cult to wean. Outcome \200 80% of patients with demyelinating GBS have a good outcome at 1yr. 5 \200\22315% overall mo rtality rate with up to 20% of survivors remaining disabled. ICU mortality is 5%. Prognosi s is worse in the elderly and in those with severe motor de \201 cit or who require prolon ged mechan- ical ventilation. \200 Autonomic support \200 Patient support group The Guillain \200\223Barre syndrome support group www.gbs.org.uk Cardiac arrhythmias and labile blood pressure should be treated promptly with standard agen ts. Resistant bradyarrythmias may require cardiac pacing. GI ileus occurs frequently but ur inary retention is less common. \200 Further reading Ashbury AK, Cornblath DR. Assessment of current diagnostic crite- ria for G uillain \200\223Barre syndrome. Arch Neurol 1990; 27: S21 \200\2234. Green D. Weakness in t he ICU: Guillain \200\223Barre syndrome, myasthe- nia gravis and critical illness polyneuro pathy/myopathy. Neurologist 2005;11: 338 \200\22347. General supportive care \200 Pneumonia is a frequent complication and usual prevent- ative measures are mandatory. Throm boembolic disease is a major risk, and LMWH, graded support stockings and physiotherapy min imize the risk of DVT. Pain is often severe and distressing. In addition to simple analgesi cs, opioids and agents to treat neuropathic pain (e.g. gabapentin) may be required. Enteral feeding is possible in many patients. If there is a severe ileus, the stomach should be dr ained via a gastric tube, and parenteral nutrition and gastric ulcer prophy- laxis started. Neurophysiotherapy, using passive \202 exion exercises and splints, is vital to prevent tendon shortening during the period of paralysis. Frequent turning and careful limb positio ning are also necessary to prevent pressure sores and nerve palsies. Effective means of com munication should be established in patients who are paralyzed. Activities to occupy patien ts are also bene \201 cial. Cognitive disturbance and depression are common in those with severe disease, and psychiatric input may be necessary. Hughes RA, Cornblath DR. Guillain \200\223Barre syndrome. Lancet 2005; 366: 1653 \200\22366. Hughes RA, Raphael JC, Swan AV, et al. Intravenous immunoglobulin for Guillain \200\223Barr e syndrome. Cochrane Database Syst Rev 2001; (1): CD002063. Hughes RA, van der Meche FG. Corticosteroids for treating Guillain-Barre syndrome. Cochrane Database Syst Rev 2002; (3): CD001446. Hughes, RAC, Wijdicks E, Barohn RJ, et al. Supportive care for Guillain \200\223Barre syndrome. Arch Neurol 2005; 62: 1194 \200\2238. van der Meche FGA, Schmitz PIM, Dutch Guillain-Barre Study Group. A randomized trial compar ing intravenous immune globu- lin and plasma exchange in Guillain \200\223Barre syndrome. N Engl J Med 1992; 326: 1123 \200\2239. Immunotherapy Two immunomodulatory therapies, plasma exchange and IV immunoglobulin (IVIG), are equally effective treatments for GBS but there is no advantage in combining the two. R elapses can occur, and most patients respond to a second course of either plasma exchange o r IVIG. \200 Plasma exchange with 3 \200\2235 treatments over 5 \200\2238 days reduces the need for resp iratory support, improves 374 M SMITH & C PRITCHARD Myasthenia gravis De \201 nition Myasthenia gravis (MG) is an autoimmune disease affecting the postsynaptic membrane of the neuromuscular junction. Other factors \200 Infection \200 Trauma and surgery \200 Pregnancy Epidemiology Mainly affects young females and older males. Clinical features MG is characterized by fatigable weakness of skeletal mus- cle. Classical ly the weakness worsens after exercise and in the evening, and is improved by rest. Ptosis, diplopia and blurred vision are the presenting features in 60% of cases. Proximal limb wea kness is more common than distal weakness. Bulbar muscle weakness may also be prominent, an d respiratory muscle weakness occurs in 20 \200\22330% of cases. In 15% of patients the dis ease is con \201 ned to the eyes (ocular MG). Incidence 0.25 \200\2232.0 per 100 000 population Causes 85% of patients with MG have IgG antibodies against post- synaptic skeletal muscle a