Neurol Ther (2018) 7:155–159 https://doi.org/10.1007/s40120-018-0092-1 CASE SERIES Treatment with Botulinum Toxin for Refractory Fever Caused by Severe Spasticity: A Case Series . . . Jacobo Lester Gerardo Esteban Alvarez-Resendiz Enrique Kle ´ riga Fernando Videgaray Gerardo Zambito Received: November 4, 2017 / Published online: January 30, 2018 The Author(s) 2018. This article is an open access publication usual drugs used for hyperpyrexia, type A ABSTRACT botulinum toxin may be an effective treatment option to control both spasticity and fever. Introduction: Brain and spinal cord injuries may cause very severe spasticity that occasion- Keywords: Botulinum toxin; Fever; Spasticity ally may be associated with persistent fever. Case Series: We present 14 patients with spas- ticity and persistent fever, treated with botuli- INTRODUCTION num toxin type A. Their spasticity improved and the fever resolved within a period no The hypothalamus is the regulatory center for greater than 48 h. In all cases, infectious and body temperature in humans , although the other non-infectious causes were ruled out. diencephalon and spinal cord also contribute Conclusions: When sustained tonic muscular . If one of these structures is damaged, tem- activity is associated with a signiﬁcant increase perature elevations above 38.3 C can occur . in body temperature and is refractory to the Temperature elevations of brain origin are associated with increased plasmatic levels of Enhanced Content To view enhanced content for this norepinephrine and dopamine-B-hydroxylase article go to http://www.medengine.com/Redeem/ A12DF0601FC379C1. . In fever of spinal cord origin, the ampliﬁ- cation of its positive feedback mechanism can J. Lester (&) induce and increase sympathetic responses . Neurology/Movement Disorders, Instituto Fever in patients with brain damage is associ- Mexicano de Neurociencias, Hospital Angeles ated with increased mortality [6, 7]; in cases Lomas, Huixquilucan, Estado de Me ´ xico, Mexico with spasticity, this is a diagnosis of exclusion, e-mail: email@example.com and other causes of fever, such as infectious or G. E. Alvarez-Resendiz non-infectious, must be ruled out . Thus, Anesthesiology, Hospital Angeles Lomas, prompt diagnosis of the cause and appropriate Huixquilucan, Estado de Me ´ xico, Mexico treatment are needed. E. Kleriga G. Zambito The production of body heat and fever Neurosurgery, Instituto Mexicano de Neurociencias, results from the interaction of various factors, Hospital Angeles Lomas, Huixquilucan, Estado de ´ such as cellular metabolism, hormonal regula- Mexico, Mexico tion, increased metabolism due to cate- F. Videgaray cholamines such as epinephrine and Internal Medicine/Infectology, Hospital Angeles norepinephrine , and muscular activity . Lomas, Huixquilucan, Estado de Me ´ xico, Mexico 156 Neurol Ther (2018) 7:155–159 Muscular activity is a major factor in the pro- Spasticity was measured using the modiﬁed duction of heat under physiological conditions Ashworth spasticity scale , and we found [1, 2]. severe spasticity in four limbs of eight patients On the other hand, spasticity is commonly (57.14%) and hemibody spasticity in three described as a motor dysfunction in which there patients (21.43%) and in the upper limbs of two is increased muscular tone with an augmented subjects (21.43%). All patients were treated for stretch reﬂex . Spasticity can be severe in their spasticity with BoNTA; 11 patients patients with brain injury (BI) or spinal cord (78.57%) received onabotulinumtoxinA, and injury (SCI) . There are various pharmaco- three (21.43%) received abobotulinumtoxinA. logical treatments for spasticity , but botuli- All patients exhibited improvement of their num neurotoxin type A (BoNTA) is among the spasticity. Before treatment with BoNTA, 11 most efﬁcient and safe treatments for this con- patients (78.57%) had a score of 5, and three dition . (21.43%) patients had a score of 4. At a 2-month Sustained states of muscle contraction have follow-up examination, four patients (28.58%) been reported to cause fever [2, 12–14]. To our improved to a score of 4, six patients (42.86%) knowledge, fever has not been described as a to a score of 3, and four patients (28.58%) to a symptom associated with spasticity. Here, we score of 2 (Table 1). present 14 patients with BI or SCI with severe To our surprise, fever resolved in all patients spasticity who also had refractory fever without (100%) in a period no greater than 48 h; at the an infectious etiology. 2-month follow-up, no recurrence was observed. METHODS DISCUSSION We report 14 cases treated between July 10, 2010, and December 16, 2016, who had BI or The patients described in this report had some SCI with severe spasticity and refractory fever. form of BI or SCI, and as a consequence of this Infectious and non-infectious causes of fever damage, they developed spasticity with con- were ruled out with cultures and with labora- current temperature elevation. In all cases, tory and imaging studies. infectious, inﬂammatory etiology was ruled out. This project was presented to the ethics and The treatment of fever in general should be research committee of our hospital and was speciﬁc for the etiology whenever possible and approved. not just targeted toward the symptom . Similar to reports by other authors, all patients received treatment with antipyretics, muscle RESULTS relaxants and physical methods without an adequate control . The patients included six women (42.86%) and In all cases, there was improvement of spas- eight men (57.14%) aged 21 to 81 years (mean ticity after application of BoNTA, which facili- 45.71 years). The cause of the persistent and tated neurorehabilitation. Fever resolved in no refractory muscular contraction was closed head more than 48 h without any recurrence. Appli- injury in four patients (28.58%), hypoxic cation of BoNTA is an