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Stroke-Like Episodes Heralding a Reversible Encephalopathy: Microbleeds as the Key to the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation—A Case Report and Literature Review
Case Report
Stroke-Like Episodes Heralding a Reversible Encephalopathy: Microbleeds as the Key to the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation—A Case Report and Literature Review Marcelo D. Mendonc¸a, MD,*† Andre Caetano, MD,* Miguel Pinto, MD,* Vera Cruz e Silva, MD,‡ and Miguel Viana-Baptista, MD, PhD*†
Background: Cerebral amyloid angiopathy (CAA) is a common, often asymptomatic disease. Lobar intracerebral hemorrhage is the most frequent manifestation of CAA. Nevertheless, presentation of CAA with subacute cognitive decline, seizures, or headache with concomitant hyperintensities on T2-weighted magnetic resonance imaging (MRI) sequences and neuropathologic evidence of inflammation has been described. This disorder is known as CAA-related inflammation (CAA-ri). Methods: Description of a stroke-like presentation of CAA-ri and systematic review of case reports and case series of CAA-ri. Results: A 75-year-old woman with a history of atrial fibrillation, and a transient episode of aphasia 2 days before, presented in the emergency room with sudden onset aphasia. Brain computed tomography disclosed a left temporal hypodensity. A diagnosis of probable stroke was given. During the following days, there was a progressive clinical deterioration. MRI revealed coalescent edematous white matter lesion, hyperintense on T2-weighted sequences, and multiple lobar microbleeds on T2*-weighted sequences. A diagnosis of CAA-ri was considered, and the patient was started on steroids with clinical and imaging improvement. From our systematic review, microbleeds were present in almost 90% of patients with CAA-ri. Conclusions: Imaging findings associated with CAAri allow the early diagnosis and treatment of this potentially reversible disorder. Aside from the most common subacute presentations, CAA-ri can have a strokelike presentation and be a stroke mimic. Key Words: Stroke—cerebral amyloid angiopathy—cerebral amyloid angiopathy-related inflammation—microbleeds. Ó 2015 by National Stroke Association
Cerebral amyloid angiopathy (CAA) is a common, often asymptomatic, disease characterized by deposition of amyloid-b in cortical and leptomeningeal vessels. A definite
diagnosis requires a neuropathologic study, but probable CAA criteria have been defined on clinical and neuroimaging grounds, namely the presence of microbleeds on
From the *Neurology Department, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; †Centro de Estudos de Doenc¸as Cr onicas (CEDOC), Nova Medical School/Faculdade de Ci^encias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal; and ‡Neuroimaging Department, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal. Received January 30, 2015; revision received April 2, 2015; accepted April 12, 2015.
The authors have reported no conflicts of interest. The authors report no relevant funding for the present study. Address correspondence to Marcelo D. Mendonc¸a, MD, Neurology Department, Hospital Egas Moniz—Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1349-019 Lisbon, Portugal. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.042
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T2*-weighted magnetic resonance imaging (MRI). Lobar intracerebral hemorrhage is the most common manifestation of CAA.2 Nevertheless, some CAA patients present a subacute cognitive decline, seizures, or headache with hyperintensities on T2-weighted MRI sequences and neuropathologic evidence of inflammation. This disorder is known as CAA-related inflammation (CAA-ri).2 An isolated abrupt onset of focal symptoms seems to be an infrequent feature, and to our knowledge, an ictal/ stroke-like presentation has never been recognized as the CAA-ri heralding manifestation. Early identification of the findings associated with CAA-ri allows early diagnosis, treatment, and avoidance of more aggressive diagnostic tests.
