44-Year-Old Man With Fever, Headache, Confusion, And Ataxia

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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 retro-

orbital pain. He also developed confusion and memory lapses, dysarthria, unsteady gait, fatigue, and anorexia. The ons

of these symptoms was subacute and worsened gradually. He was evaluated extensively in India before being transferr

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 b

an underlying opportunistic infection. He also has a history of thalassemia minor and had been diagnosed with hepatitis

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 timesVital 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 occasiona

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 testin

was, again, limited. No facial droop was apparent but the family reported noticing that the patient was mildly dysarthric;


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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 lea

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 not

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 revea

abnormal T2-weighted signal, with asymmetric midbrain enhancement as well as a faint enhancement in the basal gang

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 forPlasmodium falciparum, RPR, HIV-1,2, an

HCV all negative.Neoplastic: CT chest/abdomen normal.

Neurologic testing: Neuropsychological testing revealed difficulty with word retrieval and word generation, and impaire

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 encephal

virus.

Treatment Before Transfer

The patient received a brief course of empiric anti-TB therapy (details of which medications were used were not availabl

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, th

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. HS

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 multip

areas of enhancing, T2-bright signal in the brainstem as well as in the periventricular white matter. His CSF demonstrate

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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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, includi

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, u

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 slowin

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 lesion

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

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

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 radiatio

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 th

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 fai

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 sympto

consist primarily of dementia, ataxia, urinary incontinence, and leukoencephalopathy.[3,13] This is seen more frequently

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 resul

when using methotrexate as part of the regimen). Intra-arterial administration of mannitol is complicated and the mannito

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 neurotoxicit

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

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 follow

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 th

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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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 classificatio

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

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

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;59:1557

1562.

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 deferredradiotherapy: 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;1

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.

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44-Year-Old Man With Fever, Headache, Confusion, And Ataxia