cetylcholine receptors (AChR), often associated with an abnormality of the thymus gland. Re ceptor degradation, decrease in receptor half-life and complement-related damage to the pos tsynaptic mem- brane are characteristic of MG. Antibodies against muscle- speci \201 c rec eptor kinase (MuSK) are present in the majority of MG patients without anti-AChR antibodies (seronega- tive MG). Symptoms and signs Ptosis, often partial and unilateral, is common and most prominent on su stained upward gaze. Weakness usually progresses from ocular muscles in a craniocaudal dire ction, with upper limb weakness being more common than lower. There are no objective sensor y signs, and deep tendon re \202 exes are normal or brisk. Weakness of intercostals muscle s and the diaphragm leads to dyspnoea which improves on sitting up. Respiratory deteriorati on can occur rapidly and respiratory rate and vital capacity (VC) should be closely monitor ed. Hypercapnea is a sign of impending respiratory failure but hypoxaemia occurs late. Invo lvement of bulbar muscles is characterized by a slurred nasal voice, dif \201 culty with c hewing and swallowing and may result in aspiration pneumonia. Diagnosis The diagnosis of MG is relatively straightforward and based on recognition of a t ypical pattern of weakness, involv- ing some combination of extraocular, bulbar, facial, ne ck and limb muscles. The diagnosis is con \201 rmed by neuro- physiological investigations and detection of anti-AChR antibodies. Differential diagnosis The differential diagnosis of MG is wide. Motor neuropathies \200 \200 \200 Investigations Electrophysiological tests \200 Guillain \200\223Barre syndrome Motor neuron disease Diphtheria EMG \200 baseline compound muscle action potential (CMAP) usually normal decrement >10% in \201 rs t 4 \200\2235 CMAPs on low fre- quency (2 \200\2233Hz) repetitive stimulation 80% sensitive for diagnosis of generalized MG Myopathies \200 \200 \200 Muscular dystrophy Acquired myopathies (including electrolye disorders) Mitochondrial disor ders Single \201 bre EMG \200 \200 \200 Disorders of the neuromuscular junction \200 \200 \200 Lambert \200\223Eaton myasthenia syndrome (LEMS) Botulism Organophosphate poisoning recording of response to stimulation of a single \201 bre more sensitive (>90%) than stan dard EMG technically dif \201 cult Other \200 \200 \200 \200 Autoantibodies \200 \200 Brainstem lesions Cervical myelopathy Multiple sclerosis Thyroid disease More speci \201 c for diagnosis than EMG Anti-AChR antibodies diagnostic for MG \200 pos itive in 100% of thymoma-associated MG, in \200 70 \200\22390% of generalized MG and in 6 0% of ocular MG titres not related to severity of disease Risk factors There are many drugs and other factors that can induce or exacerbate MG. Anti-MuSK antibodies \200 positive in 70% of patients with seronegative MG. Drugs \200 \200 Edrophonium (Tensilon ) test \200 \200 Proven effects \200\224penicillamine, corticosteroids Probable effects \200\224aminoglycosi des, B-blockers, procain- amide, cipro \202 oxacin, phenytoin, lithium Possible effects \200\224anticholinergics, ampicillin, erythromycin, muscle relaxants, verapamil, chloroquin e For urgent diagnosis of severe MG only 2 \200\22310mg edrophonium (short acting anticholi n est- erase) IV Improvement in muscle strength within 45s (lasting 5min) con \201 rms MG Lo w sensitivity and speci \201 city 375 CHAPTER 22.8 Myasthenia gravis Patients with overt hypercapnea or who fail BiPAP require mechanical ventilation Respirator y support should be weaned as soon as pos- sible after the patient is free from crisis trig gers and VC >10ml/kg Tracheostomy is often not required as the duration of intubation rarel y exceeds 2 weeks Physiotherapy and antibiotics for chest infection/ pneumonia \200\224avoi d aminoglycosides and other drugs that exacerbate MG Pre-treatment with atropine minimizes risk of brady- cardia and hypotension May increase pulmonary secretions and worsen respi- ratory failure Neuroimaging \200 CT/MRI chest \200 \200 MRI brain to exclude \200 brainstem lesions \200 mass lesion s compressing cranial nerves thymoma in 20% of MG