Case Report
Meningeal Disease Masquerading as Transient Ischemic Attack Line Cuinat, MD,* Nathalie Nasr, MD,* Jeanine Manuela Kamsu, MD,† Frederic Tanchoux, MD,† Fabrice Bonneville, MD,† and Vincent Larrue, MD*
Background: Cortical subarachnoid hemorrhage and meningitis sometimes present as episodes of transient neurologic dysfunction mimicking transient ischemic attack (TIA). In the present study, we sought to determine the frequency of meningeal disease among patients treated in a TIA clinic. Methods: Data from patients consecutively admitted to a TIA clinic were retrospectively analyzed. Patients were classified as ischemic events (TIA or minor stroke) or nonischemic events using clinical data and findings from brain imaging and ultrasound studies. Results: Of 529 patients (mean age 63.5 years), 134 (25.3%) were classified as nonischemic events. Meningeal disease was the likely cause of clinical symptoms in 9 patients (1.7%; 95% confidence interval, .6%-2.8%) including 5 patients with meningitis (1 meningeal sarcoidosis, 1 rheumatoid meningitis, 1 myelomatous meningitis, 1 lymphomatous meningitis, and 1 herpes simplex virus 1 meningoencephalitis) and 4 patients with cortical subarachnoid hemorrhage (probably or possibly related to cerebral amyloid angiopathy in 3 patients). Clinical symptoms comprised motor deficit, sensory deficit, aphasia, and dysarthria. Transient neurologic dysfunction was recurrent in 7 of 9 patients. Duration of transient episodes ranged from 5-30 minutes. No patient suffered headache. No patient had nuchal rigidity. Magnetic resonance imaging (MRI) showed evidence of meningeal or meningocerebral disease in all 9 patients. Conclusions: Our study confirmed that serious meningeal disease could present as TIA, but this disease was relatively uncommon among patients treated in a TIA clinic. The findings highlight the diagnostic value of MRI in patients with suspected TIA. Key Words: Transient ischemic attack—meningeal or meningocerebral disease—cortical subarachnoid hemorrhage—cerebral amyloid angiopathy— meningitis—MRI. Ó 2014 by National Stroke Association
Introduction From the *Department of Neurology, University of Toulouse, Toulouse, France; and †Department of Neuroradiology, University of Toulouse, Toulouse, France. Received September 22, 2013; revision received January 5, 2014; accepted January 6, 2014. Address correspondence to Line Cuinat, Hospital Rangueil, Service de Neurologie, CHU Toulouse, H^ opital Rangueil, 1 Avenue Pr Jean Poulhes, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.01.006
Rapid recognition of transient ischemic attack (TIA) is important because patients with TIA may be at immediate risk of stroke.1 The sooner the patients with TIA are assessed and treated, the better the outcome.2 However, a substantial number of patients referred to TIA services are found to have experienced nonischemic events.3-8 A wide variety of diseases can cause transient focal neurologic symptoms mimicking TIA.4,9 Isolated cortical subarachnoid hemorrhage probably related to cerebral amyloid angiopathy has been increasingly reported as a cause of recurrent neurologic spells in recent years.10-12
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-6
1
L. CUINAT ET AL.
2
There are also reports of meningitis revealed by transient focal neurologic symptoms.13-17 Yet, the frequency of these diseases among patients with suspected TIA is unknown. The primary objective of the present study was to determine the rate of meningeal disease in patients referred to a TIA clinic. A secondary objective was to describe clinical and radiologic findings of these patients.
Methods Data from patients consecutively referred to the outpatient TIA clinic between August 2010 and March 2012 were retrospectively analyzed using the electronic database of our institution. Patients with transient focal neurologic symptoms were admitted to the clinic after a phone call to the vascular neurologist who estimated the likelihood of TIA. Patients with symptoms unlikely to be related to TIA, such as syncope, were reoriented to the emergency department. The initial workup in patients admitted to the clinic was performed on the day of admission. This workup included clinical assessment by a vascular neurologist, calculation of the ABCD2 (age, blood pressure, clinical deficit, duration, diabetes) score, electrocardiogram, routine blood studies (complete blood cell count, prothrombin time, activated partial thromboplastin time, C-reactive protein, fibrinogen, D-dimer, serum electrolytes, and creatinine and glucose concentrations), brain magnetic resonance imaging (MRI), transcranial color-coded sonography, and cervical duplex. Final classification of a patient as ischemic event (probable or possible TIA, or minor stroke) or nonischemic event was made by the vascular neurologist based on the findings of the initial workup. A minor stroke was defined by the presence of an acute ischemic lesion on brain imaging, whatever the duration of clinical symptoms. MRI was performed with two 1.5-T MRI systems (Philips Gyroscan NT Intera [Amsterdam, The Netherlands] and Siemens Magnetom Avanto [Erlangen, Germany]). A fast imaging protocol including axial fluid-attenuated inversion recovery (FLAIR) sequence, diffusionweighted images (DWIs) (b 5 0-1000 mm2/second), and 3-dimensional time-of-flight MR angiogram of the circle of Willis was performed in all patients. T2* gradient echo and contrast-enhanced T1-weighted images were subsequently acquired in selected patients with abnormal findings on the initial fast imaging protocol. A computed tomography (CT) scan with CT angiography was performed if MRI was unavailable and in patients with contraindication to MRI such as a pacemaker. All MRI and CT scans were analyzed by a senior neuroradiologist. The study was approved by our Institutional Review Board. Because the study was retrospective and data had been acquired as part of routine patient care, no informed consent was required.
