Acute Peripheral Neurologic disorder

Praween Lolekha, MDThammasat University

Outline

• Neural Control of Breathing• Signs and Symptoms of acute peripheral

neurologic disorder and respiratory failure

• Clinical pattern of neuromuscular failure – Guillain Barré Syndrome (GBS)– Myasthenia Gravis (MG)– Lambert-Eaton Myasthenic Syndrome (LEMS)– Botulism– Acute intermittent porphyria– Neurotoxic marine poisoning – Organophosphate poisoning

Neural Control of Breathing

• Diaphragm• Accessory muscles of inspiration

– External intercostal muscle– Scalene muscle– Sternocleidomastoid muscle

• Accessory muscles of expiration– Internal intercostal muscle– Abdominal wall muscles

• Upper airway musculature

Neural Control of Breathing

• Mechanical aspect of respiration (Ventilation)– PNS (Nerve, NMJ, Muscle)– CNS (Brainstem, Cervicomedullary

junction)• Alveolar gas exchange

(Oxygenation)– CNS: Neurogenic pulmonary edema

in subarachnoid hemorrhage, status epilepticus, head injury, brain death

Neural Control of Breathing

Mechanoreceptors-Respiratory muscle-Lungs: Pulmonary stretch receptor

Chemoreceptors-Carotid bodies-Aortic bodies

Medullary respiratoryCenter (RC center)

CN IX,X

CN X

-Phrenic n (C3-5)- Intercostal n (T2-T12)

Larygopharyngeal m.Bronchoconstrictors CN IX

Symptoms

• Acute/ Subacute onset– Dyspnea, orthopnea– Respiratory arrest– Bulbar weakness: dysarthria (nasal voice),

dysphagia– Secretion aspiration

• Gradually onset– Noctunal hypoventilation– Broken sleep pattern– Nightmares, daytime fatigue– Somnolence

Signs

• Using accessory muscles of respiration• Inability to speak in complete sentences

or count 1-20 in a single breath– 1-10 (FVC ~1000cc) , 1-25 (FVC~2000cc)

• Paradoxical abdominal motion• Mental clouding, alteration of

consciousness• Facial muscles weakness (oral, orbital)• Ptosis, ophthalmoparesis

Respiratory Investigations

• Spirometry : FVC (Forced Vital Capacity)– Normal 20-30 cc/kg– Impending respiratory failure:

FVC<15-20 cc/kg (~1000cc)• Peak flow

– Normal is ~360-840 L/min– Respiratory weakness : PF <160-200

L/min

Respiratory Investigations

• Arterial blood gases– Late feature in neuromuscular

disease– Hypoxemia, compensated

respiratory acidosis• Mouth pressure

– Maximum inspiratory pressure (MIP)<30 cmH2O

– Maximum expiratory pressure (MEP)<40 cmH2O

Neurological Disorders and respiratory failure

• Acute Ventilatory failure– CNS : Brainstem and

cervicomedullary junction lesion– PNS: Neuromuscular disease

• Motor neuron disease : ALS• Polyneuropathy : GBS , Porphyria• Neuromuscular junction disorders : MG ,

LEMS, Botulism, Organophosphate• Myopathy: DM, PM, muscular dystrophy

Peripheral neurology and respiratory failure

• Acute / Subacute– Neuropathy: Guillain Barré syndrome

(GBS) Tetrodo toxin, Prophyria– NMJ: Myasthenia gravis (MG),

Botulism,Organophosphate, Snake venoms

– Muscle: Inflammatory myopathy• Chronic progressive

– ALS (Amyotrophic lateral sclerosis)– Muscular dystrophy

Guillain-Barré syndrome

Guillain-Barré syndrome

• Self-limited, autoimmune disease• The main clinical feature

– Motor weakness (proximal > distal)– Areflexia– Paresthesia with slight sensory loss– Increased protein in CSF without

pleocytosis “Albuminocytological dissociation”

Epidemiology

Annual Incidence• 0.4-4.0 (median 1.3) : 100,000Age and Sex• Occur at all ages (8mo - 81yr)• 2 peak

– Late adolescence and young adulthood

– Elderly• Men : women = 1.25 : 1

Guillain-Barré syndrome

GBS

AIDP AMAN MFS

AIDP with 2 degeneration AMSAN

AIDP = Acute inflammatory demyelinating polyneuropathy

AMAN = Acute motor axonal neuropathy

AMSAN = Acute motor sensory axonal neuropathy

MFS = Miller Fisher syndrome (Ophthalmoparesis, ataxia, areflexia)

Etiology

• 2/3 of patients are preceded by symptoms of upper respiratory tract infection or gastroenteritis.