Case Report A 75-year-old woman was admitted in the emergency room with acute-onset aphasia. There was a history of a transient episode of aphasia 2 days before. The patient had a medical history of autoimmune thyroiditis and anxiety disorder and hypertension and dyslipidemia as vascular risk factors. She was on fluvastatin, bisoprolol, levothyroxine, alprazolam, brotizolam, domperidone,
altizide, and spironolactone and had no relevant family history. There was no history of alcohol, tobacco, or other drug use. On admission, she was afebrile and normotensive. General examination was unremarkable and neurologic examination only disclosed expression aphasia. Brain computed tomography revealed a left temporal hypodensity (Fig 1, A). The patient was admitted to an internal medicine inpatient unit with the diagnosis of stroke. On the following days, clinical deterioration with signs of left hemisphere dysfunction was accompanied by imaging progression. Successive MRIs (Fig 1, B-D) disclosed an increasingly coalescent edematous white matter lesion, hyperintense on T2-weighted sequences, and the presence of multiple lobar microbleeds on T2*-weighted sequences (Fig 1, B-1). There was no evidence of lesions with restriction on diffusion-weighted imaging at any time point. The patient was transferred to the neurology department 12 days after admission. At this time, she was afebrile and presented a decreased level of consciousness, global aphasia, and right hemiparesis. Cerebrospinal fluid revealed 282 mg/dL of proteins and 10 lymphocytes/mL, and viral polymerase chain reaction was negative for neurotropic viruses, including herpes simplex viruses 1 and 2 (a positive polymerase
Figure 1. (A) Computed tomography scan performed at admission: left temporal hypodensity with edema. (B-D) Brain magnetic resonance imaging before steroid therapy at D2 (B), D4 (C), and D12 (D). (B-1) T2*-weighted imaging with multiple microbleeds (arrowheads). T2-weighted image (B-2) and T2 fluidattenuated inversion recovery images (FLAIR) (C and D) showing progression of confluent white matter hyperintensities from D2 (B-2) until D12 (D). (E and F) FLAIR-weighted imaging after steroid treatment. Regression of T2-weighted hyperintense lesions 30 days after onset (E) and 9 months after steroid therapy (F) (except for those attributed to age-related white matter lesion).
Table 1. Summary of clinical, MRI, and therapeutic findings in previous cases of CAA-ri
Martucci et al5
Salvarani et al4
Piazza et al6
Kinnecom et al2
Scolding et al7
N Age (min-max) M/F ApoE genotype ApoE4/ApoE4 ApoE3/ApoE3 ApoE2/ApoE3 Other Clinical presentation Subacute cognitive decline and/or behavioral changes Headache Seizures Focal neurologic signs Gait abnormalities Other* Neuroimaging findings White matter changes Microbleeds Treatment No treatment Steroids Cyclophosphamide Azathioprine MMF IVIg Other immunosuppressive drug not specified Anatomopathologic study Outcome Improvement
10 75 (63-83) 3/7 NA
38 67 (42-84) 19/19 NA
10 68 (56/76) 6/4
14 63 (45-79) 9/5
9 69 (54-82) 5/4 NA
4/9 4/9 0 1/9
44% 44% 0% 11%
10/13 0/13 2/13 1/13
77% 0% 15% 8%
Summary (including current report)
50 68 (44-93) 23/27
132 68 (42-93) 65/67
7/13 2/13 4/13 0
54% 15% 31% 0%
22/36 6/36 6/36 2/36
61% 17% 17% 6%
6
60%
25
66%
9
90%
13
93%
8
89%
31
62%
92
70%
3 3 7 2 0
30% 30% 70% 20% 0%
15 20 12 0 0
39% 53% 32% 0% 0%
0 4 2 0 1
0% 40% 20% 0% 10%
6 6 1 0 1
43% 43% 7% 0% 7%
2 1 5 0 0
22% 11% 56% 0% 0%
12 16 28 3 9
24% 32% 56% 6% 18%
38 50 56 5 11
29% 38% 42% 4% 8%
10 9
100% 90%
10 8/9
100% 89%