Results A total of 529 patients were admitted to the TIA clinic during the study period. There were 273 men and 256 women with a mean age of 63.5 years (range, 16-98 years). MRI was performed in 457 patients (85.8%). The final diagnosis was as follows: minor stroke, 102 patients (19.2 %); probable TIA, 227 patients (42.9%); possible TIA, 66 patients (12.4%); and nonischemic event, 134 patients (25.3%). Causes of nonischemic events are listed in Table 1. Migraine with aura was the most common cause, followed by peripheral vestibular disorders, epilepsy, and functional disorders. Meningeal disease was found in 9 of 529 patients (1.7%; 95% confidence interval, .6%2.8%) and ranked fifth as a cause of nonischemic event. Causes of meningeal disease and patient characteristics are detailed in Table 2. There were 4 patients with cortical subarachnoid hemorrhage of whom 3 had probable or possible cerebral amyloid angiopathy according to the Boston diagnostic criteria18 (Fig 1). The cause of cortical subarachnoid hemorrhage was undetermined in the remaining patient. Five patients had meningitis including 1 meningeal sarcoidosis (Fig 2), 1 herpes simplex virus 1 (HSV1) meningoencephalitis, 1 rheumatoid meningitis, 1 myelomatous meningitis (Fig 3), and 1 lymphomatous meningitis. All cases of meningitis were suspected based on the findings of the fast protocol MRI and confirmed by cerebrospinal fluid analysis or meningeal biopsy. Patients with meningeal disease included 8 women and 1 man. Their mean age was 75.5 years (range, 59-88 years). Clinical symptoms comprised motor deficit,4 sensory deficit,4 aphasia,3 and dysarthria.2 Clinical symptoms were transient and recurrent in 7 of 9 patients. Duration of transient
Table 1. Final diagnosis in 134 patients with TIA mimic Causes of TIA mimics
N (%)
Migraine with aura Peripheral vestibular disease Epilepsy Functional disorder, anxiety Meningeal disease Transient global amnesia Vagal syncope Ocular disease Metabolic disorder, overmedication, and alcohol abuse Peripheral neuropathy Cardiac syncope Orthostatic hypotension Confusion Other
30 (22.3) 19 (14.1) 17 (12.7) 13 (9.7) 9 (6.7) 6 (4.5) 6 (4.5) 4 (3) 4 (3)
Abbreviation: TIA, transient ischemic attack.
3 (2.2) 3 (2.2) 2 (1.5) 2 (1.5) 16 (11.9)
Age, Patient y Sex 1 2 3
4
5
6
82 83 80
72
88
68
F F F
F
F
F
Past medical history Hypertension, angina pectoris Diabetes, breast cancer Hypertension
Hypertension, intracerebral hematoma Atrial fibrillation
Clinical deficit Unilateral arm and face sensory disturbance Unilateral hand sensory disturbance, dysarthria Unilateral arm and face motor weakness and sensory disturbance, dysarthria Unilateral leg sensory disturbance
Nuchal rigidity/ Headache fever No
No
No
No
No
No
Cause
ND
Probable CAA
6
ND
Possible CAA
2
ND
Cortical SAH of undetermined cause
ND
Probable CAA
WBC: 1.2/mm3; protein: 0.42 g/L; glucose: 3.4 mmol/L
HSV1 meningoencephalitis
WBC: 190/mm3 (90% plasmocyte); protein: 0.8 g/L; glucose: 4 mmol/L WBC: 32/mm3 (74% lymphocyte); protein: 1.8 g/L; glucose: 1.6 mmol/L WBC: 30/mm3 (20% PNN, 64% lymphocyte, 16% monocyte); protein: 0.75 g/L; glucose: 3.2 mmol/L WBC: 16/mm3 (87% lymphocyte); protein: 0.68 g/L; glucose: 4 mmol/L
Myelomatous meningitis
15 min
No
No
2 5 min
Unilateral motor weakness, aphasia
No
Hypertension, multiple myeloma
Aphasia
No
—
Fever
No
1 (minor persisting deficit on admission) 2 15 min
F
Hypertension
Unilateral arm motor weakness
No
No
8
59
M
Rheumatoid arthritis, pulmonary tuberculosis
Unilateral motor weakness and sensory disturbance
No
No
Hypertension, dyslipidemia, endometrial cancer
Aphasia
No
F
3
Initial CSF study
10 min
67
81
Duration of transient episode
15 min
7
9
Number of transient episodes
1 (minor persisting deficit on admission) 5
—
30 min
No
2 15 min
MENINGEAL DISEASE MASQUERADING AS TIA
Table 2. Characteristics of patients with meningeal disease
Meningeal sarcoidosis
Rheumatoid meningitis
Cerebromeningeal localization of B-cell non-Hodgkin lymphoma
Abbreviations: CAA, cerebral amyloid angiopathy; CSF, cerebrospinal fluid; HSV1, herpes simplex virus 1; ND, not done; PNN, polymorphonuclear neutrophils; SAH, subarachnoid hemorrhage; WBC, white blood cells. 3
