Successful Use of Intravenous Tissue Plasminogen Activator as Treatment for a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report and Review of Literature

Case Studies

Successful Use of Intravenous Tissue Plasminogen Activator as Treatment for a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report and Review of Literature Muhammad Taimoor Khan,

MD,

Ann Murray,

MD,

and Matthew Smith,

MD

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a common cause of hereditary stroke caused by mutation of the NOTCH3 gene. Evidence against the use of intravenous tissue plasminogen activator (IV tPA) has been suggested due to possibility of hemorrhage. We present a case of a patient with CADASIL who was successfully treated using IV tPA. Methods: A case description of a female patient who presented with stroke-like symptoms was a previously known case of CADASIL. Review of literature was done using search terms such as CADASIL, NOTCH3, and intracranial hemorrhage or brain hemorrhage. Results: A 35-yearold female patient presented to the emergency department with acute onset hemiparesis, hemiparesthesia, and motor aphasia with a National Institutes of Health Stroke Scale score of 8. The patient was a previously diagnosed case of CADASIL with a positive NOTCH3 mutation. Computed tomography scan showed no large vessel occlusion with no perfusion deficient. Patient was within window for IV tPA treatment which was administered, and she subsequently had marked improvement of all symptoms. Conclusion: There is slight evidence against the use of IV tPA for CADASIL patients who present with stroke-like symptoms but nothing is concrete. It has also been suggested that some patients who are undiagnosed have been treated with IV tPA with favorable results but unfortunately are not reported. Further studies and or large clinical trials could be beneficial for those patients who may benefit from IV tPA and who have previously been diagnosed with CADASIL. Key Words: Stroke—CADASIL—tPA—genetic—complications. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

From the Department of Neurology, West Virginia University, Morgantown, West Virginia. Received October 17, 2015; accepted December 9, 2015. The results of this case report have not been presented at any meeting or conference nor was there any grant support for this project. Address correspondence to Muhammad Taimoor Khan, MD, Department of Neurology, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.12.006

Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenetic cause of stroke secondary to mutations of the NOTCH3 gene on chromosome 19. CADASIL is characterized by a constellation of migraine with aura and subcortical strokes that lead to cognitive dysfunction.1 The pathophysiology of CADASIL is not well understood, but at least 3 theories have been proposed.2 On the basis of histopathology, the disease is characterized

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by degeneration of the medial smooth muscle cells and replacement with nonamyloid eosinophilic granular material.3 Large vessel occlusion or cortical stroke in CADASIL is rare and the P380P mutation may be protective, but the incidence is not zero.4,5 A PubMed search using the terms “CADASIL” and “thrombolysis” yields only 1 result, which lists thrombolysis as a contraindication for CADASIL patients because of presumed hemorrhage risk.6 Intracranial hemorrhages (ICH) have been described as spontaneous events in CADASIL patients, and microbleeds being described in an estimated 31%-69% of CADASIL patients.7-9 In this paper, we present a case of a known CADASIL patient presenting as an acute stroke to our emergency department and successfully being treated with intravenous tissue plasminogen activator (IV tPA) without ill effects, which will represent the first published case of IV tPA usage in a known CADASIL patient. We also present a brief literature review of the risks of hemorrhagic complications in CADASIL.

Case Report A 35-year-old female presented to our emergency department with acute onset of right-sided hemiparesis, hemiparesthesia, and transcortical motor aphasia, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 8. 8 The patient had a known diagnosis of CADASIL with positive NOTCH3 mutation, specifically at C406T (Arg110Cys), and prior history of subcortical strokes. She took aspirin 325 mg and atorvastatin 40 mg daily prior to admission and had been compliant with these medications. She immediately underwent a computed tomography scan with angiography that showed no large vessel occlusion, perfusion deficit, acute loss of gray–white junction, or hemorrhage. She was within the extended window (3-4.5 hours) for IV tPA treatment. After a lengthy discussion of risks and benefits of treatment, including the unclear nature of her hemorrhage risk, the patient opted to try IV thrombolysis with tPA. Within the next several hours after treatment, the patient’s symptoms improved and she felt back to her baseline. She underwent a magnetic resonance imaging brain scan which showed no new areas of diffusion restriction and no areas of gradient echo signal positivity, but showed extensive subcortical T2 hyperintensity, which was seen throughout including the anterior temporal regions consistent with prior subcortical infarcts and the diagnosis of CADASIL. The patient was discharged and continued on her current regimen of secondary stroke risk reduction of aspirin and atorvastatin.

