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62-Year-Old Woman With Rapidly Evolving Dementia

      A 62-year-old right-handed woman was transferred to our institution because of progressive confusion and decline in cognitive function. Eight weeks before admission, the patient began experiencing weight loss and memory problems. Her family noted that her personality had become uncharacteristically pleasant. Six weeks before admission, she became incapable of running her business, was incontinent of urine and stool, and was unable to walk.
      The patient was admitted to a medical center elsewhere because of right knee pain after she had fallen. She was disoriented, confused, and unsteady. She had a history of hypertension, diabetes mellitus, and depression. Medications on admission included fluoxetine, propoxypheneacetaminophen, and subcutaneous insulin. Findings on chest radiography, knee radiography, electrocardiography, and arterial blood gas studies were normal, as were electrolytes, creatinine, liver function tests, thyroid-stimulating hormone, and vitamin B12 level. Her glucose levels without insulin were in the range of 150 to 300 mg/dL. Urinalysis showed mild albuminuria. Results of a urine drug screen showed propoxyphene but were otherwise normal. Head computed tomography disclosed periventricular ventricular hypodensities and mild generalized cerebral atrophy. A nonenhanced magnetic resonance image (MRI) of the brain detected multiple foci of increased T2 signal involving the bilateral periventricular white matter and the left cerebellar hemisphere. Cerebrospinal fluid (CSF) examination showed clear colorless fluid with a protein concentration of 61 mg/dL (reference ranges shown parenthetically) (14-45 mg/dL), glucose concentration of 84 mg/dL (appropriate for plasma glucose concentration), and 14 cells/mm3 95% lymphocytes (<5 cells/mm3, 100% lymphocytes). Bacterial antigens and cultures were negative. An electroencephalogram (EEG) showed moderate generalized background slowing. The patient was transferred to our institution after 6 weeks of hospitalization.
      At our institution, the patient denied having fevers, night sweats, skin lesions, or pruritus. On physical examination, vital signs were normal. She had no rash, palpable adenopathy, breast abnormalities, or organomegaly. On neurologic examination, the patient was alert, inattentive, and disoriented, and she exhibited slow mental processes (bradyphrenia). She scored 12 of 38 points on a formal standardized mental status examination.
      • Kokmen E
      • Naessens JM
      • Offord KP
      A short test of mental status: description and preliminary results.
      Her reproduction of a clock was consistent with neglect of left space and perseveration. Language was fluent with mild anomia, intact repetition, variable comprehension, and frequent paraphasic errors with confabulatory invention during reading tasks. Findings on a cranial nerve examination were normal. The motor examination was limited because of the patient's inattention and poor cooperation, but her muscle tone and bulk appeared symmetric. She had at least antigravity strength in all muscles without focal weakness. Results of a sensory examination were unreliable. Muscle stretch reflexes were normal in her upper limbs but absent in her lower extremities. Inconstant pathologic grasp reflexes were observed. Plantar responses were extensor bilaterally. The patient had truncal ataxia while sitting but no appendicular dysmetria. She could bear weight briefly, but only when supported by 2 examiners.
      • 1.
        Which one of the following measures is least appropriate in the management of this patient?
        • a.
          Administration of thiamine
        • b.
          Performance of awake EEG
        • c.
          Repeated CSF examination
        • d.
          Determination of apolipoprotein E (APOE) alleles
        • e.
          Performance of neuropsychological tests
      This patient presented with subacute dementia. The findings of bradyphrenia, left neglect, and fluent aphasia demonstrate dysfunction at both the subcortical and the cortical levels. The grasp reflexes suggest bilateral frontal lobe involvement, whereas her extensor toe signs and truncal ataxia confirm bilateral pyramidal tract and midline cerebellar lesions. Therefore, the differential diagnosis should focus on diseases that cause rapid destruction of cortical and cerebellar neurons and their projections. The lower limb areflexia could be associated with the current presentation but could also be a comorbid distractor in light of her history of diabetes, a common cause of a length-dependent polyneuropathy.
      Because encephalopathies and subacute dementing illnesses often follow a rapidly deteriorating course, treatable and reversible causes must be sought rigorously and expeditiously. If a history of pronounced malnutrition or alcohol use is elicited or suspected, empiric thiamine should be administered to treat possible Wernicke encephalopathy, a cause of subacute confusion and ataxia. Findings on EEG may suggest specific disease states, such as metabolic or toxic conditions, nonconvulsive status epilepticus, or Creutzfeldt-Jacob disease (CJD). An early CSF examination is important since chronic or subacute forms of meningoencephalitis may present with dementia. Treponemal diseases such as syphilis or borreliosis, fungal disorders including cryptococcal meningitis, viral causes such as herpes simplex or human immunodeficiency virus (HIV), and bacterial causes including partially treated bacterial meningoencephalitis, mycobacterial meningoencephalitis, or Whipple disease should be considered. Alzheimer disease may become unmasked and subacutely overt, presenting as delirium when another superimposed systemic condition is present. Advanced age, family history, and the APOE4 allele are risk factors for Alzheimer disease, but the APOE4 allele has relatively poor sensitivity and specificity for Alzheimer disease; thus, it should be used primarily as an epidemiologic research tool rather than a clinical diagnostic test.