12/12
100%
7/9
78%
47/48 25/30
98% 83%
87/90 43/49
97% 88%
2 8 0 0 0 0 0
20% 80% 0% 0% 0% 0% 0%
3 7 0 0 0 0 0
30% 70% 0% 0% 0% 0% 0%
0 12/12 3/12 0 0 0 0
0% 100% 25% 0% 0% 0% 0%
0 8 2 0 0 0 0
0% 89% 22% 0% 0% 0% 0%
3/49 45/49 15/49 4/49 2/49 1/49 1/49
6% 92% 31% 8% 4% 2% 2%
21/129 93/129 29/129 6/129 2/129 1/93 3/129
16% 72% 22% 5% 2% 1% 2%
2
20%
12
86%
9
100%
42
84%
103/122
84%
10
100%
12
100%
4
44%
41/49
84%
68/81
84%
NA
NA NA
13 12 9 2 0 NA 2
34% 32% 24% 5% 0% NA 5%
38 100% 71% with mRS (score 0-3) at last follow-up
NA
NA
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Abbreviations: IVIg, intravenous human immunoglobulin; max, maximum; min, minimum; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NA, not available. Search was performed using as keywords ‘‘cerebral amyloid angiopathy related inflammation,’’ ‘‘(cerebral OR brain OR encephali*) amyloid angiopath* inflamm*,’’ and ‘‘Amyloid-Beta AND Angiitis.’’ We identified all published case reports or case series on the subject. Studies on Primary angiitis of the central nervous system with CAA were not included. We excluded those without information available in English, Spanish, or Portuguese. A total of 54 potentially relevant studies (case series or case reports) were identified. From this group, 5 were excluded based on a language criteria and one on repetition of subjects. From the remaining 48 studies, 5 were case series and 5 were collections of up to 3 case reports. Two of the 3 patients in a publication49 were described in previous case reports,36,37 so only the new case was included. A total of 131 previously described patients were identified. The results of the 5 largest case series are presented separated from the case reports. If no information was provided about the realization of a biopsy or necropsy on the case reports, we considered it not done. The last column summarizes the information from the 131 previously described patients with the addition of the current case. *Other rarer manifestations include progression to coma in 4 cases, myoclonic tremor in 2 cases, recurrent transient, positive, or migratory neurologic symptoms in 3 cases, Parkinsonian signs in 1 patient, and bilateral uveitis in 1 case.
MICROBLEEDS AND THE DIAGNOSIS OF CAA-RELATED INFLAMMATION
Variables
Case reports3,8-49
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chain reaction result for HHV6 was present but deemed unrelated to the clinical picture). EEG revealed diffuse slowing with bilateral temporal dysfunction without periodic activity. Diagnostic workup was negative for HIV, syphilis, JC virus, anti-Hu, CV2, Ma2, amphiphysin, N-methyl-D-aspartate receptor (NMDAR), and Voltage gated potassium channel (VGKC). Chest, abdomen, and pelvis scans did not presented evidence of a neoplastic process. Tumor markers (CEA, CA 19.9, CA 15.3, CA 125, NSE, and Cyfra 21.1) were negative. ApoE genotype was ε4/ε4. The patient was started on intravenous (IV) acyclovir 600 mg twice a day for 14 days as viral encephalitis was not excluded at this time and 1 g/d of IV methylprednisolone for 5 days for CAA-ri. After this, the patient was started on 60 mg oral prednisolone that was slowly tapered over the course of 6 months. Five days after steroid therapy, an improvement of neurologic status was noted. A complete recovery was clear at 15 days and accompanied by improvement in MRI findings at 30 days (Fig 1, E). Six months later, there were no focal signs on the neurologic examination, and a complete reversion of the MRI findings was seen 9 months later (Fig 1, F).