Methods of Literature Review To explore published cases of ICH in CADASIL, PubMed was searched using a combination of terms (CADASIL,

OR NOTCH3, OR “Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy”) AND (“intracranial hemorrhage” OR “brain hemorrhage” OR “brain bleed”) which was more inclusive than prior published literature review method.10 The abstracts of each identified paper were evaluated for the inclusion criteria. Inclusion criteria were case reports or series that included patients’ specific information as to possible risk factors and associations in CADASIL patients. Exclusion criteria were papers that were not peer reviewed, opinion pieces, not in English, and reviews that did not have at least 1 case reported within it. Papers meeting the inclusion criteria were read in complete form. The bibliographies of the identified papers were hand searched for references that were missed by the PubMed searches.

Literature Review Results The published cases of ICH are summarized in Table 1, which admittedly only represents 9 additional cases after the work of Rinnoci et al.10 A PubMed using the above criteria yielded 62 papers with the terms used by Rinnoci et al yielding 12 papers.10 In total, 35 cases of ICH were identified in the literature, with one being excluded secondary to it not being in English.24 Of the identified case, the average age was 58 years old. Antiplatelet agents were identified for at least 9 of these cases, representing only 26% of all the cases reported. Microbleeds were identified in nearly all cases of ICH. There were no cases of hemorrhage related to IV thrombolysis usage in CADASIL.

Discussion CADASIL is typically progressive and debilitating with 85% of patients having strokes starting anywhere from 19 to 67 years old with a global decline in function, mood disorder, and a median age at death of 65 years in men and 71 years in women.25,26 CADASIL has also been associated with microbleeds and overt ICH. The incidence of microbleeds has been reported in 31%-69% of CADASIL patients.8,9 Our search only yielded a total of 34 published cases of nonmicrobleed hemorrhage in patients with CADASIL with microbleeds being present in most of the published cases of ICH (Table 1). The risk of hemorrhage may be increased because of loss of autoregulation, which may lead to microbleeds, and/or the hemorrhagic conversion of prior ischemic strokes,27 but the actual mechanism is unknown.9,28 Additional risks for hemorrhage are age,9 diabetes, and hypertension.9,29 In one study that showed a correlation of hemorrhage with antiplatelet therapy, once patients were corrected for age this association was no longer statistically significant.7

Author, year

Number of patients

Gender

NOTCH3 mutation

Age (years)

Microbleeds (number)

ICH site

Vascular risk factors

Medication risk factors

MacLean, 20057

1

M

R133C

56

Frontal lobe

1

RagoschkeShumm, 200511 Choi, 200612

1

F

47

Cerebellar

>25

5

F 2, M 3

44-85

BG Thalamus Cerebellum Parietal

3-54

HTN HLD DM EtOH

Antiplatelet

Oh, 200813

1

M

NOTCH mutation not detected in this case R578C R544C R544C R544C 1 N/A R544C

39

Left temporal lobe

8

Aspirin

Choi, 201314

9

Did not classify between male and female

90% R544C

35-69

3-54

Werbrouck, 200615 Lee, 200916

1

M

R182C

45

5

F 1, M 4

Anticoagulant Statin None

1

M

41 56 52 50 34 46

HTN HLD HTN

Sano, 201117

R133C R544C R544C R544C R544C p.Arg332Cys

BG Thalamus Lobar Cerebellum Putamen Internal capsule Thalamus Thalamus Temporal and putamen Parietal Putamen Putamen

