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Table of Contents    
SPECIAL NI FEATURE - CLINICAL PATHOLOGICAL CONFERENCE
Year : 2020  |  Volume : 68  |  Issue : 1  |  Page : 17-19

A 66 Year Old Woman with Recurrent Stroke


1 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
2 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

Date of Web Publication28-Feb-2020

Correspondence Address:
Dr. Aneesh B Singhal
Department of Neurology, ACC-729-C, 55 Fruit St, Boston, MA - 02114
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.279684

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 » Abstract 


Recurrent strokes involving various arterial territories can carry a broad differential diagnosis. Multiple progressive infarcts in a patient with clinical signs and symptoms out of proportion to their infarct pattern on imaging should compel the clinician to broaden the differential to include inflammatory causes of stroke also. A stepwise approach, using clinical, imaging and laboratory clues to direct further invasive testing is required for proper diagnosis and management in such cases. We present the case of a 66 year old woman with recurrent strokes over the span of a few weeks with deficits and mental status changes out of proportion to her infarcts on MRI brain and an inflammatory CSF. Since commencement of treatment for the underlying inflammatory cause of her strokes, she has remained stroke free for over two years in follow up.


Keywords: Autoimmune diseases, infarction, meningitis, MRI, vasculitis
Key Messages: Inflammatory causes of stroke are treatable, and should be on the differential diagnosis for recurrent strokes in a patient with minimal vascular risk factors particularly when clinical signs and symptoms are out of proportion to the infarcts seen on imaging.


How to cite this article:
Kharal G A, Sylaja P N, Singhal AB. A 66 Year Old Woman with Recurrent Stroke. Neurol India 2020;68:17-9

How to cite this URL:
Kharal G A, Sylaja P N, Singhal AB. A 66 Year Old Woman with Recurrent Stroke. Neurol India [serial online] 2020 [cited 2020 Mar 31];68:17-9. Available from: http://www.neurologyindia.com/text.asp?2020/68/1/17/279684




A 66-year-old woman developed sudden right leg weakness, which resolved within minutes. One hour later, she developed sensory loss in the right arm that resolved gradually over a few hours. She then noted gait imbalance and an inability to concentrate or complete conversations. Her symptoms persisted for 1 week.

Her past medical history included hypertension, hyperlipidemia, chronic renal insufficiency, gout, asthma, autoimmune hepatitis, migraine, and transient uveitis 2 months prior to admission. She carried a diagnosis of pulmonary sarcoidosis since the 1970s, treated with chronic immunosuppressive therapy which was discontinued 9 months prior to admission since she had been asymptomatic for over a decade. She did not take any regular medications. She had intentionally lost 28 pounds of weight over the past one year. She did not smoke, or abuse alcohol or illicit drugs.

On admission, her cognitive status and cranial nerve, motor, and sensory examination findings were normal. Motor reflexes were brisk on the right side. Plantar reflexes were equivocal. Her gait was ataxic. The cerebellar examination was otherwise normal.


 » What Initial Work-Up Is Indicated? Top


Brain MRI showed acute and subacute infarcts in the left thalamus, left lentiform nucleus and left temporal lobe [Figure 1]a-c]. Susceptibility-weighted images were normal. MR-angiography of the head and neck arteries was normal. Contrast-enhanced cervical and thoracic spine MRI showed no lesions. Serological laboratory tests showed total cholesterol 189 mg/dL (ref. range <200 mg/dL), high-density lipoprotein 34 mg/dL (ref. range 35–100 mg/dL), low-density lipoprotein130 mg/dL (ref. range 50–129 mg/dL), total cholesterol 126 mg/dL (ref. range 40–150 mg/dL), thyroid stimulating hormone 3.09 mU/ml (ref. range 0.4–5.00 mU/ml), glycosylated hemoglobin (A1C) level 4.6% (ref. range 4.3–6.4%), erythrocyte sedimentation rate 18 mm/hr (ref. range 0–20 mm/hr), and C-reactive protein level 4 mg/L (ref. range 0–8 mg/L). Cardiac ultrasound with bubble study and inpatient telemetry were normal. She was treated with daily aspirin 81 mg and atorvastatin 80 mg pending further tests for stroke mechanism.
Figure 1: Serial brain MRI and Histopathology. (a) Admission diffusion-weighted axial image (DWI) shows an acute small infarct in the left thalamus (arrow). (b and c) Admission fluid-attenuated inversion recovery (FLAIR) axial images show small subacute infarcts in the left thalamusand fronto-temporal region (arrows). (d) Follow-up DWI obtained 4 days after admission shows a new infarct in the left putamen (arrow). (e) Follow-up FLAIR obtained 4 days after admission shows a new subacute infarct in the right thalamus (arrow) and evolution of the prior infarct in the left thalamus. (f) Histopathology (hematoxylin-eosin stain) from the right hemisphericleptomeningeal brain biopsy shows a peri-vascular non-caseating granuloma with multinucleated giant cell (arrow) and lymphocytic infiltration

