Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 55, Num. 3, 2009, pp. 214-219

Journal of Postgraduate Medicine, Vol. 55, No. 3, July-September, 2009, pp. 214-219

Grand Round Case

A 25-year-old man with progressive left-sided weakness and a mass lesion on brain imaging

Franco T¹ , Roque C¹ , Khorasanizadeh S² , McCullough LD^2,3

¹ Department of Internal Medicine, The University of Connecticut Health Center,
² Department of Neurology, The Stroke Center at Hartford Hospital and the University of Connecticut Health Center,
³ Department of Neuroscience, The University of Connecticut Health Center, Farmington CT, 06030, USA

Correspondence Address: Dr. LD McCullough, Department of Neurology, The Stroke Center at Hartford Hospital and the University of Connecticut Health Center, Farmington CT, 06030; Department of Neuroscience, The University of Connecticut Health Center, Farmington CT, 06030
lmccullough@uchc.edu

Date of Submission: 06-Dec-2008
Date of Decision: 18-Jul-2009
Date of Acceptance: 31-Jul-2009

Code Number: jp09066

PMID: 19884753

DOI: 10.4103/0022-3859.57409

A 25-year-old left-handed man presented with progressive left-sided weakness for three days. On the day of admission, the patient reported that his left lower extremity buckled beneath him and that he had to drag his left leg in order to walk. The patient was healthy and denied any constitutional symptoms, joint pains, rash or seizures. There was no recent trauma.

On physical exam, the patient appeared his stated age and was in no acute distress. Vital signs were normal. Heart, lung and abdominal exams were normal. There was no rash, skin lesions or joint swelling. On neurological exam his mental status was intact, with normal speech, comprehension and mental status. There was no neglect or visual field cut. Cranial nerve testing was normal except for mild left nasolabial fold flattening. There was no papilledema or optic atrophy. A mild 4/5 left-sided hemiparesis was present with increased tone in both the arm and the leg. The patient demonstrated marked slowing and impairment of fine motor coordination in the left hand but finger to nose testing revealed no dysmetria. Sensation of the left lower extremity was intact. However, two-point discrimination was mildly impaired in the left upper extremity. Left-sided reflexes were hyperactive with clonus at the ankle, with a positive Babinski. He walked with a wide-based gait, circumducting the left leg during the swing phase with flexion of the left arm.

What are the Possible Diagnoses in this Patient?

Most importantly when evaluating this patient, one must first localize the lesion so appropriate studies can be performed. His clinical course is quite acute. The facial weakness implies a central lesion, and as his weakness is on the same side as his arm and leg weakness, this suggests that the lesion is above the brainstem. He has signs of upper motor neuron dysfunction (corticospinal tract) with increased reflexes and clonus. There are some sensory changes in the upper extremity suggesting that the lesion is not limited to the motor tracts. He has no cortical signs (i.e., aphasia, neglect or visual field loss) and his mental status is intact. This implies primarily a subcortical lesion in the right hemisphere.

1. Multiple sclerosis or demyelinating disease.
2. Vascular event. In an older patient with risk factors this would be the most likely, although this clinical syndrome would usually not have sensory changes and could represent a "pure motor stroke" in the internal capsule. A dissection, hypercoagulable state or a patent foramen ovale should be considered in a young patient with focal findings.
3. Infection. His HIV status would be critical to evaluate, as well as any history of intravenous drug use.
4. Tumor. Although the clinical presentation seems quite acute, often a mass lesion can present with minimal symptoms until hydrocephalous, seizure, or weakness occurs.

What Diagnostic Test Would You Perform?

Neuroimaging would be the first step in the evaluation. His symptoms localize to the central nervous system CNS and facial weakness on the same side as the arm and leg weakness suggests that the lesion is in the brain above the facial nerve nucleus (in the pons). A computerized tomography (CT) scan could be considered as an initial step, although magnetic resonance imaging (MRI) with gadolinium is likely to be much more sensitive, especially for demyelinating disease. This has to be done prior to any consideration of obtaining spinal fluid. Although he had no papilledema, this can often be hard to determine with a non-dilated eye exam, and if the process is relatively acute, optic disc swelling may not have developed.

MRI showed a large ill-defined heterogeneous enhancing mass along the margins of the right lateral ventricle with diffuse associated signal abnormality consistent with white matter edema [Figure - 1]. No hemorrhage was seen. The fourth ventricle was patent. The differential at this point was a demyelinating disease, an infection, or most likely a glial tumor. His exam was surprisingly benign for the degree of edema and the size of the mass. This is consistent with a primary CNS tumor, which can often grow to a large size before clinical symptoms appear.

