Inflammatory processes within the central nervous system are challenging for the clinician, radiologist, and pathologist alike. They often can mimic other more well-known and defined disease processes. We present the case of a patient with a newly described inflammatory process that primarily involves the pons and adjacent structures, which is called chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). An 80-year-old man presented with numbness of his right hand that ultimately progressed to involve both lower extremities and face and was associated with mild dysarthria and ataxia. He had received the influenza vaccination 2 weeks prior. The biopsy revealed primarily reactive T-cell lymphocytic infiltrates with macrophages and gliosis. Treatment required long-term immunosuppressive therapy. CLIPPERS is a recently described central nervous system inflammatory condition that should be considered in the differential diagnosis when a prominent lymphocytic inflammatory infiltrate is encountered in brainstem, spinal cord, midbrain, or cerebellar biopsies.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system (CNS) inflammatory disease involving the pons. The disorder was first described in 2010 by Pittock et al1 and characterized as a T-lymphocyte predominant pontine encephalomyelitis that is responsive to immunosuppression with steroids. In the authors' case series of 8 patients, the condition often worsened after glucocorticosteroid tapering or responded incompletely and required additional immunosuppressive agents for effective treatment. Neuroimaging showed symmetrical gadolinium enhancement speckled within the pons, which can extend superiorly to the midbrain and cerebellum or inferiorly to the medulla and spinal cord. Enhancement decreases as the patient responds to immunosuppressive therapy. Our patient was an 80-year-old man initially thought to have a brainstem glioma or lymphoma. In our discussion, we describe this recently characterized CNS inflammatory disease and discuss disorders that should be included in the differential diagnosis. To our knowledge, this is the 10th case of CLIPPERS described in the literature and the first case of CLIPPERS associated with the administration of the influenza vaccine.
REPORT OF A CASE
An 80-year-old man presented in October 2010 with numbness and paresthesia in his right hand. These symptoms developed 2 weeks after receiving the influenza vaccine. In the subsequent 3 weeks, his right lower extremity and left foot were similarly affected. He also noticed a change in his voice, numbness of his face, and a “wobbly” gait. He reported no recent rashes, fever, neck stiffness, joint pains, or other systemic manifestations apart from a decrease in bowel movement frequency. He reported having fatigue and a diminished appetite without weight loss in the preceding year. A computed tomography scan of his chest, abdomen, and pelvis revealed a tumor in the right kidney. Laparoscopic resection demonstrated a renal cell carcinoma. He received no chemotherapy or radiation therapy and his symptoms improved after resection. His only other significant medical problems included hypercholesterolemia and hypertension. Physical examination was remarkable for a hoarse voice, ocular motility characterized by saccadic intrusions and impaired vertical gaze upwards, a mildly ataxic gait, and diminished sensation in his distal lower extremities.
Cranial magnetic resonance imaging (MRI) performed on November 19, 2010, showed a fairly homogeneously enhancing lesion within the central pons, within a larger area of increased signal on the fluid-attenuated inversion recovery (FLAIR) images (Figure 1, A and D). The enhancement around the periphery of the lesion was somewhat punctate or “speckled.”
A biopsy specimen of the pontine lesion in December 2010 showed a reactive, T-cell–predominant, CD3-positive, lymphocytic infiltrate with scattered macrophages and microglial cells with few plasma cells (Figures 2A, B and 3A, B). There were no microglial nodules identified. Occasional p53- and Ki-67–positive atypical astrocytes and gliosis were noted. No viral inclusions or infectious agents were seen on hematoxylin-eosin staining. No organisms were identified with Grocott methenamine silver staining and acid-fast bacteria staining, and viral immunohistochemistry findings for herpes simplex virus and human herpesvirus 8 were negative. An anti-cytokeratin (CAM 5.2) immunostain was performed because of the diagnosis of renal cell carcinoma but showed only nonspecific background staining. A luxol fast blue stain to access demyelination yielded negative results, and negative in situ hybridization findings were noted for Epstein-Barr virus–encoded RNA. Flow cytometry failed to reveal a monoclonal B lymphocyte population. A lumbar puncture was performed in December and showed clear and colorless fluid. The cerebral spinal fluid cytology showed 5 white blood cells with 79% mononuclear cells; protein, 22 mg/dL (range, 15–45 mg/dL); glucose, 72 ng/dL (range, 50–80 ng/dL); and lactic acid, 2 mmol/L (range, 0–2 mmol/L). The lactate dehydrogenase level in the cerebral spinal fluid was 26 IU/L (range, 0–24 IU/L). Venereal disease research laboratory test result was nonreactive. The patient's erythrocyte sedimentation rate was 5 mm/h (range, 0–38 mm/h) and anti-nuclear antibody, anti-Sjögren antibodies, and other serologic screening test results were normal. A repeated brain MRI performed 1 month later showed little change (Figure 1, B and E). After pontine biopsy, the patient was given dexamethasone 4 mg, four times daily, which was continued for 1 week. Although no clinical improvement was evident in the interim, a repeated cranial MRI on January 5, 2011, showed decreased enhancement of the pontine lesion (Figure 1, C and F). Clinical and radiographic features improved in May 2011 (Figure 4, A and C) when he received a course of intravenous methylprednisolone, 1 gram daily for 5 days, followed by oral prednisone 60 mg daily with gradual tapering. On June 23, 2011, a repeated MRI showed significant improvement in the contrast-enhancing lesions in the pons (Figure 4, B and D); however, the patient continued to have complaints of a glovelike paresthesia and had an ataxic gait. Methotrexate 15 mg weekly was initiated to accompany prednisone 20 mg every other day.
