EM guidemap - Akathisia and restless leg syndrome

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Introduction

Akathisia

Restless leg syndrome

Appendix
Introduction

- this guidemap is only focused on acute drug-induced akathisia, which is a specific problem that emergency physicians frequently encounter, and the guidemap does not discuss chronic akathisia, which is a common problem in psychiatric patients taking long-term neuroleptic medications

- this guidemap also discusses restless leg syndrome, which can be incorrectly diagnosed as akathisia if an emergency physician is not sufficiently cognizant of the syndrome's distinctive clinical features, which clearly mark it as a separate diagnostic entity
 
Akathisia

- akathisia has been described as a sense of "inner restlessness", which is a subjective sensation of restlessness that has a strong component of motor restlessness (the patient cannot keep physically still and maintain a static posture for an extended period of time)

- the peculiar state of mental and motor restlessness causes a state of "inner agitation", and the patient has difficulty maintaining a constant posture for several minutes, such as sitting still in a chair or standing motionless in one place => the patient is acutely aware of his strong desire to be in a restless state of constant motion, but he cannot voluntarily suppress the desire

- the patient with acute akasthisia feels very fidgety, and he has a strong urge to repeatedly change his body position eg. the sitting patient may constantly shift his position in a chair, or make constant rocking motions, or constantly cross and uncross his legs, or constantly swing his legs to-and-fro; the standing patient may constantly shift from one foot to the other foot, and he may even frantically pace about the room

(* by contrast to a patient with restless legs syndrome, the patient with akasthisia does not have any unpleasant leg dysesthesias or periodic myoclonic leg movements, and the "motor restlessness" is not exclusively provoked by rest or sleep)

- in its milder form, the patient may just appear anxious, and a physician may mistakenly diagnose "non-specific anxiety" if he is not aware of the specific clinical features of akasthisia

- in its more severe form, akathisia is associated with severe dysphoria, anxiety and marked irritability

- patients with severe drug-induced akathisia may prematurely leave the ED, and akathisia-induced violence and suicide has been thought to be a rare consequence of the patient's uncontrollable state of extreme agitation

- there are a number of classification systems used to diagnose akathisia, but they are ill-suited to an ED setting

(* see the appendix for a practical akathisia scoring system, that can be used in an ED setting to objectively assess whether an ED administered drug has caused acute akathisia)

- chronic akathisia is a common complication of long-term neuroleptic drug therapy, while acute akathisia is usually seen within minutes-to-days after recent administration of provocative drugs (even a single dose)

- drugs provoking acute akathisia include neuroleptic agents, serotonin receptor antagonists, lithium, levodopa, calcium channel blockers and phenothiazine anti-emetics eg. prochlorperazine or metoclopropamide

(* acute akathisia can rarely follow acute traumatic brain injury, and is also seen in Parkinson's disease)

- the etiology of akathisia is unknown, and a good response to propanolol suggests a hyperactive adrenergic system

- the treatment of acute drug-induced akathisia includes anticholinergic agents (diphenhydramine and benztropine) and propanolol +/- opioids

(* by contrast, levodopa and pergolide, which are very useful in treating restless leg syndrome, have no therapeutic effect in akathisia patients)

- the drug provoking the acute akathisia should be discontinued, or the dose reduced if continued therapy is mandatory

- the first dose of an anticholinergic drug can be administered parenterally if severe akathisia is present, and it should be followed by a 2 - 3 day course of oral anticholinergic drugs to prevent a relapse

- the IV route is recommended for severe reactions; IM or po adminstration should be reserved for milder reactions

- symptoms should resolve within 15 - 30 minutes following IV administration

Benztropine

- dose is 1 - 2mg IV over 2 min (peds. dose = 0.01 - 0.02 mg/kg)

- the dose may be repeated after 15 - 30 minutes if symptoms persist

Diphenhydramine

- 50 - 100mg IV over 2 min (peds. dose = 1 - 2 mg/kg)

- the dose may be repeated after 15 - 30 minutes if symptoms persist

- the anticholinergic medication can be administered prophylactically to prevent acute drug-induced akathisia eg. prior to administering prochlorperazine for the ED treatment of migraine headache

(* anticholinergic drugs are not useful for chronic akathisia)

- opioids and benzodiazepines have some therapeutic effect, but they are not as effective as highly lipophilic beta-blockers (propanolol - 10 - 30mg tid) in reducing the objective signs of akathisia
 
