Tacrolimus treatment is associated with a range of neurological adverse effects. Neurotoxicity caused by tacrolimus may result in subacute onset of tremor in a subset of patients. The commonly reported tremor phenomenology associated with tacrolimus neurotoxicity is the action tremor of bilateral upper limbs with or without rest tremor. Tremor may occur even if the plasma concentration of tacrolimus is within the therapeutic range. In this report, we highlight a case of tacrolimus-induced tremor, in which, in addition to having action and rest tremor of the upper limbs, the patient had vocal, lingual, and lower limb tremor. We demonstrate how drug cessation and temporary administration of primidone remarkably improved the tremor.
Keywords: drug-induced tremor, immunosuppressant, movement disorder, primidone, tacrolimus, tremor
|How to cite this URL:|
Lenka A, King C, Soni M, Hu N, Motamedi GK. Tacrolimus-induced generalized tremor with excellent response to primidone. Ann Mov Disord [Epub ahead of print] [cited 2022 May 16]. Available from: https://www.aomd.in/preprintarticle.asp?id=336877
| Introduction|| |
Drug-induced movement disorders have a wide spectrum of manifestations. Since drug-induced movement disorders are often distressing but reversible, familiarity with the drugs associated with movement disorders and their corresponding manifestations is crucial. Tremor is a commonly observed drug-induced movement disorder, which is associated with the use of several classes of medications, including immunosuppressants such as tacrolimus, cyclosporine, and sirolimus., However, the incidence of tremor is much higher with tacrolimus than cyclosporine and sirolimus (lowest propensity to induce tremor). The recent increase in the number of organ transplantations has increased the chronic use of these medications. Tremor is a well-known manifestation of tacrolimus neurotoxicity, which is demonstrated in our case report in a patient who developed severe generalized tremor 2 weeks after starting tacrolimus.
| Case Report|| |
Our patient was a 68-year-old, right-handed Caucasian woman who had a history of hypertension and decompensated alcoholic cirrhosis. For the latter, she underwent liver transplantation 2 weeks prior to her emergency room visit. After an uneventful postoperative stay, she was discharged to the rehabilitation facility. Besides her regular medications (polyethylene glycol, melatonin, and pantoprazole), she was prescribed three immunosuppressants (tacrolimus, mycophenolate mofetil, and prednisone) and two antimicrobials (valganciclovir and trimethoprim-sulfamethoxazole).
After taking the aforementioned medications for 10 days, she presented to the emergency room with complaints of upper limb tremor that were prominent with activity and that subsequently involved her legs. As the tremor severity increased, she had difficulty in holding objects, speaking, and ambulating. In addition, she experienced intermittent confusion.
In the emergency room, her vitals were stable. She was oriented to time, place, and person. Her speech, albeit affected by vocal tremor, was intelligible and coherent. There was rest and action tremor (both postural and intention) of both upper limbs, with a mild jerky component. Tremor amplitude was maximum during the finger-to-nose test. In addition, she experienced tremor in her legs, voice, and tongue [Video 1]. There was no asterixis. Her remaining neurological examinations were unremarkable. Complete blood count and a comprehensive metabolic panel including liver function test and ammonia level were normal. Given the fluctuation in her mental status, magnetic resonance imaging of her brain was performed that ruled out posterior reversible encephalopathy syndrome, a known side effect of tacrolimus, and other structural abnormalities. Electroencephalogram did not show any epileptiform discharges or triphasic waves.
In the absence of any identifiable metabolic derangements, infections, or structural brain lesions that could explain the subacute onset of the generalized tremor, tacrolimus neurotoxicity became the prime differential diagnosis. The patient was on 8-mg tacrolimus twice daily. Even if the whole-blood tacrolimus concentrations are within the therapeutic range, similar to that in our patient (10.8 ng/ml), it is possible to develop toxicity because of the unbound plasma fractions. Hence, tacrolimus was discontinued (switched to cyclosporine), and 60 mg/day of propranolol was recommended for the symptomatic of treatment of her tremor. However, because of bronchoconstriction, propranolol was switched to 50-mg primidone three times per day. Within 3 days after discontinuation of tacrolimus and introduction of primidone, her tremor markedly subsided [Video 2]. Furthermore, after 4 days, primidone was discontinued, since the effect of the offending medication (tacrolimus) had presumably worn off by then. The patient was re-examined 5 days after discontinuation of primidone and the tremor had resolved [Video 3].