patients thymic hyperplasia in 70% of MG patients General support \200 \200 \200 \200 Thromboembolic prophylaxis Gastric ulcer prophylaxis Adequate calori \201 c intake via ent eral feeding Neurophysiotherapy Muscle biopsy \200 \200 \200 Quantify AchR density Electron microscopy of neuromuscular junction Exclude mitochondrial d isease Anticholinesterase medication \200 Not usually required in patients who are mechanically ventilated If required, pyridostigmin e IV at 1/30 the oral dose is effective within 20min and lasts for up to 4h Routine medicat ion should be restarted at half usual doses when weaning criteria are reached Other investigations \200 Thyroid function \200 Antinuclear antibody \200 Antistriate d muscle antibodies \200 Genetic testing for hereditary MG Treatment of MG \200 Immunotherapy The most useful treatments for myasthenic crisis are plasma exchange and IVIG (see also Chapter 22.7). \200 Enhancement of neuromuscular transmission \200\224anti- cholinesterase drugs Immunosuppress ion \200\224corticosteroids and/or azothi- aprine Thymectomy \200\224thymoma or thymic hype rplasia Plasma exchange or IVIG for exacerbations Plasma exchange is often used as \201 rst-line treatment as it results in rapid improveme nt and reduces time on ventilation. Five to eight daily exchanges are performed until pulmo nary function reaches 80% of predicted. Plasma exchange may be used as preparation for thym ec- tomy in patients with respiratory muscle involvement IVIG given over 2 \200\2235 days i n a total dose of 2g/kg is as effective as plasma exchange in myasthenic crisis. Long-term immunosuppression with corticosteroids or azothiaprine is required since the improvement wi th plasma exchange or IVIG is usually transient Azathioprine takes several months to 1yr to have maxi- mum effect. \200 Myasthenic crisis Myasthenic crisis occurs when the weakness is severe enough to require en dotracheal intubation for mechanical ventilation and airway protection. 8 \200\22327% patie nts with MG experience a crisis, often in the early years after diagnosis. It is more commo n in those with bulbar weakness or thy- moma, and may rarely be the presenting feature of M G. Myasthenic crisis should be differentiated from cholinergic crisis (caused by excessive anticholinesterase treatment) which is characterized by hypersalivation, abdominal pains an d diarrhea, but is extremely rare with modern manage- ment strategies. Thymectomy \200 \200 \200 In patients with thymoma and thymic hyperplasia Not usually performed during myasthenic cri sis Pre-operative establishment of long-term immunosup- pressive therapy reduces risk of po st-operative mysa- thenic crisis More effective in younger patients Improvement of symptoms in 85% patients at 1yr Precipitating factors for myasthenic crisis \200 Respiratory tract infection (30 \200\223 40%) \200 Pulmonary aspiration (10%) \200 Trauma, including recent surgery \200 Drugs \200 Unknown (30 \200\22340%) \200 Outcome \200 \200 20 \200\22330% 10yr mortality for untreated MG Modern treatment results in excellent progno sis, with mortality rates approaching zero Myasthenic crisis has 5% mortality Intensive care management The ICU management of MG consists of general support- ive care an d speci \201 c treatment. Indications for intubation \200 \200 \200 Further reading Green D. Weakness in the ICU: Guillain \200\223Barre syndrome, myasthe- nia gravis and critical illness polyneuropathy/myopathy. Neurologist 2005; 11: 338 \200\22347. Bulbar palsy Respiratory failure VC <15ml/kg, irrespective of arterial blood gasses Respiratory support \200 Hirsch NP. The neuromuscular junction in health and disease. A trial of BiPAP may prevent the need for intubation and mechanical ventilation in the abse nce of hypercapnea and bulbar palsy Br J Anaesth 2007; 99: 132 \200\2238. Lacomis D. Myasthenic crisis. Neurocrit Care 2005; 3: 189 \200\22394. Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol 2004; 24: 41 \200\2238. 