• C oncept of “molecular mimicry”– Campylobacter jejuni– Haemophilus influenzae– CMV, EBV– Mycoplasma pneumoniae

• Prodromal infection between 1 week and 3 weeks (averaged 11 days)

Clinical Features

• Paresthesias and numbness are frequent and early symptoms

• Major clinical manifestation is muscle weakness

• Maximum deficit develop over days and nadir in 2 wks. (no progression after 4 wks.) followed by a plateau phase and gradual recovery

Motor symptoms

• Symmetrical limb weakness initially be proximal > distal muscles or global

• Usually the lower extremities before the upper (ascending paralysis)

• Trunk, intercostals, neck, bulbar and cranial nerves may be affected later

• Respiratory muscle weakness (25%)• Facial diplegia • Areflexia• Muscle wasting (after 2 wks.)

Sensory symptoms

• Pain and an aching discomfort in the muscles, mainly those of the hips, thighs and backs

• Numbness, paresthesia• Lost of joint position sense,

vibration, touch and pain distally• Ataxia

Autonomic dysfunctions

• Fluctuation of heart rate and blood pressure

• Tonic pupil• Hypersalivalation• Excessive sweating• Paralytic ileus• Urinary retention• Constipation

Electrophysiologic study

• Diagnosis of AIDP

Patients must have one of the following in two or more nerves during the first 2 weeks of illness– i) Conduction velocity <90% of lower limit of normal if amplitude i

s >50% of the lower limit of normal; <85% if amplitude is <50% of lower limit of normal.

– ii) Distal latency >110% of upper limit of normal if amplitude is normal; >120% of upper limit of normal, if the amplitude is less than lower limit of normal.

– iii) Evidence of unequivocal temporal dispersion.

– iv) F-response latency >120% of normal

“Evidence of demyelination”

CSF analysis

• Typical– Normal pressures– Few cells (typically mononuclear)– Elevated protein concentration (greater

than 50 mg/dL)– Normal sugar

• Less than one week, protein levels may not yet be elevated

• If CSF pleocytosis (>10/mm3), other diseases should be considered : HIV, malignancy

“Albuminocytological

dissociation”

Treatment

Supportive Treatment• 25-30% require i ntubation and mechan

ical ventilation• Continuous monitoring of blood pressur

e and heart rateImmunomodulating treatment• Plasma exchange• IVIg• Corticosteroid : no benefit

• PE recommended for patients– Unable to walk unaided– Worsening vital capacities– Require mechanical ventilation– Significant bulbar weakness

• Removes a total of 200-250ml/kg in 4-6 treatments on alternate days

Plasma Exchange

Immunoglobulin

• Plasma exchange and IVIg have equivalent efficacy

• Advantages of lower risk and ease of application

• IVIg is more efficacious than plasma exchange in patients with axonal GBS

• Dosage : 0.4 g/kg/day for 5 days consecutively

Myasthenia gravis (MG)

• An autoimmune disorder caused by autoantibodies against the nicotinic acethycholine recetors on the postsynaptic membrane at the NM junction

• Characterised by weakness and fatigability of the voluntary muscles.

Epidemiology

• The commonest disorder in NMJ • Annual incidence 0.25-2/100,000• Present in any age

– A bimodal peak• First peak in 3rd decade ( women >

men )• Second peak in 6th-7th decade ( men > women )

Pathophysiology

Modified Osserman Classification

• Class I: Ocular weakness• Class II: Mild weakness

– IIa : limb and/or axial involvement– IIb : oropharyngeal and/or respiratory involvement

• Class III: Moderate weakness – IIIa : limb and/or axial involvement– IIIb : oropharyngeal and/or respiratory involvement

• Class IV: Severe weakness– IVa : limb and/or axial involvement– IVb : oropharyngeal and/or respiratory involvement

• Class V: Defined by intubation c/s mechanical ventilator

Clinical features

• Weakness and fatigability of muscles on sustained or repeated activity that improves after rest

• Insidious onset• Often fluctuation • Progression

– Craniocaudal direction

Clinical features

• The most commonly affecting muscles – Levator palpebrae (ptosis)– Extraocular muscles (diplopia)– Muscle of facial expression (“Snarl” face)– Neck muscles (drop neck myopathy)– Bulbar muscles (dysphagia, nasal voice)– Proximal limb muscles

