EM guidemap - Fever + rigidity + altered LOC

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Introduction

History of the present illness

Summary of the clinical features differentiating NMS from SS

Diagnostic testing

Differential diagnosis

Medical decision-making/treatment Appendix

Introduction

- this guidemap has been designed to help an ED physician solve the diagnostic dilemma of "fever + rigidity + altered LOC" in an ED patient

- this guidemap is mainly focused on helping the physician differentiate between neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS), with a lesser emphasis on other common causes of "fever + rigidity + altered LOC"

History of the present illness

- NMS usually develops over 24 - 72 hours, although it may progress more slowly over many days (3 - 10 days) in a patient taking a neuroleptic medication

(* SS develops more abruptly within hours of a change in the dose of a provoking drug, or following the addition of an interacting drug eg. IM meperidine administered to a patient taking a MAOI)

- NMS typically begins with mental status changes and muscular rigidity => hyperthermia and autonomic dysfunction

- the mental status in NMS is always impaired and ranges from agitation => stupor => coma

(* SS is usually associated with anxiety, restlessness , agitation or hypomania; and rarely with seizures or stupor/coma - the increased anxiety may be falsely misinterpreted as an exacerbation of the underlying condition requiring treatment with a SSRI)

- the muscular rigidity in NMS is usually of the lead-pipe type and includes the trunk musculature => chest wall rigidity => decreased chest wall compliance => tachypnea and shallow respirations in "a patient seemingly turned to stone"

(* SS is usually associated with myoclonus, tremors, hyperreflexia and a lesser degree of rigidity - usually only affecting the lower limbs)

- other motor abnormalities in NMS include bradykinesia, cogwheeling, wazy flexibility and involuntary movements suggestive of Parkinson's disease

(* SS rarely has any of these prominent parkinsonian features)

- less common motor abnormalities in NMS include opisthotonus, retrocollis, trismus, oculogyric crises and seizures

(* SS may produce nystagmus, ocular oscillations, teeth chattering and incoordination; and is very rarely associated with opisthotonus and trismus)

- the fever usually follows the neuromuscular changes in NMS, and hyperpyrexia is usually a dominant feature of the condition (temperture often > 39 degrees celcius)

(* SS causes a lesser degree of hyperpyrexia, and fever is less commonly present)

- common autonomic changes in NMS include tachycardia, abnormal blood pressure, pallor, sialorrhea and diaphoresis (dysphagia and incontinence are less common)

(* SS is also associated with autonomic changes - mainly tachycardia and diaphoresis and diarrhea)

- fever + muscular rigidity in NMS => rhabdomyolyis => myoglobinuric renal failure

(* rhabdomyolysis is far less common in SS)

- other complications of NMS include aspiration pneumonia, acute respiratory failure, intravascular thrombosis, AMI, cardiovascular collapse, and pulmonary embolism

(* SS is less commonly associated with any of these complications)

- NMS is almost always secondary to neuroleptic agents - especially butyrephenones, phenothiazines and thioxanthenes (haloperidol and fluphenazine are the commonest causal agents), and has also been seen with risperidone and clozapine; and a similar syndrome is also seen in Parkinson's disease patients, who abruptly stop taking their dopaminergic drugs eg. L-dopa

- other agents rarely causing NMS include some commonly used drugs such as prochlorperazine (compazine), promethazine (phenergan) and metaclopramide (reglan)

(* SS is caused by serotonergic drugs - usually drug combinations - MAOI + tricyclics, or MAOI + SSRI, or MAOI + lithium, or MAOI + meperidine, or MAOI + dextromethorphan; or recreational drugs of abuse - MDMA, LSD, ecstasy, cocaine)

- NMS is an idiosyncratic reaction occurring in a small minority of patients taking neuroleptic drugs, and there is no direct relationship to the dosage or duration of therapy; although there may be a history of a recent change in the dose of the neuroleptic agent or the addition of another neuroleptic agent within the past 3 - 14 days

(* SS is also idiosyncratic, but the risk is partly affected by the serotonergic potentcy of a particular drug, and also influenced by the presence of additional interacting drugs)

Summary of the clinical features differentiating NMS from SS


Differentiating neuroleptic malignant syndrome
from serotonin syndrome
  Neuroleptic malignant syndrome Serotonin syndrome
Speed of onset + +++
Neuroleptic drug use +++ +/-
Serotomimetic drug use +/-  +++
Mental status changes    
       Agitation +/-  +++
       Confusion +++ ++
       Hyperactivity - +++
       Stupor/coma +++ +/-
Neuromuscular changes    
       Rigidity +++ +
       Bradykinesia +++ -
       Myoclonus - +++
       Hyperreflexia - +++
       Tremor +/- +++
Hyperpyrexia +++ ++
Autonomic changes    
        Tachycardia +++ ++
        Hypertension  ++ ++
        Diaphoresis +++ ++
        Shivering - +++
        Mydriasis - +