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Over the next 4 days the patient developed progressive non-positional headaches. She became irritable and somnolent. A follow-up brain MRI [Figure 1]d and [Figure 1]e showed interval development of new small infarcts in the right thalamus and left putamen, and evolution of the left thalamic and parenchymal infarcts. Mild leptomeningeal enhancement overlying the temporal and parietal sulci were noted on post-gadolinium images (not shown). Perfusion-MRI was normal.


 » What Additional Tests Should Be Considered? Top


Cerebrospinal fluid (CSF) examination was performed to investigate for inflammatory, autoimmune or infectious etiologies. The CSF total protein level was148 mg/dl (normal, 15–45 mg/dl), glucose 45 mg/dl (normal, 50–80 mg/dl), and total nucleated cells 164 per μL in Tube 1 and 98 per μL in Tube 2 (normal, 0–5 cells/μL), with a lymphocytic predominance.


 » What Is the Differential Diagnosis? What Additional Tests Should be Performed? Top


Section 2

The accumulating clinical deficits, recurrent small infarcts, leptomeningeal enhancement, and abnormal CSF findings suggest an inflammatory or infectious process. The differential diagnosis includes (1) systemic vasculitis with CNS involvement; (2) infectious CNS vasculitis; (3) primary angiitis of the CNS (PACNS); (4) sarcoidosis with vasculitic CNS involvement; and (5) intravascular lymphoma. Examples of systemic vasculitis that can affect the brain arteries include polyarteritis nodosa, Giant cell arteritis, antineutrophil cytoplasmic antibody (ANCA) vasculitis, Behcet's disease with CNS involvement, and systemic lupus erythematosus. Stroke from infection can result from bacterial (e.g. spirochete, mycobacterium, lyme), fungal (e.g. aspergillus, candida, cryptococcus, mucormycosis) and viral (e.g. varicella-zoster) infections.

CSF cultures were negative for bacterial, mycobacterial, fungal, and viral infections. Quantiferon tuberculosis PCR, lyme serologies and CSF varicella-zoster virus (IgM/IgG antibodies and polymerase chain reaction) were negative. ANA was positive at 1:40 (speckled pattern). Erythrocyte sedimentation rate and C-reactive protein were normal. Extensive rheumatological panel tests including rheumatoid factor, anti-double stranded DNA, anti-Ro, and anti-La antibodies were negative. Serum complement levels were normal.


 » How Does This Help Narrow the Differential? Top


The lack of systemic signs and symptoms such as fever, night sweats, skin rash, oral or genital ulcers, arthralgias, myalgias, palpable purpura, combined with the normal serum inflammatory marker levels, white blood counts, kidney and liver function tests made a systemic vasculitis unlikely. The past history of receiving prolonged immunosuppressive therapy, the subacute progression of symptoms, the abnormal CSF findings (elevated proteins, cells, hypoglycorrhacia) and leptomeningeal involvement, raise concern for insidious infections such as mycobacterial or fungal meningitis/vasculitis.[1] However, the absence of signs of meningeal irritation, the negative CSF cultures, negative Quantiferon TB gold test, and lack of exposure to tuberculosis, made tuberculosis or fungal vasculitis less likely. Moreover, stroke as a first manifestation of fungal meningitis is rare, except for angio-invasive aspergillosis; this entity most commonly involves both large and medium size vessels (e.g., internal carotid and distal middle cerebral artery) and more often causes intracerebral hemorrhage from ruptured mycotic aneurysms.[2]


 » Section 3 Top


Further tests were performed. CSF cytology was normal. The serum angiotensin converting enzyme level (ACE) was normal. ANCA-MPO (myeloperoxidase) antibody titer was positive. Positron emission tomography (PET) scan showed increased fluoro deoxy-glucose (FDG) uptake in the inguinal and axillary lymph nodes; these lymph nodes were also enlarged on a pelvic CT scan performed a year prior.

This patient's brain MRI and CSF results raise the possibility of intravascular lymphoma and PACNS.[3] Despite the absence of abnormal lymphomatous cells on CSF cytology, intravascular lymphoma could not be excluded.[4] Sarcoidosis was another consideration, however elevated ANCA-MPO antibody titers can be positive in various inflammatory or autoimmune disorders and only 5–10% of patients with neurosarcoidosis develop a cerebral arteriopathy.[5] Moreover, her PET CT scan results showed no new areas of lymphadenopathy, and she had not manifested symptoms of sarcoidosis for the past decade.