376 M SMITH & C PRITCHARD ICU neuromuscular disorders Diagnosis Diagnosis of CINM is based on evaluation of the clini- cal setting and predisposi ng factors, neurological exam- ination and electrophysiological investigations. Clinical di agnosis is not straightforward. Accurate motor and sen- sory testing is dif \201 cult or i mpossible in critically ill patients because of sedation, delirium, poor cooperation or lim ited communication. Clinicians often predict poor or fatal outcome in critically ill patien ts who are comatose and paralyzed in the absence of evidence of irreversible brain or spina l cord damage. CINM is a potentially reversible condition and patients should therefore be carefully identi \201 ed to avoid unreason- ably pessimistic prognostication. Clinical exa mination is less sensitive than electrophysiological con \201 rmation and leaves a substan tial number of patients with CINM undiag- nosed. However, electrophysiological investigatio ns detect cases of CINM that are of little or no clinical relevance. Motor weakness in an ICU patient may be related to a pre- existing neuromuscular disorder, a new-onset or previously undiagnosed neuromuscular disorder or develop as a com- plication of critical illness. Two syndromes of ICU-acquired weakness are recognized \200\224critica l illness polyneuropathy (CIP) and critical illness myopathy (CIM). CIP is an acute axonal sensory-motor polyneuropathy and CIM an acute primary myopathy. CIP and CIM frequently co-e xist and a single term, critical illness neuromyopathy (CINM), is now used to describe this association. CINM can delay weaning from mechanical ventilation and impair physical recove ry after critical illness. Epidemiology CINM is often associated with sepsis, MOF, hyperglycae- mia, immobility and th e use of corticosteroids, neuromus- cular blocking drugs, aminoglycosides, cathecholamines and parenteral nutrition. It is more common in females than males. Differential diagnosis ICU-acquired weakness must be distinguished from weak- ness resultin g from new onset or previously undiagnosed neurological disorders such as GBS, MG and brain stem or spinal cord lesions. Other rarer confounding diagnoses include poliomyelitis and ot her mypoathies, porphyria, rhabdomyolysis and atypical presentation of amyotrophic lateral sclerosis. Incidence CINM is often unrecognized but affects between 25 and 80% of intensive care patie nts. Reported incidence depends on the criteria used for diagnosis and timing of the exami- nation. Electrophysiological tests identify more patients than clinical examination. In pa tients with ICU stays >28 days, electrophysiological evidence of CINM is present in >90% pa tients up to 5yrs after discharge. Clinical features CINM presents as dif \201 culty with weaning from mechanical ventilation or unexplained weakness in conscious patients following a critical illness. CINM is charac terized by a symmetrical motor de \201 cit in all limbs, ranging from mild paresis to quad riplegia. The facial muscles are usually spared, and the \201 rst manifestation is often a weak or absent limb withdrawal with a normal facial grimace on painful simulation. Deep t endon re \202 exes are reduced or absent, but normal re \202 exes do not rule out the dia gnosis. Associated sensory loss is present in 50% of patients, but its evaluation is often limited by the patient \200\231s conscious state. Phrenic nerve involvement and intercostal muscle weakness contribute to dif \201 culty in weaning from mechan- ical ventilation. Causes The exact etiology of CINM is unclear, but in \202 ammatory mediators, microcircula tory damage, direct neurotoxicity and hyperglycaemia have been implicated. In CIP, vascular and cellular events result in nerve cell energy failure and, initially, pure functional fa ilure. With persisting critical ill- ness and continuing cellular failure, histological cha nges in the nerve cell ensue. CIM is an acute primary myopathy (i.e. not secondary to muscl e denervation) with a spec- trum extending from functional impairment of muscle with normal histology to muscle atrophy and necrosis. Histological examination often reveals signs of both pri- mary (necrosis) and secondary (denervation related) mypoathy, indicating that CIM and CIP co-exist. Risk factors \200 Symptoms and signs These are often