44-Year-Old Man With Fever, Headache, Confusion, and Ataxia (printer-friendly)

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www.medscape.com Case Presentation The patient is a 44-year-old man from India with a 2-month history of low-grade fever, headache, and neck pain.
Recent Medical History

During the 2 months before admission, the patient experienced gradual progression of his symptoms to include retroorbital pain. He also developed confusion and memory lapses, dysarthria, unsteady gait, fatigue, and anorexia. The onset of these symptoms was subacute and worsened gradually. He was evaluated extensively in India before being transferred to our hospital for further evaluation and management.
Past Medical History

The patient's past medical history is remarkable for uveitis for approximately 2 years before presentation. He had been treated with intraocular steroids and oral prednisolone (which he was taking continuously until 1-2 months prior to admission, but at varying doses, ranging from 5 to 20 mg a day); he had also received azathioprine and mycophenolate mofetil, but these had been discontinued when the most recent symptoms began because of concern that there might be an underlying opportunistic infection. He also has a history of thalassemia minor and had been diagnosed with hepatitis A as a child. He resided in Calcutta but had traveled all over the world related to his work as an entrepreneur. He had no history of tobacco, alcohol, or illicit drug use. His family history was negative for rheumatologic disease other than osteoarthritis in his mother. At the time of admission to Johns Hopkins Hospital, he was taking no medications and had no history of drug allergies.
Physical Examination

General: well-appearing Indian man, agitated at times Vital Signs: normal blood pressure and pulse, afebrile HEENT: mild meningismus, small scar present on inner lower lip (possible trauma vs ulceration) Lungs: clear to auscultation bilaterally Heart: regular, S1 and S2 normal Abdomen: soft, not tender or distended with normoactive bowel sounds Extremities: good peripheral pulses, no clubbing/edema Genitals: questionable ulceration on scrotum Skin: folliculitis, otherwise no rash
Neurologic Examination

Mental status. The patient was uncooperative, with limited attention. He was awake and oriented to self and occasionally to the name of the hospital, but not to date, city, or state. Formerly fluent in English, he followed simple commands only intermittently and had difficulty communicating in English throughout his hospitalization. He could name objects only occasionally and could not cooperate with testing for repetition or more complex commands. Cranial nerves. His pupils were equal, round, and reactive to light, and the funduscopic exam was normal, albeit limited. No afferent pupillary defect was observed. Extraocular movements were intact and visual fields were full, although testing was, again, limited. No facial droop was apparent but the family reported noticing that the patient was mildly dysarthric;
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44-Year-Old Man With Fever, Headache, Confusion, and Ataxia (printer-friendly)

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facial sensation was grossly intact. His tongue was midline and shoulder shrug was symmetric. Motor. Formal testing could not be performed because of lack of cooperation, but the patient had normal tone and at least antigravity strength in all 4 extremities. In spontaneous movements he used both sides symmetrically. Sensory. His sensation was grossly intact to noxious stimulation of all extremities. Reflexes. Reflexes were 2+ throughout and symmetric, with flexor plantar responses. Coordination. The patient was unable to cooperate with finger-nose-finger and heel-knee-shin testing but had been noted to be dysmetric on the right at the hospital in India. He also had some truncal instability. Gait. The patient's gait was quite unsteady and he was unable to take any steps. He had some retropulsion as well. Work-up in India An MRI, performed approximately 1 month after the onset of his symptoms, is shown in Figures 1 and 2. The MRI reveals abnormal T2-weighted signal, with asymmetric midbrain enhancement as well as a faint enhancement in the basal ganglia bilaterally.

Figures 1 and 2. FLAIR and T1-weighted postgadolinium images reveal asymmetric midbrain and basal ganglia enhancement.

