Authors: Aslanidis Th1a*, Drampa F2a, Mytkani K3b, Syrmou E4c
1 MD, PhD, Anesthesiology – Critical Care – Prehospital emergency medicine
2 MD, Anesthesiology – Critical Care,
3 MD, PhDc, Neurology
4 MD, MSc, PhD, Neurosurgery – Prehospital Emergency Medicine
a Intensive Care Unit, Saint Paul General Hospital, Thessaloniki, Greece
b Neurology Clinic, Saint Paul General Hospital, Thessaloniki, Greece
c 2nd Division, National Center of Emergency Care, Thessaloniki, Greece
Therapy armamentarium for multpile sclerosis include a variety of drugs. Natalizumab, a humanized antibody, is widely used in relapsing-remissing multiple sclerosis. Anticonvulsants, like topiramate, are also widely used for symptomatic relief. We hereby describe a case of Status epilepticus and topiramate induced metabolic acidosis in a female patient with multiple sclerosis under natalizumab therapy.
Multiple sclerosis (MS) is the most common demyelinating and neurodegenerative inflammatory disease in adults between 18 and 35 years of age and constitutes the second cause of neurological disability in young adults1.
There is no definite cure for multiple sclerosis (MS). Treatments available aim at relieving symptoms of the disease, treating acute exacerbations, shortening the duration of an acute relapse, reducing frequency of relapses, and preventing disease progression (disease-modifying drugs)2.
Natalizumab is a monoclonal antibody that acts as an α4 integrin) antagonist to prevent leukocyte trafficking into central nervous system (CNS). Natalizumab’s high efficacy has led to a broad use in MS both as first and second line treatment3. Topiramate, an anticonvulsant with several mechanisms of actions, is used in MS patients as symptomatic treatment for tremor, spasticity, dysaesthetic pain2.
In this report, we describe a case of Status epilepticus and topiramate induced metabolic acidosis in a female patient with multiple sclerosis under natalizumab therapy.
A 44-years old female patient was transported to Emergency Department (ED) with Mobile Intensive Care Unit (MICU) due to Status Epilepticus. Her medical history included MS (ICD10– G35) with Kurtzke Expanded Disability Status Scale (EDSS) ambulation score 6.0 and Functional System score (FSS) 5, under topirmate 50 mg p.os q.d., bromazepam 3mg p.os. q.h.s. and natalizumab 300 mg i.v. q 28d for the last 4years. A recent (4 months before) Magnetic Resonance Brain Imaging was also available. The last therapy with natalizumab was delivered 4 hours before the beginning of the seizures. Before infusion, the patient was examined for signs of infections or progressive multifocal leukoencephalopathy.
Initial treatment included diazepam 10 mg i.v. at home; yet due to continuous generalised tonic-clonic seizures, the patient received also levetiracetam 1000mg iv bolus and another 1000mg as c.i.v. infusion till arrival to the hospital. Upon arrival at hospital, seizures were controlled. Total duration of seizures was 35 min and recorded STESS (Status Epilepticus Severity) score:2.
Clinical examination at Emergency Department revealed hypotension (Blood Pressure – 140/85 mmHg), tachycardia (Heart Rate – 140 bpm), relative bradypnea (Respiratory rate of 9 bpm) with measured SpO2 in air of 85% and body temperature of 38.9o C. Neurological examination records consist of a Glasgow Coma Scale (GCS) of E1/V1/M4, normal pupils’ size and reaction, yet with left upwards gaze and positive Babinski sign in both legs. Initial arterial blood gases (ABG) analysis revealed acidosis with pH: 7.23, PaCO2:72.8 mmHg, PaO2 :50.9 mmHg (at FiO2:30%), Glu: 174 mg/dl, Lac: 1.3 mmol/l. Hb:11.5 gr/dl. Rapid Sequence Intubation (RSI) where performed, the patient was transported to computer scan (CT) imaging of chest and brain, where no serious abnormalities were noted; and then admitted at Intensive Care Unit. Calculated initial severity scores were: APACHE (Acute Physiology and Chronic Health Evaluation) II 21, SAPS II (Simplified Acute Physiology Score) 35 and SOFA (Sequential Organ Failure Assessment) score 5. Upon admission, Cerebral Spine Fluid (CSF) was also performed with normal biochemical results, and negative microbiological panel (Table 1). Diagnostic test for SARS-Cov2 (bronchoalveolar lavage-BAL) was also negative. Microbiological cultures from blood, BAL and urine were also negative.