Discussion CAA-ri is a potentially treatable encephalopathy3 with a mortality rate up to 30%4 and a vast clinical presentation.2,3 Table 1 presents a summary of the clinical presentations, treatment regimens, and outcomes found in a systematic literature review (details in the table). From a total of 132 subjects, the main presenting symptoms are mental status and cognitive changes (70%), focal neurologic deficits (42%), headache (29%), and seizures (38%), frequently in combination. Uncommon presentations include transient positive recurrent neurologic symptoms. Interestingly, a stroke-like presentation does not seem to have been previously recognized. Facing the clinical and pathologic heterogeneity of this disorder, diagnostic criteria for probable and definite CAA-ri have been proposed.3 According to this proposal, diagnosis of probable CAA-ri can be made if a patient 40 years or older presents with typical clinical and radiologic features. Nevertheless, as we discussed in our case, some presentations typically associated with other disorders (as transient recurrent neurologic symptoms or stroke-like symptoms) could in fact be an atypical presentation of CAA-ri. The concomitant presence of patchy or confluent T2 or fluid-attenuated inversion recovery hyperintensities with evidence of CAA on susceptibilityweighted sequence should be seen as suggestive of CAA-ri. In a patient older than 50 years with vascular risk factors, acute onset of neurologic focal signs usually points to the diagnosis of stroke. A recent and transient episode
of aphasia would reinforce this diagnosis. At the same time, the youngest reported case of CAA-ri was a 42-year-old patient, and the average age of onset is 68 (Table 1), making both CAA-ri and stroke more common in elderly populations. On a stroke-like presentation with an atypical course, MRI becomes necessary to the differential diagnosis. From our literature review, microbleeds are present in almost 90% of the reported CAA-ri cases. As proposed by Chung et al,3 the presence of microbleeds in a patient with asymmetric T2-hyperintense lesions should suggest the possibility of a diagnosis of CAA-ri. Recognition of the CAA pattern could preclude more invasive testing, such as brain biopsy, and allow an early start to therapy. Currently, there is no clear ‘‘optimal’’ therapeutic regimen for CAA-ri. Treatment is usually started with corticosteroids (alone or in addition to cyclophosphamide in nearly 20% of cases) leading to some improvement in the majority of patients (Table 1). But although some patients recovered without any treatment (2 patients in Martucci series5), others who did not respond to steroid treatment needed the addition of other drugs (cyclophosphamide, mycophenolate mophetil, or IV immunoglobulin). Even facing a high improvement ratio, the multidrug regimen was not successful in at least 2 subjects. There may be different pathologic mechanisms leading to different treatment responses, but further studies are necessary to clarify the patient populations in need of more aggressive and prolonged immunosuppressive treatment. The efforts of a recent international collaborative network (Inflammatory CAA and AD Biomarkers International Network) could help to clarify these needs. In our case, lack of an anatomopathologic study precludes a definite diagnosis of CAA. Nevertheless, pathologically documented cases of reversible encephalopathy with microbleeds have consistently resulted in this diagnosis. ApoE genotype ε4/ε4 seems to be particularly over-represented in CAA-ri patients, with up to 61% of patients having this genotype (Table 1). As this genotype is rarely found in healthy (0 of 398 subjects) or acute stroke subjects (6 of 100), we believe it could be a helpful marker in the diagnosis of CAA-ri.50
Conclusions In conclusion, CAA-ri may have a stroke-like presentation and the presence of microbleeds should put the clinics on the track of this diagnosis. Despite a lack of clinical trials, immunosuppressive treatment seems to have a role in the treatment of this disorder. Early recognition of CAA-ri allows for an early start of treatment. As relapses do occur,5 further studies are necessary to clarify which patient populations have a higher relapse risk and which need more aggressive and prolonged therapy. An international effort could contribute to solve this issue.
MICROBLEEDS AND THE DIAGNOSIS OF CAA-RELATED INFLAMMATION Acknowledgment: We are grateful to Aaron Koralek, PhD for his review of the final manuscript.