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Figures 1 and 2. FLAIR and T1-weighted postgadolinium images reveal asymmetric midbrain and basal ganglia enhancement. The remainder of his work-up in India is as follows: Vascular: Transesophageal echocardiogram normal, anticardiolipin and lupus anticoagulant normal, hemoglobin electrophoresis normal. Inflammatory: Antinuclear antibody (ANA)- and anti-dsDNA-negative; rheumatoid factor (RF)-negative; ESR 5; collagen replated peptide (CRP) 0.23; negative cryoglobulins. A partially completed gallium scan was negative; bone marrow biopsy was negative for sarcoid; HLA-B27 was negative. Demyelinating: Somatosensory evoked potentials, visual evoked potentials, and brainstem auditory evoked response were normal. Infection: Urine tuberculosis (TB) PCR and TB skin test negative, Ag test for Plasmodium falciparum, RPR, HIV-1,2, antiHCV all negative. Neoplastic: CT chest/abdomen normal. Neurologic testing: Neuropsychological testing revealed difficulty with word retrieval and word generation, and impaired ideational fluency. Slit-lamp exam revealed active vitreitis in both eyes. EEG: 9-10 Hz, unremarkable A lumbar puncture performed in India showed 22 WBCs (80% lymphocytes, 20% polys), 0 RBC, protein 55, glucose 60. Spinal fluid was negative for all of the following: Gram stain, acid-fast bacilli, CSF IgG index, oligoclonal bands, Cryptococcus antigen, CSF cytology, and ACE, and PCR-negative for TB, herpes simplex virus (HSV), human herpesvirus-6, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus, enterovirus, Japanese encephalitis virus.
Treatment Before Transfer

The patient received a brief course of empiric anti-TB therapy (details of which medications were used were not available); this treatment was stopped because of significant gastrointestinal side effects. He also received a daily pulse of IV solumedrol 1g for 5 days, with "worsening of symptoms" according to the family. Two days before he was transferred, the patient's MRI (Figures 3 and 4) and lumbar puncture were repeated.

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Figures 3 and 4. Repeat MRI scans reveal multiple new areas of enhancement.

Figures 3 and 4. Repeat MRI scans reveal multiple new areas of enhancement. Lumbar puncture results now revealed 25 WBCs (differential not available), a protein of 100, and CSF glucose of 41. HSV, CMV, and TB PCR remained negative, as did the Gram stain. In summary, this is a 44-year-old from India with a history of uveitis and subsequent confusion, ataxia, headache, history of low-grade fevers, with gradual progression over 2 months, and possible scrotal ulceration. MRI imaging reveals multiple areas of enhancing, T2-bright signal in the brainstem as well as in the periventricular white matter. His CSF demonstrates a primarily lymphocytic pleocytosis with low CSF glucose and elevated CSF protein. What's the most likely diagnosis? Tuberculosis Sarcoidosis Neuro-Behet's disease
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44-Year-Old Man With Fever, Headache, Confusion, and Ataxia (printer-friendly)

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Other systemic vasculitis Progressive multifocal leukoencephalopathy Multiple sclerosis/demyelinating disease Primary CNS lymphoma Astrocytoma CNS Whipple's disease Hospital Course The patient underwent a repeat MRI and lumbar puncture at the time of transfer (Figures 5 and 6).

Figures 5 and 6. FLAIR and T1-weighted postgadolinium scans 1 week after previous scans show larger areas of enhancement.

Figures 5 and 6. FLAIR and T1-weighted postgadolinium scans 1 week after previous scans show larger areas of enhancement.
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The repeat lumbar puncture revealed 35 WBCs, CSF glucose, 37 mg/dL and protein, 81 mg/dL. The white cell count differential showed 17% "other cells," and CSF cytopathology was positive for high-grade lymphoma, monoclonal B-cell population. CT scans and body PET were negative for any systemic disease elsewhere, and ophthalmologic slit-lamp exam revealed likely lymphomatous cells in the vitreous.
Final Diagnosis

Primary CNS lymphoma. Discussion Primary CNS lymphoma is a subtype of non-Hodgkin's lymphoma that is confined to the central nervous system, including the brain, eyes, meninges, and spinal cord. These lymphomas comprise 1% to 6% of malignant brain tumors in immunocompetent patients, with a peak incidence in the sixth decade of life, more often in men than in women.[1,2] In immunocompetent patients the incidence is 0.3 per 100,000 person-years.[3] Among the population with AIDS and in primary immunocompromised patients in whom this diagnosis is seen, the incidence is 4-5 per 1000 person-years.[4] Thus, 2% to 6% of persons with AIDS develop primary CNS lymphoma at some point in their disease and, at autopsy, up to 12% of these patients are found to have it.[2,4] This discussion will be limited to primary CNS lymphoma in the immunocompetent patient, rather than primary CNS lymphoma in AIDS patients, which is typically an EBV-associated malignancy (the association with Epstein-Barr virus is not seen in the subtype of immunocompetent patients as it is in AIDS patients).[4,5]
Diagnosis of Primary CNS Lymphoma