Table 1. Microbiological panel tested.
|Esherichia coli||Herpes simplex virus – 1 (HSV-1)||Chlamydia pneumonia||Streptococcus pneumoniae|
|Haemophilus influenzae||Herpes simplex virus – 2 (HSV-2)||Chlamydia psitaci||Neisseria meningitidis|
|Listeria monocytogenes||Human herpesvirus 6 (HHV-6)||Legionella spp.||Streptococcus spp.|
|Neisseria meningitidis||Human herpesvirus 7 (HHV-7)||Mycobacterium tuberculosis||Staphylococcus aureus|
|Streptococcus agalactiae||Varicella zoster virus (VZV)||Parvovirus Β19||Pseudomonas aeruginosa|
|Streptococcus pneumoniae||Cryptococcus neoformans gattii||Κυτταρολογικός έλεγχος||Haemophilus influenzae|
|Cytomegalovirus (CMV)||Adenovirus||Haemophilus influenza||Listeria monocytogenes|
|Enterovirus||Human polyomavirus 2 (JCV)|
Initially ICU therapy included sedation and analgesia with midazolam, fentanyl infusion, with early (2nd day) change to propofol and remifentanil continuous venous infusion targeting a Richmond Agitation Sedation score (RASS) around 0 and Critical Care Pain Observation Tool (CPOT) tool of 0-1. Antiepileptic regiment included levetiracetam 1gr q 12h i.v. and topiramate 100 mg p.os q.d. Yet, during the first 8 days, right arm tremor was periodically spotted. The latter was initially treated with propofol boluses, yet it significantly reduced with increased levetiracetam dosing (1.5gr q12h). The rest of her drug regiment included empiric antibiotics treatment (clindamycin 600mg/8h iv, ampicillin/sulbactam 3gr/6h iv), gastric ulcer antithrombotic prophylaxis.
Daily temperature rises up to 38.4oC with concominant tachycardia (treated with metoprolol 50mg t.i.d. p.os) despite negative repeated microbiological samples, no infection related laboratory results and addition of amikacn 10 mg/kg iv qd after the 4th day; along with a refractory covert metabolic acidosis despite mechanical ventilation raised the suspicion of a toxic effect (Table 2, Table 3).
Topiramate administration was stopped at the 8th day of her hospitalization and 2 days later both fever and metabolic acidosis reversed. Atthe morning of the 12th day, left arm tremor also seized.
A day later she was discharged from ICU without any sequels. neurological evaluation revealed impaired cognitive functions and memory and instability. Motor function gradually returned to baseline. A subsequent MRI of the brain did not reveal any new changes, comparing to the one before the incident (Supplemental file).
Table 2. Selected Laboratory exams during ICU hospitalization.
Hct- haematocrit (%),
Hb- haemoglobin (g/dl),
WBC- white cells (k/μl),
CRP- c reactive protein (mg/dl),
Glu- glucose (mg/dl),
Cr – creatinine (mg/dl),
Ur -urea (mg/dl),
BUN- blood urea nitrogen (mg/dl),
Prtot- Protein total (g/dl),
CPK- creatine phosphatase (mg/dl)
Table 3. Time course of Arterial Blood Gases exams during ICU hospitalization.
PaO2 – arterial partial oxygen pressure (mmHg),
PaCO2 – arterial partial carbon dioxide pressure (mmHg),
FiO2 -fraction of inspired oxygen (%),
HCO3 – bicarbonates (mEq/l), Lac – Lactate (mmol/l),
BE – base excess,
AGc – anion gap corrected.
Natalizumab is a humanized antibody that acts mainly towards α4β1 integrin (also known as very late antigen, VLA-4) a molecule that mediates migration of immune cells to the inflamed brain. Dosing includes 300mg infusion every 4 weeks achieving a mean plasma concentration of 110 ± 52 µg/m, while its half-life is 11 ± 4 days3-4. Several studies have proven its utility in MS, as it reduces disease activity and progression; and it has positive effects on cognition, depression, fatigue, and quality of life4. Today it is used mainly in relapsing-remitting MS (RRMS)4-5.
Natalizumab side effects vary from allergic reactions, pharyngitis, urinary tract infections, utricaria, arthralgia, fever to more serious drug induced liver injury (DILI), drug-induced immune thrombocytopenia, erythroblasts abnormalities, recurrent vaginitis, HSV infections, primary central nervous system lymphoma3-6. Serious problem is also emergence of a potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JCV with reported incidence of 3.4/1000 (95% CI 3.08–3.74) in Natalizumab treated MS patients, with higher risk in those with history of therapy duration over 2 years.3-5. In big series, up to 9% of patients reported unexpected side effect (in 62.5% of which severe) such as tachycardia, blurred vision with anxiety crisis, pneumonia, and increased γ-glutaryl transferase; while other reports mention cyclical suicidal ideation, myocardial infarction, retinal necrosis and cutaneous sarcoidosis-like reactions 7-9.
Topiramate is a sulphamate anticonvulsant used apart from treatment of epilepsy, for a numerous other conditions, such as migraine, bipolar disorder, post-traumatic stress disorder, alchohol dependence, bulimic nervosa, tobacco dependence, obsessive –compulsive spasm, idiopathic intracranial hypertension, infantile spasms and neuropathic pain10. Due to a molecular structure like acetazolamide and to inhibiting carbonic anhydrase enzyme activity, it can lead to renal tubular acidosis (type 3), as result of ultrafiltration and reabsorption of bicarbonate in both proximal and distal tubules. Clinical presentation varies from mild to severe, often accompanied with nephrolithiasis, hyperventilation, and osteopenia. Other acidosis producing diseases such as chronic renal failure or infection may aggravate patient’s condition, though genetic polymorphism of carbonic anhydrase isoenzymes may also play a role10-11. Hiperidrosis and hyperthermia (to the point of heatstroke with maximum temperature of 41.1oC) have also been reported both in children and in adults12. Suspension of drug use is the only reported efficient strategy to reverse the above conditions.