L. CUINAT ET AL.
4
Figure 1. MRI findings of an 83-year-old woman with transient unilateral hand sensory disturbance and dysarthria with final diagnosis of possible cerebral amyloid angiopathy. Magnetic resonance imaging with (A) axial fluid-attenuated inversion recovery image revealing abnormal high signal intensities in some right frontal sulci (black arrow), confirmed on (B) axial T2 gradient echo to be a subarachnoid hemorrhage, and demonstrating enhancement on (C) axial postgadolinium T1weighted image.
episodes ranged from 5-30 minutes. The 2 remaining patients had minor persisting clinical signs at the initial assessment. The ABCD2 score ranged from 2-5 and was 4 or more in 3 patients. No patient suffered headache. Nuchal rigidity was absent in all cases. Findings suggestive of meningeal disease were detected on FLAIR or DWI in all patients. Illustrative cases are shown in Figures 1 through 3. Electroencephalogram, performed in 7 patients, showed epileptiform activity only in the patient with HSV1 meningoencephalitis.
Discussion The rate of nonischemic events among patients with suspected TIA ranges from 10%-50%.3-8 Lower rates are reported by TIA services not admitting patients with symptoms associated with a low probability of TIA such as syncope. The rate of nonischemic events in the present study, which excluded most patients with syncope, was 25.3%. The most common causes of nonischemic events were migraine with aura, epilepsy, peripheral vestibular syndrome, and functional disorder, which is in good agreement with the previous reports. A wide variety of diseases, all individually uncommon, were found in the remaining patients. Meningeal disease including cortical subarachnoid hemorrhage and meningitis was the less uncommon of these uncommon diseases and ranked fifth as a cause of nonischemic event. Cortical subarachnoid hemorrhage probably caused by cerebral amyloid angiopathy and revealed by recurrent neurologic spells has been increasingly reported in recent
years.10-12 Cerebral amyloid angiopathy can be suspected on MRI when the cortical subarachnoid hemorrhage is associated with previous asymptomatic intracranial bleeding, such as cortical siderosis, microbleed, or intracerebral hemorrhage.18 Recognition of this disease among patients with suspected TIA is of primary importance because patients with cortical subarachnoid hemorrhage probably related to cerebral amyloid angiopathy are at a high risk of recurrent intracranial bleeding, and aspirin may increase this risk.19 The frequency of cerebral amyloid angiopathy as a cause of TIA mimic has not been previously reported. In the present study, cortical subarachnoid hemorrhage was found in only 4 of 529 patients referred to a TIA clinic suggesting that cerebral amyloid angiopathy is a rare, albeit clinically important, cause of TIA mimic. Patients with meningitis were a heterogeneous group comprising 2 patients with meningeal involvement by neoplastic disease, a patient with meningeal sarcoidosis, a patient with rheumatoid meningitis, and a patient with HSV1 meningoencephalitis. Previous reports on inflammatory, infectious, or neoplastic meningitis revealed by transient neurologic dysfunction mimicking TIA are scarce.15,16,20,21 The results of the present study show that these diseases were infrequent among patients referred to a TIA clinic. Taken together, however, they were not rarer than cortical subarachnoid hemorrhage. Given their severity, they should be recognized and treated promptly. Meningeal disease could not be suspected on clinical grounds in patients from the present series. Clinical signs of meningeal disease, such as headache and nuchal
Figure 2. MRI findings of a 67-year-old woman with unilateral arm motor weakness and subsequently confirmed meningeal sarcoidosis. Magnetic resonance imaging with (A) axial fluid-attenuated inversion recovery image revealing subtle left frontal leptomeningeal hyperintensities (black arrow), without hemorrhage according to (B) axial T2 gradient echo, but with abnormal enhancement on (C) axial postgadolinium T1-weighted image.