Cognitive changes are often the first symptoms of primary CNS lymphoma, and may be followed by psychomotor slowing, personality changes, disorientation, or changes from elevated intracranial pressure.[2] Two percent to 33% of patients have seizures at some point; because primary CNS lymphoma is typically a disease of white matter, seizures are not as prevalent as they would be in a patient with a primary gray matter lesion.[2] Approximately 10% to 20% of patients have apparent uveitis at the time of diagnosis and this is a well-known "mimicker" of lymphoma.[3,5] Neuroimaging most frequently reveals solitary lesions, but up to 30% of patients may have multiple lesions.[5] The lesions are typically periventricular, homogeneously enhancing, and with no central necrosis.[6] The typical locations include the corpus callosum, the thalamus, and the basal ganglia. The predilection for the corpus callosum is almost always limited to patients with primary CNS lymphoma. Involvement of the spinal cord is rare (approximately 1% of patients),[6] and although leptomeningeal involvement may only be seen on neuroimaging in 7% of patients by 1 report,[3] there is involvement of the leptomeninges in up to 40% of patients at diagnosis.[3,5] The last MRI performed on our patient revealed these clearly demarcated enhancing periventricular lesions. Earlier findings may not be so clear-cut. Furthermore, lesions on MRI may disappear quickly when steroids are given but can return at a later time.[2,3] Other conditions that can appear similar radiographically include gliomas, metastatic cancers, or inflammatory conditions[7]; in an immunosuppressed patient, toxoplasmosis can have a very similar appearance radiographically. The differential is often much broader based on early imaging findings that may not yet show distinct mass lesions. To make a definitive diagnosis, consideration of biopsy, either stereotactic or open, should be made; ideally this should not be done after a patient has completed a course of steroids because this may interfere with pathological diagnosis.[3,7] A recent autopsy study[8] demonstrated extensive lymphomatosis despite fewer lesions revealed by MRI; many of these patients had undergone MRIs within 2 weeks of death, suggesting that the MRI does truly underestimate tumor burden.

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Prognosis and Treatment

If untreated, the median survival of this disease is 4.6 months.[9] Treatment options include steroids, whole brain radiation, and chemotherapy, or some combination of these. Treatment with steroids alone may lead to rapid disappearance of lesions, but this is only a transient effect and lesions will inevitably return. Use of whole brain radiation alone leads to a response rate of greater than 90%, but many of these patients relapse as well, within 10-14 months.[3,5,9] In the past, radiation to ocular compartments was considered necessary for patients with eye involvement, as was spine radiation for patients with positive CSF cytopathology. However, new results from chemotherapeutic trials[10] indicate that extensive radiation may no longer be necessary. Preirradiation chemotherapy plus radiotherapy is another combination that has been tried using a variety of chemotherapeutic agents. The most promising results have been seen with methotrexate as the agent of choice.[2,11,12] The "DeAngelis protocol" consists of IV methotrexate at a dose of 1g/m2, followed by whole brain radiation and finally ara-C, dexamethasone, and intrathecal methotrexate. Survival has been fairly good, even up to a greater than 20% 5-year survival, but significant neurotoxicity has been reported during this survival period.[11] Various other regimens of preirradiation methotrexate-based chemotherapy have been used with varying results and some persistent neurotoxicity.[3,13-15] Neurotoxicity is probably a consequence of the whole brain radiation, and symptoms consist primarily of dementia, ataxia, urinary incontinence, and leukoencephalopathy.[3,13] This is seen more frequently in patients older than 60 years[3,13,14]; in one report, some degree of neurotoxicity was seen in up to 32% of patients.[13] Other treatment possibilities have included intra-arterial administration of mannitol to help disrupt the blood-brain barrier for subsequent chemotherapy delivery. Mannitol works by loosening the tight junctions of the blood-brain barrier by shrinking the endothelial cells osmotically, thus allowing better diffusion of chemotherapeutic agents (with the best results when using methotrexate as part of the regimen). Intra-arterial administration of mannitol is complicated and the mannitol administration has significant toxicities, including sepsis and stroke. However, the patients who tolerated this therapy experienced a median survival of greater than 40 months and less neurotoxicity because there was no associated radiation.[16] The final therapeutic approach has involved using chemotherapeutic agents alone, with the goal of lowering neurotoxicity from radiation. Combination therapy with agents such as cyclophosphamide/hydroxydoxorubicin/Oncovin (vincristine)/prednisone (CHOP), as is typically used for systemic non-Hodgkin's lymphoma, hasn't produced very promising results, although adding an alkalizing agent such as thiotepa has provided some benefit because it rapidly diffuses to the brain.[3] However, recent data have indicated excellent results in patients who receive high-dose IV methotrexate, at a dose of 8 g/m2, which is sufficient to penetrate the blood-brain barrier, thus eliminating the need for intrathecal methotrexate.[10,14] This dose is given every 2 weeks to a maximum of 8 cycles or until a complete response is achieved (MRI is performed with every other cycle), then 2 more cycles are given every 2 weeks, followed by monthly maintenance for 11 months. This regimen has much less toxicity, although creatinine clearance must be carefully followed before initiating this high-dose treatment and before oral leucovorin rescue is included; patients are hospitalized for each cycle. In a preliminary study,[10] 52% of patients experienced a complete response (defined as complete resolution of the tumor radiographically), 22% had a partial response, and 22% experienced progression of disease at 22.8 months. Median survival was not yet reached at the time that this study was completed.
Our Patient's Follow-up