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44. Machida K, Tojo K, Naito KS, et al. Cortical petechial hemorrhage, subarachnoid hemorrhage and corticosteroidresponsive leukoencephalopathy in a patient with cerebral amyloid angiopathy. Amyloid 2008;15:60-64. 45. Oh U, Gupta R, Krakauer JW, et al. Reversible leukoencephalopathy associated with cerebral amyloid angiopathy. Neurology 2010;62:494-497. 46. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 2004;55:250-256. 47. Harkness KA, Coles A, Pohl U, et al. Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy. Eur J Neurol 2004;11:59-62. 48. Wong SH, Robbins PD, Knuckey NW, et al. Cerebral amyloid angiopathy presenting with vasculitic pathology. J Clin Neurosci 2006;13:291-294. 49. Savoiardo M, Erbetta A, Di Francesco JC, et al. Cerebral amyloid angiopathy-related inflammation: an emerging disease. Neuroradiol J 2011;24:253-257. 50. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian case-control study. Stroke 1998;29:399-403.
Stroke-Like Episodes Heralding a Reversible Encephalopathy: Microbleeds as the Key to the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation—A Case Report and Literature Review Marcelo D. Mendonc¸a, MD,*† Andre Caetano, MD,* Miguel Pinto, MD,* Vera Cruz e Silva, MD,‡ and Miguel Viana-Baptista, MD, PhD*†
Background: Cerebral amyloid angiopathy (CAA) is a common, often asymptomatic disease. Lobar intracerebral hemorrhage is the most frequent manifestation of CAA. Nevertheless, presentation of CAA with subacute cognitive decline, seizures, or headache with concomitant hyperintensities on T2-weighted magnetic resonance imaging (MRI) sequences and neuropathologic evidence of inflammation has been described. This disorder is known as CAA-related inflammation (CAA-ri). Methods: Description of a stroke-like presentation of CAA-ri and systematic review of case reports and case series of CAA-ri. Results: A 75-year-old woman with a history of atrial fibrillation, and a transient episode of aphasia 2 days before, presented in the emergency room with sudden onset aphasia. Brain computed tomography disclosed a left temporal hypodensity. A diagnosis of probable stroke was given. During the following days, there was a progressive clinical deterioration. MRI revealed coalescent edematous white matter lesion, hyperintense on T2-weighted sequences, and multiple lobar microbleeds on T2*-weighted sequences. A diagnosis of CAA-ri was considered, and the patient was started on steroids with clinical and imaging improvement. From our systematic review, microbleeds were present in almost 90% of patients with CAA-ri. Conclusions: Imaging findings associated with CAAri allow the early diagnosis and treatment of this potentially reversible disorder. Aside from the most common subacute presentations, CAA-ri can have a strokelike presentation and be a stroke mimic. Key Words: Stroke—cerebral amyloid angiopathy—cerebral amyloid angiopathy-related inflammation—microbleeds. Ó 2015 by National Stroke Association
Cerebral amyloid angiopathy (CAA) is a common, often asymptomatic, disease characterized by deposition of amyloid-b in cortical and leptomeningeal vessels. A definite
diagnosis requires a neuropathologic study, but probable CAA criteria have been defined on clinical and neuroimaging grounds, namely the presence of microbleeds on
From the *Neurology Department, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal; †Centro de Estudos de Doenc¸as Cr onicas (CEDOC), Nova Medical School/Faculdade de Ci^encias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal; and ‡Neuroimaging Department, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal. Received January 30, 2015; revision received April 2, 2015; accepted April 12, 2015.
The authors have reported no conflicts of interest. The authors report no relevant funding for the present study. Address correspondence to Marcelo D. Mendonc¸a, MD, Neurology Department, Hospital Egas Moniz—Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1349-019 Lisbon, Portugal. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.042
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T2*-weighted magnetic resonance imaging (MRI). Lobar intracerebral hemorrhage is the most common manifestation of CAA.2 Nevertheless, some CAA patients present a subacute cognitive decline, seizures, or headache with hyperintensities on T2-weighted MRI sequences and neuropathologic evidence of inflammation. This disorder is known as CAA-related inflammation (CAA-ri).2 An isolated abrupt onset of focal symptoms seems to be an infrequent feature, and to our knowledge, an ictal/ stroke-like presentation has never been recognized as the CAA-ri heralding manifestation. Early identification of the findings associated with CAA-ri allows early diagnosis, treatment, and avoidance of more aggressive diagnostic tests.