Other Investigations

A lumbar puncture was performed. The cerebrospinal fluid (CSF) was negative for malignant cells and oligoclonal bands. Cytology and flow cytometry were performed on the small number of cells present and were negative for monoclonal cell populations which would be diagnostic for lymphoma. ^[1],[2] Protein, glucose and opening pressure were all within normal limits. Polymerase chain reaction (PCR) for herpes simplex virus (HSV-1 and HSV-2), JC virus (as seen with progressive multifocal leukoencephalopathy),, and Tuberculosis (TB) were negative. CSF angiotensin-converting enzyme levels were not elevated (as can be seen in sarcoidosis). Serology was remarkable for a positive antinuclear antibody test (ANA). However, further rheumatologic evaluation showed negative titers for specific antibodies and the diagnosis of a systemic vasculitis was excluded. Infectious causes were ruled out with serology that was negative for Bartonella, HIV, toxoplasmosis (IgG and IgM) and cytomegalovirus (CMV). An electroencephalogram (EEG) was within normal limits without any evidence of seizure activity.

Due to the MRI appearance of the lesion, and the high likelihood of a CNS tumor, the patient underwent a brain biopsy. The biopsy specimen [Figure - 2] showed a patchy chronic lymphocytic infiltrate that was mainly perivascular, consistent with CNS vasculitis. All special stains for organisms including TB were negative as was PCR for JC virus, CMV, HSV 1 and 2, Epstein-Barr virus (EBV) and varicella zoster virus (VZV). There was no evidence of abscess formation or non-caseating granulomatous inflammation (indicative of neurosarcoid). Immunohistochemical analysis showed a mixed lymphocytic infiltrate (CD45, CD3 and CD20), making lymphoma unlikely. There was no evidence of demyelination on luxol blue stain, myelin phagocytosis by macrophages, or perivenular infiltrates that would suggest a diagnosis of multiple sclerosis or demyelination. After a brief course of steroids his symptoms substantially improved. The patient refused other immune-modulating agents. He has remained stable with no clinical symptoms for over two years.

What is the Usual Clinical Presentation of CNS Vasculitis?

Primary angiitis of the central nervous system (PACNS) is a term that describes a spectrum of disorders that are rare and of unknown etiology. The disorder most commonly presents in males in the fourth to sixth decades of life, but can be seen at any age in either sex. ^{[3],[4],[5],[6],[7]} The clinical presentation of PACNS is variable, but most patients present with headache and encephalopathy. Focal neurological signs are rare, occurring in approximately 20% of cases at the onset of the disease. ^{[3],[4],[5],[6]} Nonspecific laboratory and imaging findings further obscure the diagnosis. Diagnosis requires an appropriate index of clinical suspicion for a given set of signs and symptoms. Infection, demyelinating diseases, collagen vascular disease and malignancies, which may present in a similar manner, must be excluded by laboratory and imaging studies. ^{[2],[3],[4],[5],[6],[7]}

PACNS is a heterogenous entity, with at least two distinct forms that can be distinguished from each other based on clinical, laboratory, angiographic and pathologic findings. ^{[3],[4],[5],[6],[7],[8]} These are classified as 1) Granulomatous Angiitis of the CNS (GACNS) and 2) Atypical Angiitis of the CNS. This includes patients presenting with mass lesions, leptomeningeal disease, and those seen in association with cerebral amyloid angiopathy (CAA). ^{[3],[4],[5],[6],[7]} Presentation of PACNS as a solitary tumor-like mass lesion (ML-PACNS) is a rare but increasingly recognized variant. ^{[8],[9],[10],[11]} However, the diagnosis of vasculitis is often not suspected in patients less than 50 years of age. In patients younger than 40 reversible vasoconstriction syndrome (RVCS) should be considered. This entity, previously called "benign angiopathy of the CNS", often does not have a benign course. RVCS has been reclassified as a vasospastic syndrome and is no longer considered a subset of PACNS. ^{[6],[12],[13],[14]} RCVS can be discriminated from PACNS by normal CSF findings, a presentation with "thunderclap" headache and focal deficits, and vasoconstriction on angiogram. ^[12] RVCS is primarily seen in women aged 20 to 40 years and can be precipitated by pregnancy, migraine or use of vasoactive substances. ^{[6],[12],[13]} In these cases vessel inflammation is notably absent. Distinguishing PACNS and RVCS is critical, as treatment with cytotoxic agents is not indicated in RVCS. ^{[3],[4],[5],[6],[12]} Most cases of RCVS can be treated with prednisone monotherapy or with combination therapy with prednisone and a calcium channel blocker. ^[6],[12]