Clinical features

• Can first present during– Pregnancy or post natally– Post general anesthesia– ICU care

• Diaphragmatic weakness• Weakness can remain localized to

one group of muscle for many years eg. Ocular MG

“Myasthenic snarl”

Associated disorder

• Thymic hyperplasia 50-70%• Thymoma 10-15%• Thyroid disease 10%• Rheumatoid arthritis• Pernicious anemia• SLE

Diagnosis of MG

• Serology: – Anti-AchR (sensitivity 80%, high specificity)

• EMG: Repetitive nerve stimulation– CMAP decremental >10% at 3 Hz (sensitivity

75%)• SFEMG:

– increase jitter +/- blocking (most sensitive but not specific)

• Edrophonium/ Tensilon test – (sensitivity 80%, not specificity)

• Ice test – (80% sensitivity, high specificity)

Repetitive Nerve Stimulation

“Decrement response”

Precipitating factors

• Physical exertion• Hot temperature• Emotional upsets• Infections• Hyperthyroidism• Surgery• Menstruations• Pregnancy (1st

trimester)• Postpartum• Hypokalemia

• Drugs induced MG– Aminoglycoside– Fluoroquinolones – B-blockers– Ca Channel blocker– High dose steroid– D-penicillamine– Chloroquine– Quinine– Quinidine– Lithium– Clopromazine– Procainnamide

Treatment

• Improve neuromuscular transmission – Acethycholineaterase inhibitors : Mestinon

• Suppress immune response– Corticosteroid– Immunosuppressant: AZA, MTX, MM etc.– IVIg

• Remove antibodies– Plasmapheresis

• Thymectomy

MG crisis

• Occur 15-20% of MG patients• Plamapheresis is the treatment of

choice except– Hemodynamic instability– Sepsis– Coagulopathy– Unavailable– First trimester of pregnancy

• Then IVIg

Diagnosis of MG

Evaluate for Thymectomy

Anticholinesterase

CrisisGeneralizedOccular

Low risk

If unsatifactory

MRI

Anticholinesterase

Intensive CareRespiratoryInfection

High risk

ImproveThymectomy

PrednisoloneImmunosuppressive

Plasmapheresis / IVIg

Not improve

Prognosis

• Ocular MG 10% 90% turn to Generalized (usually in 2 years)

• Untreated weakness fixed and atrophic

• Spontaneous remission rate 20%• 20-30% will die within 10 years

without treatment

MG crisis vs Cholinergic crisis

• Myasthenic crisis– Respiratory distress– Increased pulse and

blood pressure– Poor cough– Secretion aspiration– Dysphagia– Weakness– Improve with

edrophonium

• Cholinergic crisis– Abdominal cramps– Diarrhea– Nausea and

vomiting– Excessive secretions– Miosis– Fasciculations– Weakness– Worse with

edrophonium

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Autoimmune disease producing antibodies against presynaptic voltage-gated calcium channels

• Paraneoplastic syndrome (50-70%)– Small cell lung cancer– Lymphoma, Leukemia

• Usually presents in adulthood > 40 years with smoker

Pathophysiology

• P/Q-type VGCC antibodies attack presynaptic NMJ

Clinical Features

• Symptoms– Proximal limb weakness (Leg>arms)– Rarely, cranial nerve symptoms– Rarely, respiratory failure– Autonomic dysfunction (75%)

• Dry mouth, constipation,dilated pupils with poor reactive to light, impair sweating, orthostatic hypotension, impotence

– Lambert’s sign • Grip becomes more powerful over several

seconds

– Absent DTR but obtainable after exercise

Repetitive Nerve Stimulation

Posttetanic facilitation - incremental response >200%

Treatment

• Treating the cancer– Screened for small cell lung CA every 6

months with chest imaging for at least 2 years

• Pyridostigmine alone is usually ineffective

• 3,4 Diaminopyridine is usually beneficial, and usually enhanced by pryidostigmine

• Plasma exchange/ IVIg temporary improvement

Botulism

• Botulism is a rare, but seriousparalytic illness caused by atoxin that is produced by the bact

eria Clostridium botulinum .• C. botulinum is an anaerobic, Gra

- m positive, spore forming rod.

• 3 main kinds of botulism– The classic (food-borne) botulism

• Ingestion of toxin in food contaminated with toxin-producing bacteria.

– Infant botulism• Ingestion of spores that then germinate

and produce toxin in the infant’s gastrointestinal tract.