Case Report A 75-year-old woman was admitted in the emergency room with acute-onset aphasia. There was a history of a transient episode of aphasia 2 days before. The patient had a medical history of autoimmune thyroiditis and anxiety disorder and hypertension and dyslipidemia as vascular risk factors. She was on fluvastatin, bisoprolol, levothyroxine, alprazolam, brotizolam, domperidone,
altizide, and spironolactone and had no relevant family history. There was no history of alcohol, tobacco, or other drug use. On admission, she was afebrile and normotensive. General examination was unremarkable and neurologic examination only disclosed expression aphasia. Brain computed tomography revealed a left temporal hypodensity (Fig 1, A). The patient was admitted to an internal medicine inpatient unit with the diagnosis of stroke. On the following days, clinical deterioration with signs of left hemisphere dysfunction was accompanied by imaging progression. Successive MRIs (Fig 1, B-D) disclosed an increasingly coalescent edematous white matter lesion, hyperintense on T2-weighted sequences, and the presence of multiple lobar microbleeds on T2*-weighted sequences (Fig 1, B-1). There was no evidence of lesions with restriction on diffusion-weighted imaging at any time point. The patient was transferred to the neurology department 12 days after admission. At this time, she was afebrile and presented a decreased level of consciousness, global aphasia, and right hemiparesis. Cerebrospinal fluid revealed 282 mg/dL of proteins and 10 lymphocytes/mL, and viral polymerase chain reaction was negative for neurotropic viruses, including herpes simplex viruses 1 and 2 (a positive polymerase
Figure 1. (A) Computed tomography scan performed at admission: left temporal hypodensity with edema. (B-D) Brain magnetic resonance imaging before steroid therapy at D2 (B), D4 (C), and D12 (D). (B-1) T2*-weighted imaging with multiple microbleeds (arrowheads). T2-weighted image (B-2) and T2 fluidattenuated inversion recovery images (FLAIR) (C and D) showing progression of confluent white matter hyperintensities from D2 (B-2) until D12 (D). (E and F) FLAIR-weighted imaging after steroid treatment. Regression of T2-weighted hyperintense lesions 30 days after onset (E) and 9 months after steroid therapy (F) (except for those attributed to age-related white matter lesion).
Table 1. Summary of clinical, MRI, and therapeutic findings in previous cases of CAA-ri
Martucci et al5
Salvarani et al4
Piazza et al6
Kinnecom et al2
Scolding et al7
N Age (min-max) M/F ApoE genotype ApoE4/ApoE4 ApoE3/ApoE3 ApoE2/ApoE3 Other Clinical presentation Subacute cognitive decline and/or behavioral changes Headache Seizures Focal neurologic signs Gait abnormalities Other* Neuroimaging findings White matter changes Microbleeds Treatment No treatment Steroids Cyclophosphamide Azathioprine MMF IVIg Other immunosuppressive drug not specified Anatomopathologic study Outcome Improvement
10 75 (63-83) 3/7 NA
38 67 (42-84) 19/19 NA
10 68 (56/76) 6/4
14 63 (45-79) 9/5
9 69 (54-82) 5/4 NA
4/9 4/9 0 1/9
44% 44% 0% 11%
10/13 0/13 2/13 1/13
77% 0% 15% 8%
Summary (including current report)
50 68 (44-93) 23/27
132 68 (42-93) 65/67
7/13 2/13 4/13 0
54% 15% 31% 0%
22/36 6/36 6/36 2/36
61% 17% 17% 6%
6
60%
25
66%
9
90%
13
93%
8
89%
31
62%
92
70%
3 3 7 2 0
30% 30% 70% 20% 0%
15 20 12 0 0
39% 53% 32% 0% 0%
0 4 2 0 1
0% 40% 20% 0% 10%
6 6 1 0 1
43% 43% 7% 0% 7%
2 1 5 0 0
22% 11% 56% 0% 0%
12 16 28 3 9
24% 32% 56% 6% 18%
38 50 56 5 11
29% 38% 42% 4% 8%
10 9
100% 90%