unreliable and can be confused with other conditions. CI NM is a clinical diagnosis of exclusion and often unrecognized. The following features are useful indi- cators of other causes of weakness in ICU patients. Sepsis, systemic in \202 ammatory response syndrome and MOF are risk factors for CINM, whi ch is strongly associ- ated with the duration of MOF. Chronic corticosteroid use is an inde pendent risk factor for CINM. Neuromuscular blocking drugs have adverse effects on muscle s trength by two mechanisms \200\224prolonged neu- romuscular blockade because of drug or met abolite accumulation in the setting of renal or hepatic failure and a direct causal relatio nship to the development of CINM because of prolonged pharmacological denervation. There is an established link between hyperglycaemia and CINM. Severe electrolyte abnormalities, inc luding hypokalaemia, hyperkalaemia, hypophosphataemia and hypomagnesae- mia, may damage mus cle and lead to CIM. Bed rest and immobility due to sedation may potentiate ICU-acquired we akness. CNS involvement \200 \200 \200 Asymmetrical neurological signs Cranial nerve palsy Altered mental status Spinal cord involvement \200 \200 Sensory level Loss of anal tone and sphincter re \202 ex Neuromuscular disease \200 \200 \200 Extremity weakness and wasting Hypotonia and hypore \202 exia Autonomic dysfunction 377 CHAPTER 22.9 ICU neuromuscular disorders Investigations Electrophysiological tests Comprehensive electrophysiological studies, inclu ding motor and sensory nerves conduction studies and needle EMG in upper and lower limbs, a re able to differentiate between CIP and CIM. However, electrophysiological tests do not pr edict duration of mechanical ventilation or length of ICU stay. \200 Use of corticosteroids should be restricted to condi- tions in which they have been proven to have a signi \201 - cant impact on morbidity and mortality. Neuromuscular blocking drug s should also be used only for selected indications, such as dif \201 cult to ventilate pa tients and intractable intracranial hypertension, and only when all other means have failed . If the clinical con- dition permits, daily interruption of neuromuscular block- ing drugs is recommended to reduce the risks associated with prolonged pharmacological denervation. Sedation protocols designed to minimize the use of seda- tives and analgesics decrease the duration of mechanical ventilation and possibly the incidence and severity of CINM. Strateg ies to mobilize patients with passive stretching or active exercise seem reasonable given t heir relative safety. Electrolyte disorders, including phosphate and magne- sium depletion, should be controlled throughout the entire critical care episode. Although not proven, ade quate nutrition seems a neces- sity to prevent catabolism and muscle wasting. IVIG might re duce the development of CINM, but more studies are required before this treatment can be re c- ommended. Nerve conduction studies \200 CIP is characterized by decreased CMAP and sen- sory nerve action potential with normal con duction velocity abnormalities may be detected as early as 48h after the onset of critical illness prolongation of CMAP suggests an associated myopathy EMG \200 CIM is diagnosed by abnormal EMG during voluntary contraction in conscious and cooperative patients Direct muscle stimulation (DMS) \200 differentiates between CIP and CIM in uncooperative patients stimulating and recording elec trodes are placed in the muscle distal to the end-plate zone in CIP there is a reduced or a bsent CMAP on motor nerve stimulation but a normal response with DMS in CIM the CMAP is red uced or absent after both motor nerve stimulation and DMS technically dif \201 cult Outcome \200 CINM is an independent predictor of prolonged mechanical ventilation and increased ICU mort ality and LOS. Complete functional recovery occurs in 70% of patients. Muscle wasting and weakness are common in survivors of critical illness, and some remain severely disabled. Mi ld disabilities persist in patients with seemingly good recovery. These include reduced or absent re \202 exes, glove and stocking sensory loss, muscle