– Wound botulism• W ound infected with Clostridium botulinu

m• IVDU

Botulism

C. botulinum

• Pathogenic bacterium that found in the soil.

• Proliferates under anaerobic and alkaline conditions

• The spores can survive extreme weather and temperature conditions (>120c may be required to kill the spores).

• Toxin is heat labile (>85c inactivates the toxin)

• Toxins A,B,C1,C2,D,E,F,G

Pathophysiology

Clinical presentations

• Cranial nerve palsies (2-36hr)– Diplopia, ptosis, blurred vision– Dysarthria, dysphagia

• Descending weakness of the limbs – Upper limbs Lower limbs– Usually bilateral but can be

asymmetric.

• Respiratory paralysis• Autonomic dysfunction

Autonomic dysfunction

• Dilated pupils (<50% of patients)• Constipation, diarrhea• Nausea and vomiting• Dry mouth• Postural hypotension• Urinary retention• Heart rate R-R interval variation• Recovery of autonomic function may

take longer than NM transmission.

Diagnostic methods

• NCV and EMG– Small CMAP amplitude– Decremental response of the MAP to slow

rated of nerve stimulation (2-3 Hz)– Posttetanic facilitation (PTF) (50Hz) or post

isometric exercise incremental response to 30-100%

• Detection of toxin– Serum (30-40%) (<30% after day 2)– Stool (60%) (36% after day 3)– wound

Treatment

• Supportive care (weeks – months)• Antitoxin

– Dose not reverse paralysis when the toxin is internalized and bound at the nerve terminal.

– Lack of efficacy in some cases– Allergic reactions and serious side

effect 20%

Vincent van Gogh

Porphyria

• A heterogeneous group of inherited disorders of haem biosynthesis

• Deficiency of one of the enzyme of the haem biosynthetic pathway

• 7 main types of prophyria, classified into acute neuropsychiatric, cutaneous and mixed forms

• Acute intermittent prophyria is the commonest.

Pathway of Haem Synthesis

Acute intermittent prophyria

• Autosomal dominant (AD, 11q23)• 10-15% of gene carriers develop

symptom• 1/3 have no family history or

unidentified for several generations• Often misdiagnosed and life-

threatening condition• Deficient activity of

hydroxymethylbilane synthase• More common in women than men• Rare attacks before puberty

Clinical features

• Severe abdominal pain back• Proximal muscle weakness (arms)

quadriparesis• Peripheral motor neuropathy (wrist / foot drop)• Respiratory failure• Seizure• Hypoesthesia of a bathing-trunk distribution• Spare ankle reflexes• Autonomic neuropathy

– Tachycardia, hypertension, postural hypotension – Constipation, nausea, vomiting,

• Dehydration and hyponatremia

Precipitating factors

• Exposure to exogenous drugs– Amphetamines, cocaine– Barbiturates, phenytoin, carbamazepine,

diazepam, sodium valpoate– Estrogens, progesterones– Sulphonylureas– Tetracyclines, chloramphenicol, isoniazid– Antihistamine

• Fasting, alcohol• Stress, smoking, pregnancy• Infection

Laboratory diagnosis

• Increase urine aminolaevulinic acid and porphobilinogen

• Urine is often dark during an attac k or upon standing in the light

Management

• About 1% may be death• Avoidance of precipitating agents

– Severe pain : Opiates– Tachycardia, hypertension: propanolol– Sedation : Chlopromazine– Convulsion : gabapentin

• High carbohydrate diet or 10%glucose

• Haem arginate/ Haematin

Neurotoxic marine poisoning

• Ingestion of marine animals that contain toxic substances– Ciguatera poisoning (Ciguatoxin) – Puffer fish poisoning (Tetrodotoxin) – Paralytic shellfish poisoning (Saxitoxin)

• Affect voltage-gated Na+ channels in myelinated and unmyelinated nerves peripheral neurological effects

Puffer fish poisoning

Puffer fish poisoning

• Southeast Asia and Japan• Ingestion of fish contain

tetrodotoxin• Highest concentrations in the

liver, ovary, intestine and skin• Blockade of voltage-sensitive Na+

channels at the nodes of Ranvier.

Puffer fish poisoningGrade 1 Perioral numbness and

paraesthesia, ± GI symptoms (N/V)

5-45 min

Grade 2 Lingual and face numbness, early motor paralysis and incoordination. Slurred speech. Normal reflexs

10-60 min

Grade 3 Generalized flaccid paralysis, respiratory failure, aphonia, fixed or dilated pupils, patient is conscious.

15min-several hrs.