 
Diagnostic testing

- there is no confirmatory test for NMS or SS, and the diagnosis is based on clinical criteriae

(* see appendix for diagnostic criteriae for NMS and SS)

- routine blood testing includes a CBC, BUN/Cr, electrolytes, glucose, liver function tests, CPK, calcium, magnesium, thyroid function tests, and blood cultures

(* a CPK is consistently elevated in NMS, and less commonly elevated in SS)

- cardiac monitoring, pulse oximetry, EKG, ABG, and chest X-rays are often required for the diagnosis and/or management of the cardiorespiratory complications seen in most of the diagnostic entities causing "fever + rigidity + altered LOC"

- urinalysis for myoglobin (and C&S prn)

- a CT scan of the head is indicated if the diagnosis is uncertain, or if there are any focal neurological signs or focal seizures

- a LP is indicated whenever meningitis is a definite diagnostic possibility

- a toxicology screen for neuroleptic and serotonergic drugs may rarely be indicated if there is no drug history available (because the patient is uncommunictive/unresponsive and there is no other way to access pertinent historical information)

Differential diagnosis

Meningitis and encephalitis

- first consider and exclude a CNS infectious process (meningitis and encephalitis) in all febrile patients with altered mental status - by routinely performing blood cultures and a spinal tap for CSF analysis and culture

- empiric antibiotic treatment is advisable if meningitis cannot be clinically excluded

- altered LOC and fever are the dominant features in meningitis or encephalitis, while rigidity is far less common (compared to NMS)

- marked hypertonia in an encephalopathic patient suggests rabies or tetanus => inquire about recent animal bites or exposure to bats; malaria should be considered in patients who have recently travelled to areas where malaria is endemic

A severe febrile illness in a patient with an underlying extra-pyramidal disorder (which may produce rigidity and bradykinesia) often mimics NMS, and is far more common than NMS

(* always inquire about any underlying extra-pyramidal disorders before making a presumptive diagnosis of NMS)

Malignant hyperthermia syndrome

- characterized by the abrupt onset of muscular rigidity, hyperthermia, altered mentation and hypermetabolism following the use of a precipitating drug

- usually precipitated by inhalational anesthetics or succinylcholine

- occurs idiosyncratically within minutes of administration of the precipitating agent eg. administration of succinylcholine during rapid sequence intubation

- a family history of MH is common (autosomal dominant gene with variable expression and incomplete penetrance); as is a personal history of previous similar episodes

- underlying musculoskeltal abnormalities are often present (kyphosis, scoliosis, pectus excavatum, dislocated patellae, hernias and poor crowded teeth)

- early signs include masseter spasm => rapid progression to generalised hypertonia + hyperpyrexia

- complications include metabolic acidosis, rhabdomyolysis, hyperkalemia and autonomic hyperactivity

Lethal catatonia syndrome

- patients have a long history of psychosis +/- catatonia

- can occur in the absence of any anti-psychotic medications

- may be precipitated by other medical diseases eg. infections, metabolic or endocrine derangements

- frequently begins with a prodrome of labile mood, anorexia, insomnia => unrelenting agitation +/- bizarre repetitive mannerisms and echophenomena +/- bizarre suicide attempts +/- disorganized thought processes

(* NMS usually begins with rigidity + stupor, while lethal catatonia usually begins with psychotic excitement)

- refusal of food and drink is common, as are other psychosocial withdrawal or excitement phenomena such as negativism, mutism, impulsivity or combativeness

- severe cases proceed to stuporous exhaustion + hyperpyrexia + autonomic instability + rigidity or wazy flexibility + life-threatening complications eg. rhabdomyolysis, renal failure, aspiration pneumonia, cardiovascular collapse, seizures, coma, intra-vascular thrombosis or DIC

- there is no specific laboratory finding that will confirm the diagnosis, and the diagnosis is based on the clinical presentation and the subsequent evolution of the disease

Heat stroke syndrome

- most cases occur during periods of extreme ambient heat (during the summer months), especially when the patient has a limited ability to effectively manage heat or limit significant exposure to the heat

- elderly patients, who live a sedentary lifestyle and who do not have adequate cooling systems at home are at greatest risk - especially if they suffer from obesity, co-morbid diseases, psychiatric illness or chronic substance abuse +/- taking certain predisposing medications eg. diuretics, anti-cholinergics, anti-hypertensive agents

- prodromal symptoms of heat exhaustion (nausea, weakness, dizziness, headache, muscle cramps and confusion) may precede the full-blown heat stroke syndrome