Interestingly, this patient had significant clinical and radiological improvement within days after a brief course of steroids [Figure - 3] and has maintained remission off all therapies. This clinical picture is typical of younger patients with amyloid-negative PACNS, who often respond well and quickly to treatment, suggesting that these patients represent a distinct immunological subset of PACNS. ^{[9],[10],[11],[15],[16]} Patients with ML-PACNS present acutely with focal neurological deficits, most often within one month of symptom onset. In contrast older amyloid-positive patients have a more protracted course ( > six months to presentation) and present with headaches and encephalopathy. ^{[9],[10],[15]} ML-PACNS patients can be distinguished by their younger age, rapid response to steroid therapy, more "benign" course, and lymphocytic infiltrate on biopsy. MRI may also be useful in the identification of this unique subset of patients. ^{[4],[8],[10],[11],[16]} These clinical differences are important for physicians to recognize, so the appropriate diagnosis is considered.

How is Primary Angiitis of the Central Nervous System Usually Diagnosed?

Current diagnostic criteria for PACNS include the following: An unexplained acquired neurological deficit, angiographic or histological features of CNS vasculitis, and no evidence of a systemic condition associated with these CNS findings. ^{[3],[4],[5],[6],[17]} A brain biopsy is often required to establish the presence of inflammation and exclude infection, neoplasm, atypical multiple sclerosis or an alternative cause of vasculopathy, especially in younger patients with atypical imaging findings. ^{[4],[5],[6],[18],[19]}

Neuroimaging is gaining increasing power as a diagnostic tool. ^{[4],[5],[6],[20],[21],[22]} MRI offers a noninvasive strategy with sensitivity of 50-100%, but specificity near 100% in biopsy-proven cases. ^[5],[6],[21] MRI features of PACNS vary considerably, but generally consist of bilateral asymmetrical supratentorial lesions predominantly in the subcortical and deep white matter. ^{[4],[5],[6],[8],[21],[22],[23]} Multiple infarcts of different ages are thought to be suggestive of cerebral vasculitis, especially if the lesions are located in a variety of vascular territories and do not have a typical embolic appearing pattern. Multiple infarctions are frequently bilateral and involve both cortical and subcortical areas. ^{[3],[4],[5],[21]} Rarely (4-6%), MRI can simulate a mass lesion suggestive of a primary brain tumor ^{[8],[10],[11],[16]} as in this case.

Should a Cerebral Angiogram Have Been Performed?

Angiographic diagnosis of vasculitis is based on the demonstration of one or multiple stenosis of brain vessels and diffuse vessel caliber changes. Inflammatory changes of very small brain arteries which are below the resolution limits of cerebral angiography will escape detection and cause falsely negative angiograms. ^{[2],[5],[6],[14],[18],[20],[22],[23],[24],[25]} While MRA offers a noninvasive diagnosis of PACNS, conventional angiography is somewhat more sensitive than MRA for detecting intracranial vessels. However, even conventional catheter angiography has a false-negative rate of up to 30% as arteries under 100-200 micrometers are beyond the limit of resolution. ^{[5],[6],[22],[24]} The diagnostic value of angiography has been a subject of recent debate, as the positive predictive value may be as low as 37% as it may not be able to reliably differentiate "vasculitis" from "vasculopathy". ^[14] Recently, it has been suggested that "angiography negative" patients may also have a more benign clinical course, like those with ML-PACNS. ^[25]

What are the Typical Findings on Cerebrospinal Fluid Analysis in Primary Angiitis of the Central Nervous System?

In one of the largest case series to date, CSF evaluation of 110 patients showed one or more abnormalities in the vast majority (88%). ^[5] Therefore obtaining CSF, if possible, can aid in the diagnosis, especially if MRI or angiogram findings are also consistent with the diagnosis of PACNS. Changes include a mildly increased leukocyte count or total protein concentration or both. ^[5],[6],[15] Patients with a diagnosis of PACNS made by biopsy had greater leukocyte counts (up to 17 cells/ml) and greater total protein concentrations (up to 98 mg/dl). ^[5] Our patient had a benign CSF profile further obscuring the diagnosis.

What Other Studies Should be Performed?

PACNS is often a diagnosis of exclusion. Although, most tests are negative in PACNS they are necessary to rule out other possible etiologies which could mimic the clinical picture and imaging of PACNS. Hemoglobin levels, leukocyte counts, platelet counts, and erythrocyte sedimentation rates are typically within reference levels. ^{[3],[4],[5],[6],[15],[17]} Serum test results are usually negative for rheumatoid factor, antinuclear antibodies and anticardiolipin antibodies. Levels of antineutrophil cystoplasm antibodies, complement and human immunodeficiency virus testing are also normal in PACNS. ^{[3],[4],[5],[6]} Weakly positive ANA (with negative dsDNA), c-ANCA, and p-ANCA autoantibodies were found in 14-29% of PACNS patients in one large series, but titers did not exceed 1:40 in any patient, and may be a consequence of polyclonal immune activation associated with the acute phase response. ^[5]

What are the Typical Findings of Primary Angiitis of the Central Nervous System on Biopsy?