In our case, we believe that metabolic acidosis and daily temperature rise is caused by topiramate administration. Increased dosing regiment (compared to patient’s baseline) may contribute to aggravation of the condition, as we cannot exclude the absence of mild symptomatology before hospital admission (while on lower daily regiment). Discontinuation of topiramate reversed both conditions. Another interesting fact is time connection with natalizumab administration and onset of status epilepticus. Microbiological and imaging evaluation for PML was negative. Though there is scarce data (one report) that natlizumab therapy may reduce seizure activity in MS14, we cannot exclude drug-triggered epilepsy. Right arm tremor, which initially treated as inadequate sedation, reduced with increased anticonvulsant therapy, and eventually ceased at a timetable in accordance with natalizumab’s half-time; reinforces our hypothesis. Other hypotheses could for emergence of epilepsy could be a new small cortical or juxtacortical MS lesion or an immune reconstitution inflammatory response syndrome; yet these are more distant probabilities15. Available data from long term use of natalizumab do not report any drug -induced seizures16, yet the overall relative literature is limited.
The above patient seems to have suffered from unexpected complications of 2 drugs arisen at the same time. Though clinicians are always in alert for therapy side effects; situations where side effects are emerging simultaneously from two (or more) drugs can be extremely challenging to handle; especially when clinical manifestation is out of the expected range. Thorough daily analysis of the available data and testing unconventional hypotheses may be helpful in this condition.
Conceptualisation: T.A.; Case Management: E.S, T.A, F.D; Literature Review: T.A, K.M. Draft preparation: T.A., K.M.
Availability of supporting data
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethical approval and consent to participate
No IRB approval required.
The authors would like to thank Dr. Ourania Agalliadou-Dioritou, head of the Intensive Care Unit for her support to the management of the case
Consent for publication
Patient consent obtained
The authors declare that they have no competing interests.
Received: December 2020, Accepted: December 2021 Published: March 2021.
- GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019; 18(3): 269–285.
- Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Curr Opin Neurol. 2018;31(6):752-759.
- Hoepner R, Faissner S, Salmen A, et al. Efficacy, and side effects of natalizumab therapy in patients with multiple sclerosis. J Cent Nerv Syst 2014; 6:41-49.
- Brandstadter R, Katz Sand I. The use of natalizumab for multiple sclerosis. Neuropsychiatr Dis Treat. 2017; 13:1691-1702.
- Wang L, Qi CH, Zhong R, et al. Efficacy of alemtuzumab and natalizumab in the treatment of different stages of multiple sclerosis patients. Medicine (Baltimore).2018;97(8): e9908.
- Nixon M, Menger RP, Kalakoti P, et al. Natalizumab-Associated Primary Central Nervous System Lymphoma. World Neurosurg. 2018; 109:152-159.
- Giacoppo S, Ruscica M, Grimaldi LM, et al. The Italian Pharmacovigilance Program: An Observational Study of Adverse Effects of Natalizumab in Multiple Sclerosis Therapy. Med Sci Monit. 2017;23:4230-4240.
- Durcan R, Heffron C, Sweeney B. Natalizumab induced cutaneous sarcoidosis-like reaction. J Neuroimmunol. 2019; 333:476955.
- Darki A, Masoumi P, Soleimani A, et al. Myocardial infarction in a patient with multiple sclerosis after receiving natalizumab. Mult Scler Relat Disord. 2018; 25:26-28.
- Khalil NY, AlRabiah HK, Al Rshoud S, et al. Topiramate: Comprehensive profile. Profiles Drug Subst Excip Relat Methodol. 2019; 44:333-378.
- Fernández-de Orueta L, Esteban-Fernández J, Aichner HF, Casillas-Villamor A, et al. Topiramate-induced metabolic acidosis: a case study. Nefrologia. 2012;32(3):403-404.
- Salek T, Andel I, Kurfurstova I. Topiramate induced metabolic acidosis and kidney stones – a case study. Biochem Med (Zagreb). 2017;27(2):404-410.
- Canel L, Zisimopoulou S, Besson M, et al. Topiramate-induced severe heatstroke in an adult patient: a case report. J Med Case Rep. 2016;10:95.
- Sotgiu S, Murrighile MR, Constantin G. Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report. BMC Neurol. 2010;10:84.
- Clifford D. Neurological IRIS: Riding the tide of immune recovery. Curr Opin Neurol. 2015; 28(3): 295–301.
- Butzkueven H, Kappos L, Wiendl H, et al. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP). J Neurol Neurosurg Psychiatry 2020;91(6):660-668.
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|Citation: Aslanidis Th., Drampa F., Mytkani K., Syrmou E. Status epilepticus and topiramate induced metabolic acidosis in a patient with multiple sclerosis under natalizumab therapy. Greek e j Perioper Med. 2021;20(b):42-49.|
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