- hyperpyrexia + altered LOC are the dominant features, and significant rigidity is uncommon

- anhidrosis and a "hot, dry skin" suggests the diagnosis, but anhidrosis may be a late and inconsistent finding

(* diaphoresis is more common in NMS and SS)

- hepatic damage with disproportionately high liver enzymes is also suggestive, and the urine may be brown and turbid resembling "machine oil"

- complications include hypotension and distributive shock, high output cardiac failure, acute oliguric renal failure, coagulopathy and DIC

Thyroid storm

- underlying hyperthyroid disease symptoms are present

- thyromegaly +/- thyroid orbitopathy +/- thyroid myopathy are present

- rigidity and extra-pyramidal signs are uncommon

(* see my "thyroid storm" guidemap for further clinical details)

Anti-cholinergic/sympathomimetic drug toxicity

- history of known drug overdose (or plant ingestion - Jimson weed and Amanita muscara mushrooms) may be available

- a characteristic toxidrome may be present

- anticholinergic toxicity is suggested by dry flushed skin, dry mucous membranes, dilated pupils, decreased bowel sounds and urinary retention in association with fever and altered LOC

(* "red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare")

- sympathetic overdose is associated with central nervous overactivity (agitation, delirium, hallucinations, decompensation of previous psychiatric disorders, hyperreflexia, rigidity and seizures), cardiovascular stimulation (tachyarrhythmias, hypertension, myocardial injury), and gastrointestinal stimulation (abdominal cramps, vomiting and diarrhea)

(* see the excellent chapters on "sympathomimetic" and "anticholinergic" toxicity in the online textbook of emergency medicine at http://www.emedicine.com for futher clinical information and a review of the clinical management/treatment)

Acute delirium tremens due to alcohol withdrawal

- dominant features include a hyperadrenergic state (anxiety, insomnia, nausea, emesis, tachycardia, tachypnea, hypertension, diaphoresis, hyperreflexia), which progresses => seizures, global disorientation, muscular rigidity, coma, hyperpyrexia

(* see the excellent chapter on "delirium tremens" in the online textbook of emergency medicine at http://emedicine.com for further details)

Medical decision-making and treatment

- most of the patients with the syndrome of "fever + rigidity + altered LOC" will require ICU admission, standard cardiorespiratory supportive measures, IV hydration and standard cooling measures

Neuroleptic malignant sydrome

1) Withdraw the offending neuroleptic agent(s)

2) Provide supportive cardiorespiratory care, correct volume depletion and maintain an adequate urine flow (~2cc/kg/hour) to prevent renal failure secondary to rhabdomyolysis

3)  Treat the hyperpyrexia by rapid cooling measures eg. aerosolized tepid water spray + evaporative cooling +/- ice packs to the groin and axillae

4) Dantrolene (0.8 - 3.0 mg/kg IV q 6 h ) can be used to treat the severe muscle spasms/rigidity

- some authorities suggest an initial IV bolus of 2mg/kg repeated twice prn
- dantrolene is hepatotoxic at levels > 10mg/kg/day and is contra-indicated in patients with active liver disease

5) Bromocriptine mesylate (2.5mg - 10 mg) may possibly shorten the duration of the illness and can be administered alone, or in combination with dantrolene, and repeated every 8 hours

(* there is no definite evidence that combination therapy with dantrolene and bromocriptine is better than either drug used alone)

6) Other, less commonly utilized drugs include:- amantidine, levodopa, benztropine, and diphenhydramine

7) Prophylactic heparin therapy to prevent venous thrombosis

Serotonin syndrome

1) The inciting medications should be withdrawn

2) Provide supportive cardiorespiratory care and rapid cooling measures prn

3) Benzodiazepines are first-line drugs, and they are used to treat any neuro-excitatory symptoms or any significant muscle rigidity

- diazepam = 0.2 - 0.4 mg/kg IV prn

- lorazepam = 0.05 mg/kg IV prn

4) Propanolol (0.01 - 0.1mg/kg IV or 0.5 - 1.0mg/kg po q 6h prn) is rarely required for the treatment of any sympathetic hyperactivity, excessive restlessness or tremors

5) Chlorpromazine (0.5 mg/kg IV or IM) can be used for severe agitation

6) Cyproheptadine - 0.5 mg/kg/day (4 mg po q 2 - 4 h in an average-sized adult)

(* there is no specific antidote for SS and the use of propanolol, chlorpromazine and cyproheptadine is only based on a limited number of anecdotal reports)

Malignant hyperthermia

1) Withdraw the precipitating agent

2) Dantrolene (2 - 3 mg/kg IV prn q 10 minutes x 3; a maximum of 10 mg/kg/day) is the drug-of-choice for severe cases