| Discussion|| |
This report highlights the importance of detailed assessment of medications in patients with subacute onset de novo involuntary movements. An earlier study described the spectrum of tacrolimus neurotoxicity in 44 patients and reported severe postural hand tremor in 23% (2–30 days after the initiation of tacrolimus). A recent study reported tremor in 82% patients on tacrolimus after kidney transplantation. The exact mechanism of tacrolimus-induced neurotoxicity is not known; however, it is speculated that increased production of endothelin and toxic free radicals from tacrolimus-induced mitochondrial dysfunction play a role., Since tacrolimus is a highly lipophilic drug that binds to plasmatic low-density lipoprotein, several factors related to lipid homeostasis have been speculated to have an association with the emergence of neurotoxicity. These include the following: (i) low cholesterol level, especially low-density lipoprotein, which may potentially increase the free concentration of the drug and (ii) increased expression of the low-density lipoprotein receptors in the astrocytes present in the blood–brain barrier, which may potentially augment the entry of the drug to the central nervous system. The severity of tacrolimus-induced tremor may not have a linear relationship with the plasma tacrolimus concentration.
Symmetric action tremor of the upper limbs with or without rest tremor is the most commonly reported manifestation of tacrolimus-induced tremor. Craniofacial and lower limb tremor are relatively less common. In addition to upper limb tremor (rest + action), our patient had lower limb postural tremor, lingual tremor, and vocal tremor, none of which have been clearly elucidated in previous studies. Patients continue to experience tremor for a few days even after discontinuation of tacrolimus, due to its long half-life. Hence, symptomatic treatment of debilitating tremor is important, and any of the antitremor medications (propranolol, benzodiazepine, primidone) may be tried for the same. Unfortunately, our patient experienced bronchoconstriction with propranolol, which necessitated the introduction of primidone, and the tremor subsided within a day. She remained almost tremor free (she had subtle intention tremor) even after discontinuing primidone for 6 days, which reinforces the fact that her tremor was indeed caused by tacrolimus toxicity. As mentioned above, there are other drugs such as cyclosporine and sirolimus that are pharmacologically close to tacrolimus, yet they possess a relatively lower propensity to induce tremor. Therefore, patients with distressing tacrolimus-induced tremor may be switched to the other aforementioned drugs. A clinical trial reported that switching from an immediate-release formulation of tacrolimus to an extended-release formulation resulted in a clinically meaningful improvement in hand tremor in kidney transplant patients. Therefore, if available, an extended-release formulation of tacrolimus may be preferred over an immediate-release formulation.
| Conclusion|| |
Tacrolimus-induced tremor predominantly manifests with a combination of rest and action tremor of the upper limbs, but it may also involve the lower limbs, tongue, and voice. Tremor may emerge even when the blood tacrolimus level is within the therapeutic range, and the tremor severity has no linear relationship with the plasma concentration of tacrolimus. Based on our observations, we suggest that primidone may be considered for the temporary symptomatic treatment of tremor.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
- (1) Research Project:
- A. Conception,
- B. Organization, C.Execution
- (2) Manuscript:
- A. Writing of the First Draft,
- B. Review and Critique.
A.L.: 1A, 1B, 1C, 2A
C.K: 1B, 1C, 2A
M.S: 1B, 1C, 3B
N.H: 1A, 1B, 2B
G.M: 1A, 1B, 2B
Ethical compliance statement
Formal approval from the Institution Ethics Committee was not necessary as this is a case report involving a single patient who had provided informed written consent.
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Conflicts of interest
There are no conflicts of interest.
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Department of Neurology, MedStar Georgetown University Hospital, Washington, DC - 20007.
Source of Support: None, Conflict of Interest: None