CLIPPERS is a newly described treatable inflammatory brainstem CNS disease. The inflammatory focus involves the pons with extension into adjacent CNS areas. Clinically, our patient developed sensory abnormalities and ataxia compatible with a cerebellar-brainstem lesion. The hallmark radiologic finding of this disease is a speckled, infiltrative gadolinium enhancement of the pons and other adjacent involved structures,1–4 which corresponds to the lymphocytic perivascular inflammatory pattern seen histologically. Our patient initially had a lesion that was homogeneous with speckled peripheral enhancement. Subsequent images showed a more speckled, heterogeneous lesion that improved with steroid immunosuppressive therapy. Because patients with CLIPPERS have been shown to improve with glucocorticosteriod therapy, our patient's dose was tapered, which may have caused the return of the inflammation and clinical symptoms. Chronic pharmacologic therapy with immunosuppressive agents is typically required for remission of symptoms.1–4
CLIPPERS, a diagnosis of exclusion, requires the discussion of more common entities. Restricted acute disseminated encephalomyelitis in the brainstem is a consideration given the patient's history of vaccination, but was not supported given the radiologic and pathologic appearance. Acute disseminated encephalomyelitis involves autoimmune demyelination, unlike CLIPPERS, which can be seen on imaging and with histochemical stains.5,6 Furthermore, acute disseminated encephalomyelitis is often a diffuse white matter disease producing multiple lesions in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, whereas CLIPPERS is a focal disease of the brainstem.6 Bickerstaff brainstem encephalitis occurs in a similar location as CLIPPERS but is radiologically distinct. Whereas CLIPPERS has scattered punctate gadolinium enhancement of the pons, Bickerstaff brainstem encephalitis features a uniform nongadolinium enhancement that can be found in the upper brainstem, thalamus, and the pons on MRI.1,4,7,8 The histopathologic findings of Bickerstaff brainstem encephalitis do show chronic perivascular inflammation with activated microglia similar to CLIPPERS, but it is usually accompanied by edema and occasional microglial nodules.8 Common viral and fungal causes were excluded by histochemical and immunohistochemical stains, although rarer pathogens may be the causative agent. However, the lack of microglial nodules in the biopsy specimen and the patient's clinical features did not favor a viral etiology.
Central nervous system lymphoma and high-grade glioma were initially considered in the differential diagnosis of our patient. The biopsy specimen showed a prominent, diffuse lymphocytic infiltrate, but immunohistochemistry, flow cytometry, and lack of atypical lymphocytes did not support a diagnosis of lymphoma. Prominent macrophages and microglia seen in the biopsy were not associated with Langerhans histiocytes or emperipolesis, thus excluding Langerhans histiocytosis and Rosai-Dorfman disease. The biopsy specimen did show focal atypical astrocytes with a low Ki-67 labeling index, making a glioma unlikely. Central nervous system vasculitis and neurosarcoidosis were also considered in the differential of disease with similar radiologic findings, but were excluded owing to the lack of clinical and pathologic evidence for either condition.1,4 Although the possibility of a paraneoplastic disease was entertained because the patient had a renal cell carcinoma, this syndrome has not been typically associated with this cancer. The possibility of central pontine myelinolysis was also entertained, but no history of hyponatremia was found. Demyelinating diseases were excluded on the basis of radiologic findings and a lack of demyelination. Since CLIPPERS is a diagnosis rendered when other, more common diseases have been excluded, this process requires thorough clinical, radiologic, and pathologic correlations.
CLIPPERS has been proposed to be an inflammatory process of unknown etiology.1,4 Pontine inflammation requiring long-term immunosuppressive agents suggests an autoimmune disorder. The perivascular inflammation is the common histologic clue in the diagnosis and may be the consequence of the location of the antigen inciting the disorder. Vaccination for influenza 2 weeks before the development of CLIPPERS raises the tantalizing possibility that this may be the triggering event. The patient had no prior neurologic symptoms and after excluding more common CNS pathologic disorders, CLIPPERS appears to be the most likely diagnosis. To the best of our knowledge, this is the first reported case of CLIPPERS after vaccination. The neurologic complications of vaccination are fortunately rare, but can include panencephalitis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, cerebellar ataxia, parkinsonism, transverse myelitis, Bell palsy, myasthenia gravis, neuropathy, sensorineural hearing loss, seizures, mental retardation, and autism.9–11 CLIPPERS is another complication that should be added to this list. Many of the diseases listed previously are autoimmune in nature, further adding credibility to the possible underlying autoimmune cause of CLIPPERS.
In summary, CLIPPERS is a newly described condition that should be considered by pathologists when a prominent lymphocytic inflammatory infiltrate is encountered in specimens of the brainstem, spinal cord, midbrain, or cerebellum. The histopathologic features must be correlated with the clinical and radiologic findings to arrive at an accurate diagnosis. Awareness of this new entity helps to differentiate this disease process from other brainstem disorders.
From the Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, Kentucky (Drs Hillesheim, Parker, and Parker Jr); and the Departments of Radiology (Dr Escott) and Neurology (Dr Berger), University of Kentucky School of Medicine, Lexington.
The authors have no relevant financial interest in the products or companies described in this article.