accepted treatment for ischemic encephalopathy in three (21.43%), spasticity [2, 15, 16], and to our knowledge, cervical SCI in three (21.43%), hypertensive BoNTA has not been reported for the treatment intracerebral hemorrhage in one (7.14%), sub- of fever in patients with spasticity. arachnoid hemorrhage in one (7.14%), intrac- There are other pathological entities, such as erebral hemorrhage secondary to complications exertional heat stroke (EHS)  and malignant of carotid artery stent placement in one hyperthermia (MH), in which a disorder of cal- (7.14%), and stroke due to thrombotic throm- cium homeostasis within muscle cells causes bocytopenic purpura in one (7.14%). muscle contraction . MH was ﬁrst described Neurol Ther (2018) 7:155–159 157 Table 1 Patients’ general information No. Gender Age Diagnosis Spasticity Spasticity Spasticity Botulinum (years) anatomical and initial score 2-month toxin type application area score follow-up and units 1 M 32 TBI 4 limbs 5 3 ABTA 1500 IU 2 F 56 Hypertensive hemorrhage 4 limbs 5 3 OBTA 600 IU 3 F 33 HIE 4 limbs 5 4 ABTA 1500 IU 4 M 25 TBI 4 limbs 5 3 OBTA 600 IU 5 F 21 TBI 4 limbs 5 3 ABTA 1500 IU 6 F 51 Left frontal subarachnoid Left hemibody 4 2 OBTA hematoma due to 400 IU cavernous angioma rupture 7 F 80 Ischemic stroke secondary to Left hemibody 5 3 OBTA TTP 400 IU 8 M 34 HIE 4 limbs 5 4 OBTA 600 IU 9 M 35 TBI Left hemibody 5 4 OBTA 600 IU 10 M 54 SCI Upper limbs 4 1 OBTA 400 IU 11 F 54 HIE 4 limbs 5 4 OBTA 600 IU 12 M 76 SCI Upper limbs 5 2 OBTA 400 IU 13 M 36 SCI Upper limbs 4 2 OBTA 300 IU 14 M 53 Brain hemorrhage secondary 4 limbs 5 3 OBTA to carotid procedure 600 IU F female, M male, TBI traumatic brain injury, HIE hypoxic-ischemic encephalopathy, TTP thrombotic thrombocytopenic purpura, SCI spinal cord injury, ABTA abobotulinumtoxinA, OBTA onabotulinumtoxinA as a rare complication of general anesthesia  muscle contraction, there is a persistent but has also been reported in a head injury increase in the free myoplasmic calcium con- patient as well as in one with SCI [18, 19]. centration, producing a biochemical reaction Even though in most cases with spasticity that accelerates mitochondrial activity with an there is no fever associated with sustained increase in oxygen consumption. MH is 158 Neurol Ther (2018) 7:155–159 associated with elevation of the production of More studies should be done in patients with carbon dioxide that depletes aerobic metabo- similar characteristics and should emphasize lism and increases anaerobic metabolism, lead- the causes of fever, as well as how BoNTA ing to an imbalance of intracellular and decreases body temperature in these subjects. extracellular ionic interchange that results in This ﬁnding may also be extended to cases of damage to the myocytes [12, 20]. The inter- dystonia and rigidity. ruption of the active transport across the cell membrane consumes energy due to the high exchange of adenosine triphosphate (ATP); this ACKNOWLEDGEMENTS exchange may be responsible for the tempera- ture elevation in EHS  and MH . There Centro de Neurorehabilitacio ´ n Angeles. Pre- are also situations where other states of sus- sented as a poster in the XLII Annual Congress tained muscular activity, such as dopaminergic of the Mexican Association of Infectology and withdrawal malignant syndrome, which is Clinical Microbiology. Puebla, Puebla, Mexico. associated with rigidity, can cause fever regard- May 24-27, 2017. less of whether they cause muscle damage . To our knowledge, there are no reports of fever Funding. No funding or sponsorship was associated with spasticity. received for this study or publication of this Sustained muscle contraction has been con- article. The article processing charges were sidered as a cause of hyperpyrexia . This funded by the authors. complication ﬁrst appears in the intensive care setting but may persist for months . Authorship. All named authors meet the MH is treated with dantrolene, which inhibits International Committee of Medical Journal the release of calcium from the sarcoplasmic Editors (ICMJE) criteria for authorship for this reticulum with muscle relaxant action. Impor- article, take responsibility for the integrity of tantly, dantrolene does not have any action on the work as a whole, and have given their the neuromuscular junction , but BoNTA does approval for this version to be published. . BoNTA acts as a metalloproteinase with a peripheral cholinergic effect on nerve endings; Disclosures. Jacobo Lester, Gerardo Esteban this effect causes reversible inhibition of presy- Alvarez-Resendiz, Enrique Kle ´ riga, Fernando naptic acetylcholine (Ach) release without Videgaray and Gerardo Zambito have nothing motor neuron loss . After BoNTA is applied to disclose. directly into the muscle, it passes through the endosomal membrane and causes a reversible but Compliance with Ethics Guidelines. The persistent inhibition of neurotransmitter release project was presented to the ethics and research due to intracellular endopeptidase activity against committee of our hospital and was approved. the proteins necessary for Ach release . How spasticity potentially causes fever is unclear. We Data Availability. The datasets generated hypothesize that, if the muscle contraction is the during and/or analyzed during the current cause of fever, BoNTA could reduce the energy study are available from the corresponding imbalance of ATP in myocytes caused by severe author on reasonable request. We conﬁrm that spasticity and directly decrease body temperature. Table 1 is original and was produced by the However, we cannot rule out other sites of action authors for this particular publication. for BoNTA. BoNTA may be a good treatment alternative Open Access. This article is distributed under the terms of the Creative Commons for refractory fever in patients with spasticity. 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