The patient underwent a leptomeningeal biopsy targeting the affected regions in the right hemisphere. Histopathology showed perivascular granulomatous inflammation and peri-vascular non-caseating granulomas [Figure 1]f. These findings were consistent with granulomatous cerebral arteritis from neurosarcoidosis.[6]


 » Discussion Top


Sarcoidosis, first described in 1877 by Sir Jonathan Hutchinson, is a granulomatous disease that can involve any organ in the body. Brain involvement occurs in 5–15% cases.[7] Neurosarcoidosis can manifest with aseptic meningitis, raised intracranial pressure, cranial neuropathy, endocrinopathy from hypothalamus and pituitary gland involvement, parenchymal nodules, psychiatric manifestations, and spinal cord lesions.[7]

Granulomatous angiitis causing recurrent strokes is a rare complication.[5],[8] Both ischemic and hemorrhagic strokes can occur due to inflammation, thrombosis, and fragility of the vessel wall. Pathology typically shows peri-vascular granuloma formation, although direct granulomatous invasion of blood vessels is also reported.[9] Small- and medium-sized arteries are preferably affected and thus cerebral angiography is usually normal.[9]

Immunosuppressive agents, particularly steroids in the acute period, followed by steroid sparing-agents e.g., tumor necrosis factor-alpha (TNF-a) inhibitors, appear to be promising treatments.[7],[10] Our patient was treated with intravenous methylprednisone 1 gram daily for 3 days followed by 60 mg prednisone daily. Her neurological deficits resolved over a span of 1-2 weeks. She was then started on infliximab, a TNF-a inhibitor, and prednisone was tapered off over a few months. She has remained stable without clinical or radiographic relapses over a follow-up period of 2 years.

Our case has several educational aspects. Multiple acute small infarcts in various arterial territories, carry a broad differential diagnosis. A step-wise approach, using clinical, imaging and laboratory clues to direct further invasive tests such as CSF examination and a targeted brain biopsy, is required for proper diagnosis and management. Stroke from neurosarcoidosis-associated granulomatous angiitis can develop many years after systemic sarcoidosis. It can be the first manifestation of CNS involvement from sarcoidosis. Inflammatory cerebral arteriopathies are a treatable cause of stroke. Prognosis in such cases can be favorable if the underlying inflammatory process is identified and treated promptly.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Disclosure: This case was discussed as a CPC (discussant, PN Sylaja, MD) at the Indian Stroke Conference 2017.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Garkowski A, Zajkowska J, Moniuszko A, Czupryna P, Pancewicz S. Infectious causes of stroke. Lancet Infect Dis 2015;15:632.  Back to cited text no. 1
    
2.
Starkey J, Moritani T, Kirby P. MRI of CNS fungal infections: Review of aspergillosis to histoplasmosis and everything in between. Clin Neuroradiol 2014;24:217-30.  Back to cited text no. 2
    
3.
Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: Diagnostic criteria and clinical approach. Cleve Clin J Med 1992;59:293-306.  Back to cited text no. 3
    
4.
Fonkem E, Dayawansa S, Stroberg E, Lok E, Bricker PC, Kirmani B, et al. Neurological presentations of intravascular lymphoma (IVL): Meta-analysis of 654 patients. BMC Neurol 2016 ;16:9.  Back to cited text no. 4
    
5.
Younger DS. Granulomatous angiitis. Neurol Clin 2019;37:267-77.  Back to cited text no. 5
    
6.
Rosen Y. Pathology of sarcoidosis. Semin Respir Crit Care Med 2007;28:36-52.  Back to cited text no. 6
    
7.
Iannuzzi MC, Rybicki BA, Teirstein AS. Medical progress. Sarcoidosis. N Eng J Med 2007;357:2153-65.  Back to cited text no. 7
    
8.
Meyer JS, Foley JM, Campagna-Pinto D. Granulomatous angiitis of the meninges in sarcoidosis. AMA Arch Neurol Psychiatry 1953;69:587-600.  Back to cited text no. 8
    
9.
Jachiet V, Lhote R, Rufat P, Pha M, Haroche J, Crozier S, et al. Clinical, imaging, and histological presentations and outcomes of stroke related to sarcoidosis. J Neurol 2018;265:2333-41.  Back to cited text no. 9
    
10.
Gelfand JM, Bradshaw MJ, Stern BJ, Clifford DB, Wang Y, Cho TA, et al. Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series. Neurology 2017;89:2092-100.  Back to cited text no. 10
    


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