MENINGEAL DISEASE MASQUERADING AS TIA
5
Figure 3. MRI findings of a 68-year-old woman with transient aphasia and past medical history of refractory immunoglobulin A myeloma. Myelomatous meningitis was confirmed after cerebrospinal fluid analysis. Magnetic resonance imaging depicting on (A) and (B) axial fluid-attenuated inversion recovery images, discrete high signal intensities filling left precentral sulcus (black arrow) and some vermian sulci, confirmed to be pathologic on (C) contrast-enhanced T1-weighted image.
rigidity, were absent in all cases. Several studies have shown that a high ABCD2 score can help discriminate patients with TIA from those with nonischemic events.6-8 In the present study, 3 of 9 patients with meningeal disease had an ABCD2 score of 4 or more. Furthermore, 7 of 9 patients with meningeal disease had recurrent neurologic episodes. This clinical profile has been associated with increased risk of stroke among patients with TIA.22 The clinical presentation of most patients with meningeal disease was thus suggestive of TIA with a high risk of stroke. Meningeal disease could only be suspected based on MRI findings. FLAIR and/or DWI demonstrated meningeal or meningocerebral lesions in all cases. Radiologic diagnosis was then refined by using additional T2* and contrast-enhanced T1-weighted images. These results suggest the usefulness of the duo FLAIR/DWI as a screening tool for meningeal disease in patients presenting as TIA or minor stroke. Potential mechanisms of transient focal neurologic dysfunction in patients with meningeal disease include brain ischemia, seizure, and cortical spreading depression.11 None of the patients from the present series had evidence of acute brain ischemia on MRI. The relatively long duration of transient symptoms (several minutes) and the characteristics of motor symptoms (motor weakness without myoclonus or dystonia) were not suggestive of seizures. Electroencephalogram, performed in 7 patients, showed epileptiform activity only in the patient with HSV1 meningoencephalitis. Several strengths of the present study should be noted. The sample size was large. Although the study was retrospective, patients were consecutively admitted to the TIA clinic during the study period. Patients were investigated using the same predefined protocol. Classification of patients into diagnostic subtypes was made by the same vascular neurologist. Some limitations should also be considered. All the patients could not have MRI. Thus, it is possible that our estimate of the prevalence of meningeal disease was not accurate because CT is less sensitive than MRI for the recognition of this disease. Nevertheless, MRI was performed in most (85.8%) patients and reasons for not performing MRI (lack of availability of MRI or contraindication related to patient condition) were unplanned. The
prevalence of meningeal disease among patients who had MRI was 9 of 457 (1.9%; 95% confidence interval, .7%-3.2%). Transient neurologic episodes have been reported in patients with chronic hemorrhagic lesions associated with cerebral amyloid angiopathy, such as microbleed, intracerebral hemorrhage, or cortical siderosis, but no evidence of acute bleeding.23 Because T2* images were not obtained in all patients from the present series we may have overlooked some such lesions. Cerebrospinal fluid analysis was performed only in patients with suggestive findings from MRI. We cannot exclude that some patients without abnormalities on MRI had meningitis.13 On the basis of the findings in the present study, we suggest that in future studies of patients with transient focal neurologic symptoms, those with recurrent episodes and no cerebrovascular explanation to their symptoms have cerebrospinal fluid analysis even in the absence of suggestive abnormalities on MRI.
Conclusions The present study confirmed that serious meningeal disease could be revealed by transient focal neurologic symptoms mimicking TIA, but this disease was relatively uncommon among patients treated in a TIA clinic. The findings highlight the diagnostic value of MRI in patients with suspected TIA.
References 1. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283-292. 2. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet 2007;370:1432-1442. 3. Amort M, Fluri F, Sch€ afer J, et al. Transient ischemic attack versus transient ischemic attack mimics: frequency, clinical characteristics and outcome. Cerebrovasc Dis 2011;32:57-64. 4. Dennis MS, Bamford JM, Sandercock PA, et al. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989;20:333-339.
6 5. Fallon C, Noone I, Ryan J, et al. Assessment and management of transient ischaemic attack—the role of the TIA clinic. Ir J Med Sci 2006;175:24-27. 6. Josephson SA, Sidney S, Pham TN, et al. Higher ABCD2 score predicts patients most likely to have true transient ischemic attack. Stroke 2008;39:3096-3098. 7. Quinn TJ, Cameron AC, Dawson J, et al. ABCD2 scores and prediction of noncerebrovascular diagnoses in an outpatient population: a case-control study. Stroke 2009; 40:749-753. 8. Sheehan OC, Merwick A, Kelly LA, et al. Diagnostic usefulness of the ABCD2 score to distinguish transient ischemic attack and minor ischemic stroke from noncerebrovascular events: the North Dublin TIA Study. Stroke 2009;40:3449-3454. 9. Caplan LR. Funny turns. They do mean something. Arch Neurol 2008;65:601-602. 10. Kumar S, Goddeau RP Jr, Selim MH, et al. A traumatic convexal subarachnoid hemorrhage: clinical presentation, imaging patterns, and etiologies. Neurology 2010; 74:893-899. 11. Raposo N, Viguier A, Cuvinciuc V, et al. Cortical subarachnoid haemorrhage in the elderly: a recurrent event probably related to cerebral amyloid angiopathy. Eur J Neurol 2011;18:597-603. 12. Izenberg A, Aviv RI, Demaerschalk BM, et al. Crescendo transient Aura attacks: a transient ischemic attack mimic caused by focal subarachnoid hemorrhage. Stroke 2009; 40:3725-3729. 13. Papavasileiou V, Milionis H, Cordier M, et al. Aseptic meningoencephalitis mimicking transient ischaemic attacks. Infection 2013;41:485-491.