atrophy, dysasthe- sia and fo ot drop. Other electrophysiological tests \200 phrenic nerve conduction studies and diaphragmatic EMG may be indicated in patients who fai l to wean from mechanical ventilation Muscle biopsy \200 Not used routinely because it is invasive and the results are not immediately available Myo sin/actin ratio reduced in CIM Three types of histological changes are recognized \200\224 acute necrotizing, thick myosin \201 lament loss and \201 bre atrophy Allows diagnosis of other causes of muscle pathology \200 Further reading De Jonghe B, Sharshar T, Lefaucher JP, et al. Paresis acquired in the inten sive care unit: a prospective multicenter study. JAMA 2002; 288: 2859 \200\22367. Dhand UK. Clinical approach to the weak patient in the intensive care unit. Respir Care 2006; 51: 1024 \200\22340. Neuroimaging \200 Fletcher SN, Kennedy DD, Ghosh IR, et al. Persistent neuromuscu- lar and neurophysiologic a bnormalities in long-term survivors of prolonged critical illness. Crit Care Med 2003; 31: 1012 \200\2236. MRI of the spinal cord and brain to exclude cord com- pression and brainstem lesions Other \200 Latronico N, Peli E, Botteri M. Critical illness myopathy and neuropathy. Curr Opin Crit Care 2005; 11: 126 \200\22332. Serum CK \200\224variably raised but may be normal Latronico N, Shehu I, Seghelini E. Neuromuscular sequelae of Prevention and treatment There is no proven treatment for established CINM, and management focuses on prevention by avoidance of risk factors. \200 critical illness. Curr Opin Crit Care 2005; 11: 381 \200\22390. Schweickert W, Hall J. ICU-acquired weakness. Chest 2007; 131: 1541 \200\2239. Aggressive treatment of sepsis and MOF minimizes the risk of developing CINM, shortens its duration and reduces severity in established cases. The link between elevated blood glucose levels and CINM is well established. Tight glycaemic control with insulin infusion is asso ciated with a 50% reduction in the evolution of CIP and mortality bene \201 t in criticall y ill sur- gical patients. Tight glycaemic control in medical ICU patients results in a sma ller reduction in the incidence of CIP but signi \201 cant reductions in the duration of m echan- ical ventilation. 378 L THWAITES Tetanus Tetanus is a toxin-mediated disease caused by the bacte- rium Clostridium tetani resulting in: \200 \200 Special investigations should be ordered according to the clinical indications. In addition to routine blood tests, the following are helpful: \200 \200 Skeletal muscle rigidity and spasm Autonomic nervous system instability ABG CXR (aspiration is common) The disease is completely preventable by vaccination, and in recent years global vaccinatio n initiatives in infants and young women have begun to have an impact on the disease incide nce. Nevertheless, in the developing world, tetanus continues to be a common cause of morta lity and morbid- ity of neonates, children and young adults. In countries with well establi shed vaccination programs, the disease is rare and usually occurs in the elderly or cer- ta in \200\230high risk \200\231 groups such as IV drug users. In either setting, mortality f rom severe disease is high and good outcome is dependent on high quality care. Natural history Historically two periods have been used to characterize the progression of tetanus disease: \200 Incubation period: the asymptomatic period from infec- tion to the \201 rst symptom (typi cally 7 \200\22310 days). This can- not be calculated if no entry wound is found. Period of onset: the period from \201 rst symptom to \201 rst spasm (typically 24 \200\22372h). Shorter periods are associated with more rapidly progress- ing and severe disease. More acc urate prognosis can be calculated using speci \201 c prognostic scores. Tetanus gradually increases in severity over 1 or 2 weeks, with spasms reaching maximum intensity during the second week, and maximal autonomic disturbance during the second and third weeks. These gra dually improve, although muscle rigidity may persist for up to 6 weeks. A recurrence of spa sms or worsening of severity may sug- gest a persistent source of C. tetani infection.