Relapse of Takayasu arteritis as a cause of suicidal poisoning and subsequent major ischemic stroke successfully treated with thrombolytic therapy

Introduction. Takayasu arteritis (TA) is a rare large vessel arteritis, affecting primarily aorta and its major branches. Its clinical manifestations can vary significantly – from asymptomatic to serious vascular events. Acute neurological complications are frequent at the onset of the disease and in relapses. Anxiety and depression are more frequent in TA patients than in general population as well as during relapses. Prevalence of transient ischemic attack or ischemic stroke in TA patients is approximately 10–20%. Case report. We presented a patient with TA that began with a depressive episode resulting in attempted suicide by bromazepame poisoning. This was subsequently followed by major ischemic stroke caused by thrombosis of the left middle cerebral artery (probably due to aortic arch embolism) successfully treated with intravenous thrombolysis. Conclusion. Intravenous thrombolysis appears to be safe and effective in patients with TA and stroke.


Introduction
Takayasu arteritis (TA) is a large vessel arteritis, affecting primarily aorta and its major branches.Its clinical manifestations can vary significantly -from asymptomatic to serious vascular events, occurring both at the beginning of the disease and during relapses (i.e.active phase).In the presented case, relapse of the disease began with a depressive episode resulting in attempted suicide by bromazepame poisoning.Ischemic stroke occurred subsequently, also in the active phase of the disease, and was successfully treated with intravenous thrombolysis.
To the best of our knowledge, this is the first report of TA relapse manifesting with depression and attempted suicide, followed by ischemic stroke and successful intravenous thrombolysis.

Case report
A 61-year old female was found in a state of unconsciousness, on the floor of her home with a scalp laceration.The patient was in a shallow coma, Glasgow Coma Scale (GCS) score 7 with otherwise unremarkable neurological examination, subfebrile (37.2 о С) and hypotensive (80/60 mmHg) with ECG showing regular sinus rhythm at a rate of 68/min.She was initially examined in the local hospital, intravenous dopamine and normal saline were administered, and head laceration was sutured.Multislice computed tomography (MSCT) of the head was done at local hospital and no signs of ischemia, hemorrhage, or other brain lesions were noted.
Drug overdose was suspected since empty packages of prescribed medications were found in her vicinity and she was transported to the Military Medical Academy for toxicology screening.Upon admission to emergency room, benzodiazepine antagonist -flumazenil (0.2 mg iv) was administered with partial improvement of consciousness.She was admitted to the Toxicology Clinic in a soporous state (GCS 9), with slurred speech and unresponsive, miotic pupils.Bromazepame plasma concentration was 1.02 mg/L (levels above 0.3 mg/L are considered toxic, coma is virtually invariable above 1.0 mg/L) with serum positive for 3-OHbromazepame metabolite (this suggests even higher blood levels of bromazepame than those detected).Toxicology screening for ramipril and amlodipine (concomitant therapy, also suspected in overdose) were negative.Laboratory analyses at this time showed marked leukocytosis of 22.1*10 9 (normal values: 4-11*10 9 /L) and very high creatine kinase levels of 4,390 (normal 26-200 U/L).Leukocytes remained elevated throughout the course of treatment (> 20*10 9 /L).Acute phase reactants -erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values at that time were unavailable.The patient was treated with flumazenil in the total dose of 2.3 mg during three days, rehydrated, intubated with continuous cardiorespiratory support and had good recovery further on.From day four she was fully alert and responsive, with unremarkable neurological exam.There was no record in personal medical history regarding depressive disorder or previous suicide attempts.The patient and her family denied any psychiatric symptoms prior to this.According to the patient, an argument with her daughter provoked her to act in this manner.Psychiatric exam found her to be suffering from an anxious-depressive disorder without current suicidal tendencies, and she was prescribed with trazadone 50 mg/day and lorazepame 3 mg/day.The personal history revealed that she was diagnosed with TA, at the age of 59, according to the current criteria 1 .The disease was presented a few months prior to diagnosis, with general weakness, malaise, arthralgia and low-grade fever.During hospitalization at that time, significantly elevated acute phase reactants were noted, while cardiac ultrasound showed only mild aortal sclerosis.However, position emission tomography (PET) scan showed increased accumulation of fluorine-18 fluorodeoxyglucose (18F-FDG) in the projection of all of the major aortic branches (brachiocephalic trunk, carotid and subclavian arteries) and MSCT aortography showed aortal wall thickening (4.5 mm) from descendent part to iliac arteries.Corticosteroid and azathioprine therapy was introduced as regular long lasting treatment.
Several months prior to attempted suicide, the patient on her own stoped taking recommended therapy.Besides this, she was treated with ipratropium bromide /fenoterolhydrobromide for chronic obstructive pulmonary disease, and was taking medium doses of ramipril, hydrochlorothiazide and nifedipine for arterial hypertension.The personal history also revealed the presence of fatty liver, gallbladder calculosis and chronic gastritis.
On the ninth day after admission, while still not taking immunosuppressive drugs, acute neurological impairment occurred, manifested as sensorimotor aphasia and severe right-sided weakness.National Institute of Health Stroke Scale (NIHSS) score was 13.She was normotensive, ECG showed regular sinus rhythm.MSCT of the brain showed discrete zone of subcortical hypodensity in the left operculum (Figure 1), while MSCT brain angiography showed left medial cerebral artery (MCA) occlusion (Figure 2).Besides this, a few chronic ischemic lesions in the left lentiform and caudate nucleus and right subcortical frontal regions were observed (Figure 1).