L. CUINAT ET AL. 14. Karpinsky NC, Powell H. Case of the month: July 1997— diabetic male with transient ischemic attacks. Brain Pathol 1998;8:235-236. 15. Chowdhry V, Kumar N, Lachance DH, et al. An unusual presentation of rheumatoid meningitis. J Neuroimaging 2005;15:286-288. 16. Hamslik T, Boulard JC, Moulonguet-Doleris L, et al. Transient ischaemic attack, infectious meningitis, or neurosarcoidosis? Postgrad Med J 1995;71:764-766. 17. Staudinger R, Levine D, Swaminathan B, et al. Neurolisteriosis presenting as recurrent transient ischemic attacks. Ann Neurol 2000;48:661-665. 18. Linn J, Halpin A, Demaerel P, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010;74:1346-1350. 19. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010;75:693-698. 20. McCorry DJ, Crowley P. Transient global amnesia secondary to herpes simplex viral encephalitis. QJM 2005; 98:154-155. 21. Cooney DR, Cooney NL. Meningeal carcinomatosis diagnosed during stroke evaluation in the emergency department. Int J Emerg Med 2011;4:52. 22. Purroy F, Jimenez Caballero PE, Gorospe A, et al. Recurrent transient ischaemic attack and early risk of stroke: data from the PROMAPA study. J Neurol Neurosurg Psychiatry 2013;84:596-603. 23. Charidimou A, Peeters A, Fox Z, et al. Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy multicentre magnetic resonance imaging cohort study and meta-analysis. Stroke 2012;43:2324-2330.
Meningeal Disease Masquerading as Transient Ischemic Attack Line Cuinat, MD,* Nathalie Nasr, MD,* Jeanine Manuela Kamsu, MD,† Frederic Tanchoux, MD,† Fabrice Bonneville, MD,† and Vincent Larrue, MD*
Background: Cortical subarachnoid hemorrhage and meningitis sometimes present as episodes of transient neurologic dysfunction mimicking transient ischemic attack (TIA). In the present study, we sought to determine the frequency of meningeal disease among patients treated in a TIA clinic. Methods: Data from patients consecutively admitted to a TIA clinic were retrospectively analyzed. Patients were classified as ischemic events (TIA or minor stroke) or nonischemic events using clinical data and findings from brain imaging and ultrasound studies. Results: Of 529 patients (mean age 63.5 years), 134 (25.3%) were classified as nonischemic events. Meningeal disease was the likely cause of clinical symptoms in 9 patients (1.7%; 95% confidence interval, .6%-2.8%) including 5 patients with meningitis (1 meningeal sarcoidosis, 1 rheumatoid meningitis, 1 myelomatous meningitis, 1 lymphomatous meningitis, and 1 herpes simplex virus 1 meningoencephalitis) and 4 patients with cortical subarachnoid hemorrhage (probably or possibly related to cerebral amyloid angiopathy in 3 patients). Clinical symptoms comprised motor deficit, sensory deficit, aphasia, and dysarthria. Transient neurologic dysfunction was recurrent in 7 of 9 patients. Duration of transient episodes ranged from 5-30 minutes. No patient suffered headache. No patient had nuchal rigidity. Magnetic resonance imaging (MRI) showed evidence of meningeal or meningocerebral disease in all 9 patients. Conclusions: Our study confirmed that serious meningeal disease could present as TIA, but this disease was relatively uncommon among patients treated in a TIA clinic. The findings highlight the diagnostic value of MRI in patients with suspected TIA. Key Words: Transient ischemic attack—meningeal or meningocerebral disease—cortical subarachnoid hemorrhage—cerebral amyloid angiopathy— meningitis—MRI. Ó 2014 by National Stroke Association
Introduction From the *Department of Neurology, University of Toulouse, Toulouse, France; and †Department of Neuroradiology, University of Toulouse, Toulouse, France. Received September 22, 2013; revision received January 5, 2014; accepted January 6, 2014. Address correspondence to Line Cuinat, Hospital Rangueil, Service de Neurologie, CHU Toulouse, H^ opital Rangueil, 1 Avenue Pr Jean Poulhes, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.01.006
Rapid recognition of transient ischemic attack (TIA) is important because patients with TIA may be at immediate risk of stroke.1 The sooner the patients with TIA are assessed and treated, the better the outcome.2 However, a substantial number of patients referred to TIA services are found to have experienced nonischemic events.3-8 A wide variety of diseases can cause transient focal neurologic symptoms mimicking TIA.4,9 Isolated cortical subarachnoid hemorrhage probably related to cerebral amyloid angiopathy has been increasingly reported as a cause of recurrent neurologic spells in recent years.10-12
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-6
1
L. CUINAT ET AL.
2
There are also reports of meningitis revealed by transient focal neurologic symptoms.13-17 Yet, the frequency of these diseases among patients with suspected TIA is unknown. The primary objective of the present study was to determine the rate of meningeal disease in patients referred to a TIA clinic. A secondary objective was to describe clinical and radiologic findings of these patients.