Restless leg syndrome

- restless leg syndrome (RLS) is a distinct, but often misdiagnosed, syndrome of unknown etiology

- onset at any age, and the clinical course is typically chronic and progressive with periods of relative remission and exacerbation

- affects ~ 2 - 6% of the adult population, and elderly people may be more commonly affected (10 - 15%)

- population surveys note that ~ 25% of surveyed people complain of occasional unpleasant sensations and restlessness in their legs at bedtime, but it is not clear when to classify those people as having the restless leg syndrome

- the disorder may be found in first-degree relatives suggesting an autosomal dominant pattern of inheritance

- RLS occurs frequently in pregnancy

- RLS is a clinical diagnosis, and it usually has 4 major clinical features

Primary features of restless leg syndrome

- the uncomfortable sensations in the legs are variably described - electric current sensation, tingling, creepy crawly sensation (like insects tunneling through the legs)

- some patients cannot describe the intensely uncomfortable dysesthetic sensation, and they only declare that the "indescribable" sensation produces a strong urge to move the legs

- a voluntary attempt to avoid moving the legs makes the unpleasant symptoms considerably worse

- a minority of patients actually describe the sensation as painful (< 20%)

- the urge to move often causes the patient to walk about, although the patient may try a variety of other movements in order to relieve the discomfort (rocking, shaking, stretching, stationary bicycling or marching in place) => active movements may produce temporary relief

- one of the most distinctive features is that rest, either quiet wakefulness or attempts to sleep, evokes the sensory symptoms and motor restlessness

- symptoms are not present in the day when the patient is actively moving, and the unpleasant symptoms occur when the patient sits or lies down (eg. prolonged sitting while watching TV or attending a meeting, or when riding a train or airplane), and an inability to sit for prolonged periods can seriously disrupt the patient's work

- the symptoms show a distinct circadian rhythm and are often worse in the evening and early night hours (between 6pm - 4am)

- other associated clinical features - not required for the diagnosis - include periodic limb movements during sleep, periodic limb movements while awake, and insomnia

- periodic limb movements during sleep (PLMS), which occur in 70% of RLS patients, are repetitive, often sterotyped movements that occur every 15 - 45 seconds during non-REM sleep and last 0.5 - 5 seconds

- PLMS often affects the legs, causing dorsiflexion of the toes, and flexion of the ankles and knees and hips

- PLMS rarely affects the upper limbs

- periodic limb movements while awake (PLMW) may occur, and they consist of involuntary brisk flexion movements - usually of the legs - that may occur randomly, periodically or in clusters

- insomnia and day-time fatigue are common side-effects if the dysesthesias or PLMS disrupts sleep

Differential diagnosis

- the diagnosis of restless leg syndrome is based on the 4 distinctive clinical features, but other diseases must also be considered, and excluded

Diagnostic testing

- RLS is a clinical diagnosis (based on the 4 - 6 clinical features), and limited diagnostic testing is necessary

- routine tests include serum ferritin and serum iron and hemoglobin to r/o iron deficiency, blood glucose to r/o diabetes, serum creatinine to r/o renal failure

- some experts recommend further testing - serum folic acid, serum magnesium and serum TSH

- needle electromyography and nerve conduction studies are performed if polyneuropathy is suspected

- all night polysomnography is useful to document sleep disturbance and PLMS, or if associated sleep apnea is suspected

(* hypothyroidism and diabetes are more common in patients with RLS, but are not thought to be causally-related; vitamin B12 and folate deficiency are sometimes found; other rare associations include:- rheumatoid arthritis, Sjogren's syndrome, fibromyalgia, polyneuropathy due to alcohol or amyloidosis or diabetes or carcinoma or porphyria, avitaminosis, cryoglobulinemia, chronic myelopathy, lumbosacral plexus lesions, Parkinson's disease, COPD and partial gastrectomy => see the appendix for a complete list)

Treatment

- not all patients require drug therapy, and therapy is necessary if the patient is functionally impaired by severe waking symptoms of RLS, or if resultant insomnia produces day-time fatigue

- vigorous physical activity just prior to bedtime can aggravate the symptoms, and should be avoided

- empirically avoiding caffeine and alcohol and nicotine may sometimes be helpful

- anti-emetics that act on the dopaminergic system (metoclopromide or droperidol) may exacerbate the condition, and should be avoided

- tricyclic antidepressants, lithium, dopamine antagonists and SSRIs may exacerbate the condition, or relieve the condition