Our patient received the high-dose IV methotrexate protocol, and after a few cycles his gait and cognition were already improving. He has not required either intrathecal chemotherapy or ocular radiation for his documented ocular lymphoma. His first follow-up MRI reveals some improvement in abnormal signal (Figures 7 and 8), and a follow-up ophthalmologic exam after 3 cycles showed normal vitreous with no tumor cells.
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44-Year-Old Man With Fever, Headache, Confusion, and Ataxia (printer-friendly)

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Figures 7 and 8. MRIs after 2 cycles of high-dose methotrexate show some resolution of enhancing lesions.

Figures 7 and 8. MRIs after 2 cycles of high-dose methotrexate show some resolution of enhancing lesions.
References

1. Schabet M. Epidemiology of primary CNS lymphoma. J Neurolooncol. 1999;43:199-201. 2. Schlegel U, Schmidt-Wolf IG, Deckert M. Primary CNS lymphoma: clinical presentation, pathological classification, molecular pathogenesis and treatment. J Neurol Sci. 2000;181:1-12. Abstract 3. Basso U, Brandes AA. Diagnostic advances and new trends for the treatment of primary central nervous system lymphoma. Eur J Cancer. 2002;38:1298-1312. Abstract 4. Goplen AK, Dunlop O, Liestol K, Lingjaerde OC, Bruun JN, Maehlen J. The impact of primary central nervous system lymphoma in AIDS patients: a population-based autopsy study from Oslo. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:351-354. Abstract 5. Plasswilm L, Herrlinger U, Korfel A, et al. Primary central nervous system (CNS) lymphoma in immunocompetent patients. Ann Hematol. 2002;81: 415-423. Abstract 6. Buhring U, Herrlinger U, Krings T, Thiex R, Weller M, Kuker W. MRI features of primary central nervous system
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lymphomas at presentation. Neurology. 2001;57:393-396. Abstract 7. Gliemroth J, Kehler U, Gaebel C, Arnold H, Missler U. Neuroradiological findings in primary cerebral lymphomas of non-AIDS patients. Clin Neurol Neurosurg. 2003;105:78-86. Abstract 8. Lai R, Rosenblum MK, DeAngelis LM. Primary CNS lymphoma: a whole-brain disease? Neurology. 2002;59:15571562. 9. Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg. 1994;81:188-195. Abstract 10. Batchelor T, Carson K, O'Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21: 1044-1049. Abstract 11. DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol. 1992;10: 635-643. Abstract 12. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz C. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation therapy oncology group study 93-10. J Clin Oncol. 2002;20: 4643-4648. Abstract 13. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: The next step. J Clin Oncol. 2000;18: 3144-3150. Abstract 14. Watanabe T, Katayama Y, Yoshino A, Komine C, Yokoyama T, Fukushima T. Long-term remission of primary central nervous system lymphoma by intensified methotrexate chemotherapy. J Neurooncol. 2003;63:87-95. Abstract 15. O'Brien P, Roos D, Pratt G, et al. Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol. 2000;18: 519-526. Abstract 16. Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: First example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am 1996;2: 166.

Medscape General Medicine. 2003;5(3) 2003 Medscape

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