Methods Data from patients consecutively referred to the outpatient TIA clinic between August 2010 and March 2012 were retrospectively analyzed using the electronic database of our institution. Patients with transient focal neurologic symptoms were admitted to the clinic after a phone call to the vascular neurologist who estimated the likelihood of TIA. Patients with symptoms unlikely to be related to TIA, such as syncope, were reoriented to the emergency department. The initial workup in patients admitted to the clinic was performed on the day of admission. This workup included clinical assessment by a vascular neurologist, calculation of the ABCD2 (age, blood pressure, clinical deficit, duration, diabetes) score, electrocardiogram, routine blood studies (complete blood cell count, prothrombin time, activated partial thromboplastin time, C-reactive protein, fibrinogen, D-dimer, serum electrolytes, and creatinine and glucose concentrations), brain magnetic resonance imaging (MRI), transcranial color-coded sonography, and cervical duplex. Final classification of a patient as ischemic event (probable or possible TIA, or minor stroke) or nonischemic event was made by the vascular neurologist based on the findings of the initial workup. A minor stroke was defined by the presence of an acute ischemic lesion on brain imaging, whatever the duration of clinical symptoms. MRI was performed with two 1.5-T MRI systems (Philips Gyroscan NT Intera [Amsterdam, The Netherlands] and Siemens Magnetom Avanto [Erlangen, Germany]). A fast imaging protocol including axial fluid-attenuated inversion recovery (FLAIR) sequence, diffusionweighted images (DWIs) (b 5 0-1000 mm2/second), and 3-dimensional time-of-flight MR angiogram of the circle of Willis was performed in all patients. T2* gradient echo and contrast-enhanced T1-weighted images were subsequently acquired in selected patients with abnormal findings on the initial fast imaging protocol. A computed tomography (CT) scan with CT angiography was performed if MRI was unavailable and in patients with contraindication to MRI such as a pacemaker. All MRI and CT scans were analyzed by a senior neuroradiologist. The study was approved by our Institutional Review Board. Because the study was retrospective and data had been acquired as part of routine patient care, no informed consent was required.
Results A total of 529 patients were admitted to the TIA clinic during the study period. There were 273 men and 256 women with a mean age of 63.5 years (range, 16-98 years). MRI was performed in 457 patients (85.8%). The final diagnosis was as follows: minor stroke, 102 patients (19.2 %); probable TIA, 227 patients (42.9%); possible TIA, 66 patients (12.4%); and nonischemic event, 134 patients (25.3%). Causes of nonischemic events are listed in Table 1. Migraine with aura was the most common cause, followed by peripheral vestibular disorders, epilepsy, and functional disorders. Meningeal disease was found in 9 of 529 patients (1.7%; 95% confidence interval, .6%2.8%) and ranked fifth as a cause of nonischemic event. Causes of meningeal disease and patient characteristics are detailed in Table 2. There were 4 patients with cortical subarachnoid hemorrhage of whom 3 had probable or possible cerebral amyloid angiopathy according to the Boston diagnostic criteria18 (Fig 1). The cause of cortical subarachnoid hemorrhage was undetermined in the remaining patient. Five patients had meningitis including 1 meningeal sarcoidosis (Fig 2), 1 herpes simplex virus 1 (HSV1) meningoencephalitis, 1 rheumatoid meningitis, 1 myelomatous meningitis (Fig 3), and 1 lymphomatous meningitis. All cases of meningitis were suspected based on the findings of the fast protocol MRI and confirmed by cerebrospinal fluid analysis or meningeal biopsy. Patients with meningeal disease included 8 women and 1 man. Their mean age was 75.5 years (range, 59-88 years). Clinical symptoms comprised motor deficit,4 sensory deficit,4 aphasia,3 and dysarthria.2 Clinical symptoms were transient and recurrent in 7 of 9 patients. Duration of transient
Table 1. Final diagnosis in 134 patients with TIA mimic Causes of TIA mimics
N (%)
Migraine with aura Peripheral vestibular disease Epilepsy Functional disorder, anxiety Meningeal disease Transient global amnesia Vagal syncope Ocular disease Metabolic disorder, overmedication, and alcohol abuse Peripheral neuropathy Cardiac syncope Orthostatic hypotension Confusion Other
30 (22.3) 19 (14.1) 17 (12.7) 13 (9.7) 9 (6.7) 6 (4.5) 6 (4.5) 4 (3) 4 (3)
Abbreviation: TIA, transient ischemic attack.