- a certain percentage of patients have low serum ferritin levels (< 50 ng/ml) suggesting iron deficiency, and they respond well to iron replacement therapy

- affects 10 - 25% of dialysis patients, and RLS may disappear after renal transplantation

- although the cause is unknown, patients often respond to low doses of levodopa

- other useful agents include opioids, benzodiazepines, clonidine and certain anticonvulsants (gabapentin)

- no drug has been officially approved by the FDA for this condition, and recommendations are mainly based on case reports and non-blinded studies involving small numbers of patients

- the chosen drug should be used at the lowest dose, and titrated upwards slowly

Levodopa

- carbidopa-levodopa is the most frequently used agent for initial treatment

- therapy is started with a very low dose (one half of a 25/100 tablet taken 1 hour before bedtime), and titrated upward until the desired effect is achieved

- an additional low dose of a long-acting levodopa (Sinemet-CR) may be useful for late night symptoms

- avoid > 200mg of levodopa per day, to minimize the likelihood of dopa-induced augmentation (aggravation of RLS symptoms), which eventually occurs in > 50% of patients taking levodopa

- levodopa should be discontinued if dopa-induced augmentation occurs (rebound of RLS symptoms late at night or earlier in the afternoon)

Other dopaminergic agents

- bromocriptine (Parlodel) and pergolide (permax) are also effective, and may produce less augmentation, particularly when high doses are required for severe RLS symptoms

- two newer dopa agonists, pramipexole (Mirapex) and ropinirole (Requip), are gaining favor

Benzodiazepines

- have non-specific sleep-inducing properties and are used for insomnia due to RLS or PMLS

- clonazepam (0.5 - 2mg) is frequently prescribed, and alternative choices include temazepam (7.5 - 30mg) or triazolam (0.125 - 0.25mg)

- may potentiate accompanying sleep apnea and cause daytime sedation

Opioids

- opioids may be helpful for patients with painful dysesthesias

- direct comparisons between various opioids are lacking; codeine (30mg) or propoxyphene (65 - 130mg) are frequently used

- because of their addictive potential, these agents are reserved for patients who have failed to respond to other medications, and when pain is a major symptom

- clonidine has been used in patients with RLS + hypertension or uremia

Anticonvulsants

- carbamazepine (tegretol) and gabapentin may be useful in certain patients, especially if neuropathic features, or an accompanying peripheral neuropathy, is present
 
Appendix

Practical akathisia scoring system suitable for use in an ED setting

Akathisia scale:

Objective: Two-minute seated observation

1) Inability to remain seated (is the patient shifting)?
2) Any semi-purposiveful or purposeless leg or foot movements?

Subjective: Three questions

1) Do you feel restless within or the urge to move, especially in the legs?
2) Are you unable to keep your legs still?
3) Are you unable to sit still or stand still?

Drug-induced akathisia = Change in objective scale of 1 point + change in subjective scale of 2 points (from pre-drug treatment to post-drug treatment)

* Objective scale

* Subjective scale Akathisia is diagnosed if both an increase in the objective scoring of 1 point or greater, and an increase in the subjective scoring of 2 points or greater are noted

The degree of akasthisia is reflected by the total score from all 5 questions

Restless leg syndrome symptom-complex

1) Unpleasant deep-seated lower limb sensations
2) Sensations precipitated by rest and temporarily relieved by activity
3) Compelling motor restlessness
4) Symptoms worse during the evening or late at night
5) Presence of periodic limb movements (PLMS)
6) Resultant sleep-onset, or sleep-maintenance, insomnia

Factors that may contribute to, or be associated with RLS (in order of frequency)

A treatment approach for RLS used at the Mayo Clinic Sleep Centre

 Step One

For mild RLS (symptoms are intermittent or only mildly disruptive to onset or maintenance of sleep), consider use of either a benzodiazepine or a low potentcy opiod, which can be used intermittently

Step Two

For moderate or severe RLS (symptoms are continuous, moderatedly to severely disruptive to onset or maintenance of sleep or unresponsive to medications listed in step one), carbidopa-levodopa is the drug of choice

Step Three

If levodopa is ineffective, or use is limited by side-effects, or daytime augmentation occurs, discontinue use and institute pergolide

Step Four

If pergolide is ineffective, use is limited by side-effects, or daytime augmentation occurs, consider use of higher potentcy opioids, bromocriptine, clonidine, or gabapentin

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.