Fig. 1 -Multislice computed tomography (MSCT) axial noncontrast head scan shows left opercular hypodense lesion corresponding ischemia.
Since the patient was in therapeutic window for thrombolysis, 1 hour from symptoms onset, intravenous recombinant tissue plasminogen activator (rTPA) was administered according to standardized protocol 2,3 .During the first 24-hour observation period, a significant clinical improvement was noted, primarily improvement of speech (minor dysphasia) and of right hand limb strength, NIHSS being 7. Control brain MSCT with angiography 24 hours after thrombolysis showed M2 and M3 segments patent, presumably through collaterals and M1 occluded.No radiological signs of acute ischemia were noted.Thrombolytic therapy was without brain hemorrhage or any other medical complication (Figure 3).The patient was released from hospital ten days after ischemic stroke (18 days from the attempted suicide).NIHSS upon release was 2 -a discrete right facial paresis and a minimal right hand paresis.She was advised to take aspirin 100 mg/day, atorvastatin 40 mg/day, methylprednisolone 20 mg/day for two weeks, then 15 mg/day, trazadone 50 mg/day and lorazepame 3 mg/day proscribed by psychiatrist and her usual bronchodilatative and antihypertensive therapy.
At follow-up visits, after one and six months, inflammation parameters (ESR and CRP, as well as complete blood count) were within normal range, the patient did not have new neurological, psychiatric nor any other symptoms, and overall recovery was good.subsequent development of major ischemic stroke, severe neurological impairment and successful thrombolytic treatment.Elevated parameters of systemic inflammation confirmed TA relapse 3 .Disease activity affects quality of life and mental and functional status in TA patients.Anxiety was found to be significantly higher in TA patients than in healthy controls 4 .Depression is twice more common in TA patients 5 .However, anxiety and depression have significantly higher incidences in active disease than in remission 5 .There are no published papers assessing incidence and prevalence of suicide attempts and suicides in patients with TA.To the best of our knowledge, this is the first published case of suicide attempt as principal manifestation of TA relapse.
Takayasu arteritis is a relatively rare systemic vasculitis with estimated incidence of 2.6 per million 5 .Spectrum of TA symptoms is wide, ranging from asymptomatic to serious, often psychiatric and neurological manifestations 6,7 .Natural course is virtually unpredictable regarding initial presentation, onset of disease activity and symptom severity 8 .Asymptomatic progression is not uncommon [6][7][8][9] .The first symptoms of TA in our patient appeared at 59 years, which is rather late considering the second and the third decade of life as the usual time of TA clinical presentation 6 .Most frequent neurological symptoms are headache, dizziness, visual disturbance, transitory ischemic attacks and ischemic stroke 6,7,9 .
Literature data regarding ischemic stroke due to TA is sparse and consists mostly of case reports and case series [10][11][12][13][14][15][16][17][18] .There are only few, mostly retrospective studies currently available assessing stroke in the setting of TA 9 .The prevalence of ischemic stroke in patients with TA is found to be, depending on study, between 5% and 15%, especially at the onset of the disease and during the relapses [11][12][13][14][15][16] .Etiology of ischemic stroke in patients with TA is various: artery-toartery embolism -from aortic arch and its major branches, carotid stump syndrome, hypercoagulable state, or cardiogenic emboli due to aortic regurgitation 9 .Thrombosis of the left middle cerebral artery was the cause of major ischemic stroke in our patient, probably due to aortic arch embolism.Other possible causes of stroke were excluded -cardiogenic embolism, carotid artery embolism, thrombophilias, hypertension and atrial fibrillation.
The presence of TA is not regarded as contraindication for intravenous thrombolysis in patients with stroke according to present guidelines for acute ischemic stroke treatment 2 .Reported cases of rTPA use in TA patients with acute ischemic stroke are extremely rare and in the available literature there is only one published paper 10 .Furthermore, there are no randomized clinical trials regarding therapy of neurologic complications in TA.R-TPA application in presented case resulted in the complete recovery without complications.
Therapeutic approach in TA is oriented in general to diminishing disease activity with corticosteroids and immunosuppressants 19 .The presented patient did not take recommended corticosteroid and immunosuppressant therapy, which was a probable cause of TA relapse.Treatment of arterial hypertension and other secondary manifestations is also advised in order to decrease the incidence of end-vessel pathology 8 .Low dose aspirin use could be associated with lower frequency of repeated ischemic events in patients with TA 20 , and this was our therapeutic choice as secondary prevention.

Conclusion
Acute psychiatric and neurological symptoms in patients with TA are more frequent than in general population, and tend to occur more often during relapses.This is, to the best of our knowledge, the first reported clinical case of suicide attempt caused by TA relapse, as well as one of the two reports of successful intravenous thrombolysis after ischemic stroke in a patient with TA.Intravenous thrombolysis with rtPA appears to be safe and effective in patients with TA and stroke.