There are no distinguishing features on neuroimaging, angiography or CSF analysis that can differentiate PACNS from other mass lesions, making brain biopsy necessary for diagnosis in these cases. Diagnostic histopathological features of PACNS include transmural vascular inflammation involving leptomeningeal or parenchymal vessels, infiltrating inflammatory cells, the presence of vascular wall fibrinoid necrosis, and parenchymal findings consistent with ischemia. ^{[3],[5],[6],[15],[19]} Additionally, vascular amyloid deposition can be seen with immunoperoxidase staining of Beta-amyloid proteins in the amyloid variant of PACNS. ^[15] PCR of rearranged immunoglobulin heavy-chain allows differentiation of polyclonal versus monoclonal B or T cell activation and assessment of monoclonal gene rearrangement, aiding in the diagnosis of CNS lymphoma. ^[1],[2] Cerebral biopsy is an invasive procedure which many clinicians attempt to avoid. However, the predictive value of angiography in the setting of normal CSF and an abnormal MRI is not well-documented and may be much lower than previously thought. ^{[5],[6],[14],[18]} Biopsies directed to an imaging abnormality (targeted biopsies) and which include the leptomeninges are more often positive than those that do not. ^[19] Thus, where possible, a targeted biopsy that includes a portion of the leptomeninges is recommended to maximize diagnostic potential. ^[19] In cases such as ours, biopsy is often the only way to diagnose this disease.

What are the Current Treatment Options for Patients with Primary Angiitis of the Central Nervous System?

Although there have been no controlled trials of therapy in PACNS, anecdotal evidence suggests that most patients respond positively to therapy. The standard treatment regimen for CNS vasculitis is a combination of high-dose steroids and cytotoxic agents, typically cyclophosphamide. ^[5],[6] The overall response rate to monotherapy with either prednisolone or monotherapy with cyclophosphamide or dual therapy with prednisolone and cyclophosphamide is approximately 80%. ^[5],[7] Recently, several cases of PACNS have been reported that presented at a younger age, with mass lesions and few CSF abnormalities. These patients had a good response to a single course of steroid or cyclophosphamide treatment without relapses, ^{[9],[10],[11],[16]} similar to our patient. Currently, most experts recommend treatment with oral cyclophosphamide for three to six months followed by azathioprine or methotrexate. ^[5],[6] If there is suboptimal response to effective immunosuppressive therapy, the patient should be reevaluated as this indicates that the initial diagnosis may have been incorrect and another etiology, such as lymphoma becomes more likely.

Lessons Learned from this Case

In this case, MRI revealed an ill-defined, heterogenously enhancing mass near the right ventricle with diffuse associated signal abnormality likely representing edema and mild associated mass effect, which was highly suspicious of a neoplasm [Figure - 1]. Tissue characterization was required to make the diagnosis and a brain biopsy was performed to evaluate the lesion. The biopsy provided histological confirmation of vasculitis [Figure - 2] with lymphocytic infiltration of small vessels. There was no evidence of demyelinating disease or macrophage infiltration.

PACNS presenting as a mass lesion is an extremely rare presentation of a rare disease (annual incidence 2.4/1,000,000 person-years) and may represent a relatively uncharacterized subset of PACNS. ^{[6],[8],[9],[10],[11],[16]} Interestingly, this patient had significant clinical and radiological improvement within days after a brief course of steroids [Figure - 3] and has maintained remission off all therapies. This clinical picture appears to be more typical of younger patients with amyloid-negative PACNS and likely represents a distinct immunological subset of PACNS. ^{[8],[9],[10],[11],[15],[16]}

Currently, definitive diagnosis of PACNS requires an angiogram or brain biopsy with histological analysis. ^{[3],[4],[5],[6],[7],[13],[17],[18]} Early aggressive treatment with steroids can lead to full remission in ML-PACNS, but the disease can be fatal if left untreated. Therefore, prompt diagnosis is critical. While there are some potentially useful imaging modalities employing MR which has high sensitivity, brain biopsy remains the gold standard of diagnosis and should be considered early in the clinical course. Although PACNS rarely presents as CNS mass lesions (4-6%), ^[9],[10] it should be considered in the differential diagnosis, especially in young patients so that appropriate treatment can be initiated.

Acknowledgements

LDM is supported by the NIH (NS050505 and NS055215).

References

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