HTN Smoking Alcohol HTN

Smoking

Antiplatelet

Pradotto, 201218

1

M

Arg680Cys

65

Frontal lobe

GRE sequence findings not mentioned in paper 3

None

Delgado, 201119 Rinnoci, 201310

1 4

M F 1, M 3

55 54, 58, 67, 77, 39

Lian, 201320 Mehta, 201321 Owen, 201322

1 1 1

M F M

Declined genetic test p.Arg1231Cys p.Arg1231Cys p.Arg728Cys p.Cys1298Phe A90C G1336T C268T

46 55 42

Subcortical hemisphere Thalamus/IC Thalamus/IC Thalamus/IC SAH (interpeduncular) BG Cerebellum Vitreous hemorrhage

GRE not shown in paper 25 2 5 25 18 Several None

Low-dose low molecular weight heparin None None

Oh, 201423

1

F

P1008S

46

Pontine

Massive confluent

6 Microbleeds were not surveyed because T2weighted GRE was not performed in study

Nicotine and alcohol dependence HTN (fundus lesions)

None HTN Smoking (past), HLD

Smoking None None-risk factors were excluded HTN (140/99 mmHg) on presentation

None None

Antiplatelet

CADASIL PATIENT TREATED WITH IV TPA: CASE REPORT REVIEW OF LITERATURE

Table 1. PubMed search results and summary

Statin None None None

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Abbreviations: BG, basal ganglia; DM, diabetes mellitus; EtOH, ethyl alcohol/ ethanol; GRE, gradient echo; HLD, hyperlipidemia; HTN, hypertension; IC, internal capsule; ICH, intracranial hemorrhage; SAH, subarachnoid hemorrhage.

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The subcortical nature of the infarctions may make the NIHSS a poor predictor of disability with a nonacute NIHSS score of less than 6 having only a 33.3% specificity for modified Rankin Scale score of less than 3.28 Although, large vessel occlusion or cortical strokes in CADASIL are rare with the P380P mutation possibly being protective, the incidence is not zero.2,3 It is unclear if an elevated NIHSS, as in this patient, would be predictive of a larger vessel occlusion. The very nature of CADASIL involving silent, progressive subcortical strokes and microhemorrhages could be argued as a contraindication in some patients, but possibly not in others depending on the individualized risk-benefit ratio. A PubMed search using the terms “CADASIL” and “thrombolysis” yields only 1 result, which lists thrombolysis as a contraindication for CADASIL patients because of presumed hemorrhage risk.4 Other review authors argue that ischemic stroke is possible in CADASIL patients and they should be treated with IV thrombolysis if they meet the criteria.5 The American Heart Association/American Stroke Association guidelines for stroke therapy list history of previous ICH or prior stroke in the last 3 months as exclusions, but CADASIL is not listed specifically.6 It is intuitive that other CADASIL patients have been treated with IV tPA before, particularly early in the disease prior to genetic diagnosis, but have not been reported in the literature. Given the relatively low number of published cases in the literature, there is likely a spectrum of disease for which avoidance of therapeutics with increased hemorrhagic risk may be reasonable in some but not in others.

Conclusion Further study needs to be undertaken to assess the potential risks posed by factors such as microbleeds, age, hypertension, and diabetes, particularly in the setting of stroke intervention and secondary stroke prevention. We hope that this case generates further study into this topic. It remains unclear if IV thrombolysis should be withheld from patients with CADASIL presenting with what appears to be a large vessel occlusion at this time based on the available literature with a likely increased but illdefined risk of hemorrhagic complications.

Ethical Standards and Patient Consent We declare that all human and animal studies have been approved by the “West Virginia University Institutional Review Board” and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The patients’ informed consent was waived as per the Institutional Review Board approval of this retrospective study.

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