A 66 Year Old Woman with Recurrent Stroke
Keywords: Autoimmune diseases, infarction, meningitis, MRI, vasculitisKey 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.
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.
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.
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.
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.
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.
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. 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.
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. Despite the absence of abnormal lymphomatous cells on CSF cytology, intravascular lymphoma could not be excluded. 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. 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.
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. 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.
Granulomatous angiitis causing recurrent strokes is a rare complication., 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. Small- and medium-sized arteries are preferably affected and thus cerebral angiography is usually normal.
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., 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.
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