10 8/9
100% 89%
12/12
100%
7/9
78%
47/48 25/30
98% 83%
87/90 43/49
97% 88%
2 8 0 0 0 0 0
20% 80% 0% 0% 0% 0% 0%
3 7 0 0 0 0 0
30% 70% 0% 0% 0% 0% 0%
0 12/12 3/12 0 0 0 0
0% 100% 25% 0% 0% 0% 0%
0 8 2 0 0 0 0
0% 89% 22% 0% 0% 0% 0%
3/49 45/49 15/49 4/49 2/49 1/49 1/49
6% 92% 31% 8% 4% 2% 2%
21/129 93/129 29/129 6/129 2/129 1/93 3/129
16% 72% 22% 5% 2% 1% 2%
2
20%
12
86%
9
100%
42
84%
103/122
84%
10
100%
12
100%
4
44%
41/49
84%
68/81
84%
NA
NA NA
13 12 9 2 0 NA 2
34% 32% 24% 5% 0% NA 5%
38 100% 71% with mRS (score 0-3) at last follow-up
NA
NA
e3
Abbreviations: IVIg, intravenous human immunoglobulin; max, maximum; min, minimum; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NA, not available. Search was performed using as keywords ‘‘cerebral amyloid angiopathy related inflammation,’’ ‘‘(cerebral OR brain OR encephali*) amyloid angiopath* inflamm*,’’ and ‘‘Amyloid-Beta AND Angiitis.’’ We identified all published case reports or case series on the subject. Studies on Primary angiitis of the central nervous system with CAA were not included. We excluded those without information available in English, Spanish, or Portuguese. A total of 54 potentially relevant studies (case series or case reports) were identified. From this group, 5 were excluded based on a language criteria and one on repetition of subjects. From the remaining 48 studies, 5 were case series and 5 were collections of up to 3 case reports. Two of the 3 patients in a publication49 were described in previous case reports,36,37 so only the new case was included. A total of 131 previously described patients were identified. The results of the 5 largest case series are presented separated from the case reports. If no information was provided about the realization of a biopsy or necropsy on the case reports, we considered it not done. The last column summarizes the information from the 131 previously described patients with the addition of the current case. *Other rarer manifestations include progression to coma in 4 cases, myoclonic tremor in 2 cases, recurrent transient, positive, or migratory neurologic symptoms in 3 cases, Parkinsonian signs in 1 patient, and bilateral uveitis in 1 case.
MICROBLEEDS AND THE DIAGNOSIS OF CAA-RELATED INFLAMMATION
Variables
Case reports3,8-49
M.D. MENDONC¸A ET AL.
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chain reaction result for HHV6 was present but deemed unrelated to the clinical picture). EEG revealed diffuse slowing with bilateral temporal dysfunction without periodic activity. Diagnostic workup was negative for HIV, syphilis, JC virus, anti-Hu, CV2, Ma2, amphiphysin, N-methyl-D-aspartate receptor (NMDAR), and Voltage gated potassium channel (VGKC). Chest, abdomen, and pelvis scans did not presented evidence of a neoplastic process. Tumor markers (CEA, CA 19.9, CA 15.3, CA 125, NSE, and Cyfra 21.1) were negative. ApoE genotype was ε4/ε4. The patient was started on intravenous (IV) acyclovir 600 mg twice a day for 14 days as viral encephalitis was not excluded at this time and 1 g/d of IV methylprednisolone for 5 days for CAA-ri. After this, the patient was started on 60 mg oral prednisolone that was slowly tapered over the course of 6 months. Five days after steroid therapy, an improvement of neurologic status was noted. A complete recovery was clear at 15 days and accompanied by improvement in MRI findings at 30 days (Fig 1, E). Six months later, there were no focal signs on the neurologic examination, and a complete reversion of the MRI findings was seen 9 months later (Fig 1, F).