3 (2.2) 3 (2.2) 2 (1.5) 2 (1.5) 16 (11.9)
Age, Patient y Sex 1 2 3
4
5
6
82 83 80
72
88
68
F F F
F
F
F
Past medical history Hypertension, angina pectoris Diabetes, breast cancer Hypertension
Hypertension, intracerebral hematoma Atrial fibrillation
Clinical deficit Unilateral arm and face sensory disturbance Unilateral hand sensory disturbance, dysarthria Unilateral arm and face motor weakness and sensory disturbance, dysarthria Unilateral leg sensory disturbance
Nuchal rigidity/ Headache fever No
No
No
No
No
No
Cause
ND
Probable CAA
6
ND
Possible CAA
2
ND
Cortical SAH of undetermined cause
ND
Probable CAA
WBC: 1.2/mm3; protein: 0.42 g/L; glucose: 3.4 mmol/L
HSV1 meningoencephalitis
WBC: 190/mm3 (90% plasmocyte); protein: 0.8 g/L; glucose: 4 mmol/L WBC: 32/mm3 (74% lymphocyte); protein: 1.8 g/L; glucose: 1.6 mmol/L WBC: 30/mm3 (20% PNN, 64% lymphocyte, 16% monocyte); protein: 0.75 g/L; glucose: 3.2 mmol/L WBC: 16/mm3 (87% lymphocyte); protein: 0.68 g/L; glucose: 4 mmol/L
Myelomatous meningitis
15 min
No
No
2 5 min
Unilateral motor weakness, aphasia
No
Hypertension, multiple myeloma
Aphasia
No
—
Fever
No
1 (minor persisting deficit on admission) 2 15 min
F
Hypertension
Unilateral arm motor weakness
No
No
8
59
M
Rheumatoid arthritis, pulmonary tuberculosis
Unilateral motor weakness and sensory disturbance
No
No
Hypertension, dyslipidemia, endometrial cancer
Aphasia
No
F
3
Initial CSF study
10 min
67
81
Duration of transient episode
15 min
7
9
Number of transient episodes
1 (minor persisting deficit on admission) 5
—
30 min
No
2 15 min
MENINGEAL DISEASE MASQUERADING AS TIA
Table 2. Characteristics of patients with meningeal disease
Meningeal sarcoidosis
Rheumatoid meningitis
Cerebromeningeal localization of B-cell non-Hodgkin lymphoma
Abbreviations: CAA, cerebral amyloid angiopathy; CSF, cerebrospinal fluid; HSV1, herpes simplex virus 1; ND, not done; PNN, polymorphonuclear neutrophils; SAH, subarachnoid hemorrhage; WBC, white blood cells. 3
L. CUINAT ET AL.
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Figure 1. MRI findings of an 83-year-old woman with transient unilateral hand sensory disturbance and dysarthria with final diagnosis of possible cerebral amyloid angiopathy. Magnetic resonance imaging with (A) axial fluid-attenuated inversion recovery image revealing abnormal high signal intensities in some right frontal sulci (black arrow), confirmed on (B) axial T2 gradient echo to be a subarachnoid hemorrhage, and demonstrating enhancement on (C) axial postgadolinium T1weighted image.
episodes ranged from 5-30 minutes. The 2 remaining patients had minor persisting clinical signs at the initial assessment. The ABCD2 score ranged from 2-5 and was 4 or more in 3 patients. No patient suffered headache. Nuchal rigidity was absent in all cases. Findings suggestive of meningeal disease were detected on FLAIR or DWI in all patients. Illustrative cases are shown in Figures 1 through 3. Electroencephalogram, performed in 7 patients, showed epileptiform activity only in the patient with HSV1 meningoencephalitis.
Discussion The rate of nonischemic events among patients with suspected TIA ranges from 10%-50%.3-8 Lower rates are reported by TIA services not admitting patients with symptoms associated with a low probability of TIA such as syncope. The rate of nonischemic events in the present study, which excluded most patients with syncope, was 25.3%. The most common causes of nonischemic events were migraine with aura, epilepsy, peripheral vestibular syndrome, and functional disorder, which is in good agreement with the previous reports. A wide variety of diseases, all individually uncommon, were found in the remaining patients. Meningeal disease including cortical subarachnoid hemorrhage and meningitis was the less uncommon of these uncommon diseases and ranked fifth as a cause of nonischemic event. Cortical subarachnoid hemorrhage probably caused by cerebral amyloid angiopathy and revealed by recurrent neurologic spells has been increasingly reported in recent
years.10-12 Cerebral amyloid angiopathy can be suspected on MRI when the cortical subarachnoid hemorrhage is associated with previous asymptomatic intracranial bleeding, such as cortical siderosis, microbleed, or intracerebral hemorrhage.18 Recognition of this disease among patients with suspected TIA is of primary importance because patients with cortical subarachnoid hemorrhage probably related to cerebral amyloid angiopathy are at a high risk of recurrent intracranial bleeding, and aspirin may increase this risk.19 The frequency of cerebral amyloid angiopathy as a cause of TIA mimic has not been previously reported. In the present study, cortical subarachnoid hemorrhage was found in only 4 of 529 patients referred to a TIA clinic suggesting that cerebral amyloid angiopathy is a rare, albeit clinically important, cause of TIA mimic. Patients with meningitis were a heterogeneous group comprising 2 patients with meningeal involvement by neoplastic disease, a patient with meningeal sarcoidosis, a patient with rheumatoid meningitis, and a patient with HSV1 meningoencephalitis. Previous reports on inflammatory, infectious, or neoplastic meningitis revealed by transient neurologic dysfunction mimicking TIA are scarce.15,16,20,21 The results of the present study show that these diseases were infrequent among patients referred to a TIA clinic. Taken together, however, they were not rarer than cortical subarachnoid hemorrhage. Given their severity, they should be recognized and treated promptly. Meningeal disease could not be suspected on clinical grounds in patients from the present series. Clinical signs of meningeal disease, such as headache and nuchal
Figure 2. MRI findings of a 67-year-old woman with unilateral arm motor weakness and subsequently confirmed meningeal sarcoidosis. Magnetic resonance imaging with (A) axial fluid-attenuated inversion recovery image revealing subtle left frontal leptomeningeal hyperintensities (black arrow), without hemorrhage according to (B) axial T2 gradient echo, but with abnormal enhancement on (C) axial postgadolinium T1-weighted image.
