According to recent guidelines, we use the term craniocervical dystonia instead of the eponym “Meige syndrome” to describe this patient’s intermittent episodes of involuntary blinking, blepharospasm, tongue protrusion, platysmata contractions and anterocollis ([1,5], Additional file 1: Video 1). Most of these movements were observed when he attempted to talk and were not preceded by an intense urge to move or talk. Tongue tremor at rest and patterned episodes of tongue protrusion while maintaining an open mouth were noted [Additional file 1: Video 1]. In fact, dystonic tremor has been described as inconstant and often exacerbated by an attempt to maintain posture [6]. Finally, this patient did not complain of dysphagia and there were no abnormal movements of the jaw.
In patients with craniocervical dystonia, an 11% chance of spontaneous remission has been reported, particularly those with blepharospasm [7]. Yet, it is important to identify potentially reversible causes.
Fluoroquinolones are commonly used antibiotics that can have CNS excitatory effects through a dose-dependent, GABA-A receptor antagonist mechanism [3,4]. Ciprofloxacin has been shown to be a more potent GABA antagonist than other quinolones in vitro [3]. Moreover, an in vivo EEG study demonstrated pronounced decrease in delta and theta, as well as augmentation of alpha wave bands after ofloxacin infusion. These effects were augmented by flumazenil and reversed by midazolam [4]. In general, quinolones are rarely associated with neurological adverse reactions, mostly dizziness, headache and insomnia. They have a <0.5% rate of serious neurological reactions including abnormal movements, alteration of consciousness and epileptic spells. However, ciprofloxacin has a rate of up to 4% [8-10]. New agents are developed by chemically modifying older compounds to improve their spectrum, potency, pharmacokinetics and safety. Levofloxacin, derived from ofloxacin, received marketing approval in the US in 1997. Remarkably, the recommended dose of levofloxacin is equivalent to a 2.5 times higher ofloxacin dose. Levofloxacin has a <0.001% rate of severe neurologic reactions, mostly reported as convulsions [8-10].
A diverse reversible hyperkinetic movement phenomenology has been reported in relation to ciprofloxacin (tremor [9,11], myoclonus [12-14], orofacial dyskinesias [15,16], chorea [17], tic disorder [18], palatal tremor [19] and stereotypy [17]), levofloxacin (tremor and chorea [20]), ofloxacin (tic disorder [21]) and gemifloxacin (dystonia [22]).
The pathophysiology of dystonia encompasses dysfunction of inhibitory basal ganglia and cortical circuits [2]. Through GABA antagonism, quinolones could potentially predispose to abnormal inhibition and trigger dystonic movements. To the best of our knowledge, dystonia has not been reported in association with levofloxacin. Additionally, segmental dystonia has not been described as a side effect of quinolones.
A case of acute-onset multifocal dystonia (involving the four extremities with sparing of axial muscles) has been reported in a 36 year-old woman three days after initiation of gemifloxacin. Her abnormal movements quickly resolved with intravenous administration of promethazine 50 mg [22]. A 43 year-old woman presented with confusional state, “dystonic posturing of the feet”, diffuse chorea and stereotypy preceding generalized tonic-clonic seizures after ciprofloxacin intake [17]. In another report, a 49 year-old woman was noted to have intermittent 1-hour episodes of facial grimacing every 4–6 hours that were described as “oral facial dyskinesia” induced by ciprofloxacin [15], but may have included blepharospasm. Finally, a 68 year-old man taking ciprofloxacin was noted to have 15–30 second episodes of “orofacial dyskinesias” consisting of facial grimacing and distortions, puckering and pursing of the lips, without eyelid involvement. These episodes resolved shortly after ciprofloxacin was discontinued [16].
Levofloxacin is excreted primarily unchanged in urine [23]. Therefore, dose adjustments are required in individuals with impaired renal function. HD does not effectively remove the drug from the body [24]. Dosing guidelines recommend 500 mg on the first day, followed by 250 mg every 48 hours for patients with ESRD on HD [25]. Our patient, an older ESRD patient on HD, was taking 500 mg twice daily for 3 days before dystonia onset.
As hypothesized in other reports, neurotoxic levels of levofloxacin were likely reached due to a combination of renal impairment, age-related decline in cerebral function and reduction of plasma volume leading to higher plasma and CNS drug concentrations. Similar to other reported cases of quinolone-associated hyperkinetic movements, dystonia disappeared completely after discontinuation of levofloxacin [Additional file 2: Video 2]. Benzodiazepines were not used in this case, but can be considered to reverse the GABA inhibition related to quinolone intoxication [26]. Due to the ethical implications of a “quinolone challenge”, it was felt that the time course of the patient’s dystonia in relation to levofloxacin intake and discontinuation was a strong evidence for this association.