Grade 4 Severe respiratory failure and hypoxia, hypotension, bradycardia, unconsciousness

15min- 24 hr

• The clinical effects develop rapidly and severity depend on the amount of ingestion

Puffer fish poisoning

• Most cases resolve after 5 days but may be longer in severe poisoning.

• Clinical diagnosis• Urine (5days) and serum (<24 hr)

tetrodotoxin for confirmation• Nerve conduction studies: reduced

amplitudes of compound motor and sensory potentials, slow conduction velocities. Prolong distal and F wave latencies

Management

• No antidote• Supportive and careful observation • Life-threatening effects are

unlikely after 24 hrs.• Atopine can be used to treat

bradycardia.• Respiratory support may be

needed for a period of 24-72 hrs.

Organophosphate Poisoning

• Well absorbed by dermal, respiratory and gastrointestinal

• Irreversible binding to cholinesterase enzymes

• Excess cholinergic stimulation

Acetylcholine in PNS

Acute intoxication

• DUMBBELS– Defecation– Urination– Miosis– Bronchorrhea– Bradycardia– Emesis– Lacrimation– Salivation

• SLUDGE– Salivation– Lacrimation– Urination– Defecation– Gastric secretion– Emesis

Receptor Organ Clinical EffectAutonomic -Postgang. Muscarinic(Parasympathetic)

-Postgang. Muscarinic(Sympathetic)-Pregang. Nicotinic(Sympathetic)

EyeMouthLungsHeartsGI tractGU tractSweat glands

Adrenal

Miosis, LacrimationSalivationBronchorrhea, bronchospasmBradyarrhythmia, prolong QTDiarrhea, emisis, increase motilityUrinary incontinenceDiaphoresis

Increase catecholamines

NMJ-Nicotinic Skeletal

muscleFasciculation, weakness, paralysis

CNS-Muscarinic/ nicotinic Brain Seizure, coma, depression,

agitation

Intermediate syndrome

• 5-65% in patients with organophosphate poisoning

• A myasthenia-like syndrome• Down-regulation of overstimulated AchR (pre

and postsynaptic dysfunction)• Occur 1-3 days after the acute cholinergic

Hallmarks– Proximal muscle weakness– ± Respiratory failure– Motor cranial nerve dysfunction– Diminished reflexes

• Recovery occurs 5-18 days

Organophosphate-induced delayed polyneuropathy

• 1-4 wks after cholinergic signs• Cramping muscle pains in the legs• Progressive weakness of the lower

extremities upper extremities• Distal > Proximal • Loss of reflexes• Axonopathy with Wallerian

degeneration and spinal cord atrophy• No treatment

Management

• Serum cholinesterase ± red cell cholinesterase

• Adequate decontamination– Clothing– Activated charcoal, Gastric lavage (<2hrs),

• Treatment of the parasympathetic– Clearing pulmonary secretions– Atropine (antimuscarinic) 2-5mg iv q 5-15 min until

secretions clear / drip 0.02-0.08mg/kg/hr.• Treatment in reversing nicotinic signs (motor

weakness, fasciculation)– Pralidoxime (<24 hr, reactivate AchE)

• Treatment seizure– Benzodizepines

Neurological Respiratory Failure

Level of consciousness

History of Drugs, Toxic substance

Normal consciousnessPoor, Unconsciousness

Long tract signs Brain stem signs

-Brainstem lesion: infraction-Increase ICP-Brain herniation

PNS

AcuteChronic

Polyneuropathy : GBSNMJ : MG crisis

BotulismToxin : Porphyria

Tetrodotoxin

-Drugs-Metabolic-Infection-Other systems

ALSMuscular dystrophyMyopathyCritical illness myopathy,neuropathy

Others

Other systemsYes

No

Airway:-COPD, asthmaAlveoli:-Pneumonia

CNS

Onset Tone Motor Sensory DTR Autonomic

Ant. horn cell- ALS

Chronic

Asymmetric

Normal -

Neuropathy-GBS-Porphyria-Tetrodotoxin

AcuteAcuteAcute

SymmetricAssending

DistalMildMild

Distal, perioral

Normal

+++

NMJ-MG -LEMS-Botulism-Organophosphate

Gradual

Gradual

AcuteAcute

SymmetricProximalProximal

Dessending

Proximal

NormalNormalNormalDelay distal

Normal

-+++

Muscle-Myopathy-Muscular dystrophy

Chronic

Chronic

SymmetricProximalProximal

NormalNormal

Normal

Normal

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The END