3) Cardiorespiratory support prn

4) Cooling measures prn

5) IV hydration prn

Lethal catatonia

1) Provide cardiorespiratory support

2) Discontinue all psychotropic medications

3) Benzodiazepines prn

4) Dantrolene and bromocriptine have been used with mixed results

5) Electro-convulsive therapy is only effective before severe progression of the condition has occurred

Heat stroke

1) Remove all clothing

2) Institute rapid evaporative cooling using an aerosolized tepid water spray and a large fan +/- ice packs to the groin and axillae until the core temperature reaches < 38.5 degrees celcius

3) Chlorpromazine (0.5 mg/kg IV) may be necessary to reduce shivering

4) IV benzodiazepines can be used to control agitation or seizures

5) IV hydration (modest) is usually required to treat the distributive shock

6) Treat any coagulopathy prn

Alcohol withdrawal states

1) Benzodiazepine therapy is the mainstay of drug therapy

Lorazepam 2 - 4 mg prn IV or diazepam 2 - 4 mg prn IV

2) Phenobarbital can also be administered using a regularly scheduled dosing format to provide background therapy

Dose of phenobarbital = 30 - 120 mg po or IV 6 6h

Thyroid storm

(* see the "thyroid storm" guidemap for further details)

Meningitis

(* see the "meningitis" guidemap for further details - still to be written)

Anti-cholinergic and sympathomimetic toxicity

(* see the relevant chapters in the online textbook of emergency medicine at http://www.emedicine.com)

Sympathomimetic toxicity

Anticholinergic toxicity

Appendix

Research criteriae for neuroleptic malignant syndrome (from DSM-IV)

A) The development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication

B) Two (or more) of the following

- diaphoresis
- dysphagia
- tremor
- incontinence
- change in level of consciousness
- mutism
- tachycardia
- elevated or labile blood pressure
- elevated CPK C) The symptoms in criteriae A) and B) are not caused by another substance (eg. phencyclidine) or a neurological disorder or other general medical condition

D) The symptoms in criteriae A and B are not better accounted for by a mental disorder (eg. catatonia)

Alternative criteriae for the diagnosis of neuroleptic malignant syndrome

All three required

1) Hyperthermia

2) Severe extra-pyramidal effects

    Two or more of

    - lead pipe rigidity
    - trismus
    - pronounced cogwheeling
    - dysphagia
    - sialorrhea
    - choreifrom movements
    - oculogyric crises
    - dyskinetic movements
    - retrocollis
    - opisthotonus
    - flexor-extensor posturing

3) Autonomic dysfunction

    Two or more of

    - hypertension
    - tachycardia
    - tachypnea
    - prominent diaphoresis
    - incontinence

Sternbach's suggested diagnostic criteriae for serotonin syndrome

1) Coincidental with the addition of or increase in known serotonergic agent to an established medication regimen, at least three of the following features are present (usually at least one from each class)

Behavioural and cognitive changes

Neuromuscular hyperactivity Autonomic instability 2) Other etiologies have been ruled-out

3) A neuroleptic agent has not been started or increased in dosage prior to the onset of the above symptoms and signs

Some drugs associated with serotonin syndrome

Increase serotonin synthesis      Increase serotonin release

L tryptophan                                        Amphetamines
                                                            Cocaine
                                                            Codeine
                                                            Dextromethorphan
                                                            Fenfluramine
                                                            Levodopa
                                                            LSD/psilocin/mescaline
                                                            MDMA (Ecstasy)
                                                            Pentazocine
                                                            Reserpine

Decrease serotonin degradation     Decrease serotonin re-uptake

Amphetamines                                     Amphetamines
All MAOI's                                         Carbamazipines
Selegeline (Deprenyl)                         Citalopram
                                                            Cyclic antidepressants
                                                            Cocaine
                                                            Dextromethorphan
                                                            Fluoxetine
                                                            Fluvoxamine
                                                            Meperidine
                                                            Methadone
                                                            Paroxetine
                                                            Sertraline
                                                            Tramodol
                                                            Trazodone
                                                            Venlafaxine

Serotonin modulators                  Increase serotonin activity via dopamine agonism

trazodone                                             bupropion
nefazadone                                           lithium
mitrazapine                                          L-Dopa
buspirone                                             bromocriptine
 
Disclaimer: My EM guidemaps reflect my personal approach to problem-solving/managing clinical cases in an ED setting and they should not be regarded as the standard of care. They merely represent the personal opinions of the author and they should only be used in clinical practice if the reader-user has substantial reason to believe that the clinical advice contained in the guidemaps is valid and accurate. The guidemaps are not meant to be "authoritative" and the reader-user should consult standard medical textbooks and expert opinion articles/guidelines for more authoritative advice. The reader-user should particularly confirm all drug doses, their indications and contra-indications, prior to their use.