Discussion CAA-ri is a potentially treatable encephalopathy3 with a mortality rate up to 30%4 and a vast clinical presentation.2,3 Table 1 presents a summary of the clinical presentations, treatment regimens, and outcomes found in a systematic literature review (details in the table). From a total of 132 subjects, the main presenting symptoms are mental status and cognitive changes (70%), focal neurologic deficits (42%), headache (29%), and seizures (38%), frequently in combination. Uncommon presentations include transient positive recurrent neurologic symptoms. Interestingly, a stroke-like presentation does not seem to have been previously recognized. Facing the clinical and pathologic heterogeneity of this disorder, diagnostic criteria for probable and definite CAA-ri have been proposed.3 According to this proposal, diagnosis of probable CAA-ri can be made if a patient 40 years or older presents with typical clinical and radiologic features. Nevertheless, as we discussed in our case, some presentations typically associated with other disorders (as transient recurrent neurologic symptoms or stroke-like symptoms) could in fact be an atypical presentation of CAA-ri. The concomitant presence of patchy or confluent T2 or fluid-attenuated inversion recovery hyperintensities with evidence of CAA on susceptibilityweighted sequence should be seen as suggestive of CAA-ri. In a patient older than 50 years with vascular risk factors, acute onset of neurologic focal signs usually points to the diagnosis of stroke. A recent and transient episode
of aphasia would reinforce this diagnosis. At the same time, the youngest reported case of CAA-ri was a 42-year-old patient, and the average age of onset is 68 (Table 1), making both CAA-ri and stroke more common in elderly populations. On a stroke-like presentation with an atypical course, MRI becomes necessary to the differential diagnosis. From our literature review, microbleeds are present in almost 90% of the reported CAA-ri cases. As proposed by Chung et al,3 the presence of microbleeds in a patient with asymmetric T2-hyperintense lesions should suggest the possibility of a diagnosis of CAA-ri. Recognition of the CAA pattern could preclude more invasive testing, such as brain biopsy, and allow an early start to therapy. Currently, there is no clear ‘‘optimal’’ therapeutic regimen for CAA-ri. Treatment is usually started with corticosteroids (alone or in addition to cyclophosphamide in nearly 20% of cases) leading to some improvement in the majority of patients (Table 1). But although some patients recovered without any treatment (2 patients in Martucci series5), others who did not respond to steroid treatment needed the addition of other drugs (cyclophosphamide, mycophenolate mophetil, or IV immunoglobulin). Even facing a high improvement ratio, the multidrug regimen was not successful in at least 2 subjects. There may be different pathologic mechanisms leading to different treatment responses, but further studies are necessary to clarify the patient populations in need of more aggressive and prolonged immunosuppressive treatment. The efforts of a recent international collaborative network (Inflammatory CAA and AD Biomarkers International Network) could help to clarify these needs. In our case, lack of an anatomopathologic study precludes a definite diagnosis of CAA. Nevertheless, pathologically documented cases of reversible encephalopathy with microbleeds have consistently resulted in this diagnosis. ApoE genotype ε4/ε4 seems to be particularly over-represented in CAA-ri patients, with up to 61% of patients having this genotype (Table 1). As this genotype is rarely found in healthy (0 of 398 subjects) or acute stroke subjects (6 of 100), we believe it could be a helpful marker in the diagnosis of CAA-ri.50
Conclusions In conclusion, CAA-ri may have a stroke-like presentation and the presence of microbleeds should put the clinics on the track of this diagnosis. Despite a lack of clinical trials, immunosuppressive treatment seems to have a role in the treatment of this disorder. Early recognition of CAA-ri allows for an early start of treatment. As relapses do occur,5 further studies are necessary to clarify which patient populations have a higher relapse risk and which need more aggressive and prolonged therapy. An international effort could contribute to solve this issue.
MICROBLEEDS AND THE DIAGNOSIS OF CAA-RELATED INFLAMMATION Acknowledgment: We are grateful to Aaron Koralek, PhD for his review of the final manuscript.
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