MENINGEAL DISEASE MASQUERADING AS TIA
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Figure 3. MRI findings of a 68-year-old woman with transient aphasia and past medical history of refractory immunoglobulin A myeloma. Myelomatous meningitis was confirmed after cerebrospinal fluid analysis. Magnetic resonance imaging depicting on (A) and (B) axial fluid-attenuated inversion recovery images, discrete high signal intensities filling left precentral sulcus (black arrow) and some vermian sulci, confirmed to be pathologic on (C) contrast-enhanced T1-weighted image.
rigidity, were absent in all cases. Several studies have shown that a high ABCD2 score can help discriminate patients with TIA from those with nonischemic events.6-8 In the present study, 3 of 9 patients with meningeal disease had an ABCD2 score of 4 or more. Furthermore, 7 of 9 patients with meningeal disease had recurrent neurologic episodes. This clinical profile has been associated with increased risk of stroke among patients with TIA.22 The clinical presentation of most patients with meningeal disease was thus suggestive of TIA with a high risk of stroke. Meningeal disease could only be suspected based on MRI findings. FLAIR and/or DWI demonstrated meningeal or meningocerebral lesions in all cases. Radiologic diagnosis was then refined by using additional T2* and contrast-enhanced T1-weighted images. These results suggest the usefulness of the duo FLAIR/DWI as a screening tool for meningeal disease in patients presenting as TIA or minor stroke. Potential mechanisms of transient focal neurologic dysfunction in patients with meningeal disease include brain ischemia, seizure, and cortical spreading depression.11 None of the patients from the present series had evidence of acute brain ischemia on MRI. The relatively long duration of transient symptoms (several minutes) and the characteristics of motor symptoms (motor weakness without myoclonus or dystonia) were not suggestive of seizures. Electroencephalogram, performed in 7 patients, showed epileptiform activity only in the patient with HSV1 meningoencephalitis. Several strengths of the present study should be noted. The sample size was large. Although the study was retrospective, patients were consecutively admitted to the TIA clinic during the study period. Patients were investigated using the same predefined protocol. Classification of patients into diagnostic subtypes was made by the same vascular neurologist. Some limitations should also be considered. All the patients could not have MRI. Thus, it is possible that our estimate of the prevalence of meningeal disease was not accurate because CT is less sensitive than MRI for the recognition of this disease. Nevertheless, MRI was performed in most (85.8%) patients and reasons for not performing MRI (lack of availability of MRI or contraindication related to patient condition) were unplanned. The
prevalence of meningeal disease among patients who had MRI was 9 of 457 (1.9%; 95% confidence interval, .7%-3.2%). Transient neurologic episodes have been reported in patients with chronic hemorrhagic lesions associated with cerebral amyloid angiopathy, such as microbleed, intracerebral hemorrhage, or cortical siderosis, but no evidence of acute bleeding.23 Because T2* images were not obtained in all patients from the present series we may have overlooked some such lesions. Cerebrospinal fluid analysis was performed only in patients with suggestive findings from MRI. We cannot exclude that some patients without abnormalities on MRI had meningitis.13 On the basis of the findings in the present study, we suggest that in future studies of patients with transient focal neurologic symptoms, those with recurrent episodes and no cerebrovascular explanation to their symptoms have cerebrospinal fluid analysis even in the absence of suggestive abnormalities on MRI.
Conclusions The present study confirmed that serious meningeal disease could be revealed by transient focal neurologic symptoms mimicking TIA, but this disease was relatively uncommon among patients treated in a TIA clinic. The findings highlight the diagnostic value of MRI in patients with suspected TIA.
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