      • National Institute on Aging/Alzheimer's Association Working Group
      Apolipoprotein E genolyping in Alzheimer's disease.
      Neuropsychological tests may assist in diagnosing dementia, localizing regional cerebral dysfunction, and identifying dementia mimics, including depression with pseudodementia, benign senile forgetfulness, and confusional states.
      Our patient's hemoglobin level was 11.7 mg/dl., with normal mean corpuscular volume and ferritin levels. Platelet and leukocyte counts were normal. The erythrocyte sedimentation rate was 43 mm/1 h. Antinuclear antibodies, antidouble-stranded DNA, antineutrophil neutrophil cytoplasmic antibodies, cryoglobulins, complement levels, antineuronal nuclear antibodies (or anti-Hu), and anti-Purkinje cell antibodies (anti-Yo) were normal. Results of serologic tests for Lyme disease, syphilis, and HIV were negative. Findings on chest radiography and electrocardiography were unremarkable.
      A contrast-enhanced MRI of the brain is the neuroimaging procedure of choice in subacute dementing processes. In this patient, MRI excluded extra-axial or intra-axial space-occupying mass lesions, such as a chronic subdural hematoma or a primary or metastatic brain tumor. No ventriculomegaly, sulcal flattening, or transependymal CSF signal was present; therefore, normal-pressure hydrocephalus was excluded. The finding of multiple periventricular white matter lesions suggested that central nervous system (CNS) vasculitides, multi-infarct dementia, neurosarcoidosis, acute disseminated encephalomyelitis, and CNS lymphoma should all remain in the differential diagnosis.
      A repeated EEG showed moderate generalized background slowing without epileptiform activity. A repeated CSF examination showed clear and colorless fluid with an opening pressure of 13 cm H2O (6-20 em H2O), glucose level of 73 mg/dL (appropriate for serum glucose concentration), protein level of mg/dL, and 16 cells/mm3 (95% lymphocytes). Cerebrospinal fluid cytology; cultures for bacteria, tuberculosis, fungi; and viruses; and VDRL serologic test results were all negative.
      • 2.
        Which one of the following diagnostic possibilities is least likely to account for the CSF and EEG findings in this patient?
        • a.
          Aseptic meningoencephalitis
        • b.
          Primary CNS lymphoma
        • c.
          CNS vasculitis (granulomatous angiitis of the CNS)
        • d.
          Acute disseminated encephalomyelitis
        • e.
          Prion disease (CJD)
      Causes of a mild lymphocytic pleocytosis with an elevated CSF protein concentration include CNS infectious, neoplastic, or inflammatory disorders such as aseptic meningoencephalitis, meningeal metastasis, lymphoma, paraneoplastic encephalomyelitis (limbic encephalitis), vasculitides, and neurosarcoidosis as well as demyelinating diseases such as acute disseminated encephalomyelitis or multiple sclerosis. All these disorders could present with regional or generalized background slowing on EEG. Although brain biopsy or autopsy remains the reference standard for the diagnosis of CJD, the absence of periodic sharp wave complexes on EEG, the abnormal CSF, and the absence of myoclonus substantially decrease the probability of CJD in this patient.
      An enhanced MRI of the brain showed confluent and enhancing T2-hyperintense lesions in the periventrieular cerebral white matter (Figure 1). These periventricular lesions had advanced substantially compared with the findings on MRI performed a week before, mirroring her deteriorating clinical status.
      Figure thumbnail gr1
      Figure 1T2-weighted magnetic resonance image of the brain showing confluent and enhancing hyperintense lesions in the periventricular cerebral white matter.
      • 3.
        Which one of the following entities would least likely account for the periventricular white matter lesions seen on this patient's MRI?
        • a.
          Metastatic cancer
        • b.
          Diabetes mellitus
        • c.
          Primary CNS vasculitis
        • d.
          Demyelinating disease
        • e.
          CNS lymphoma
      Metastatic cancer usually presents with single or multiple space-occupying lesions surrounded by edema and is frequently located in the interface between gray and white matter. The lesions on this patient's MRI are located in the periventrieular white matter and show no mass effect or edema; therefore, they are not consistent with metastatic cancer. The T2-hyperintense periventricular white matter lesions on this patient's MRI are an entirely nonspecific finding. The age of the patient, degree of observed changes, and accompanying clinical context are crucial factors in determining whether such changes are meaningfully abnormal. These findings may represent small-vessel ischemic changes due to hypertension, diabetes, or aging. When more extensive or confluent, such lesions may reflect inflammatory, vasculitic, or lymphoproliferative lesions (eg, neurosarcoidosis, acute disseminated encephalomyelitis, multiple sclerosis, CNS lymphoma, or intravascular lymphomatosis [IL]).
      A stereotactic brain biopsy showed IL. Further histopathologic characterization of this neoplasm demonstrated positive immunoperoxidase staining with LCA and L26 and negative staining for CD3, supporting a diagnosis of cell non-Hodgkin lymphoma.
      • 4.
        Which one of the following is a relatively favorable prognostic factor for the condition diagnosed in our patient?
        • a.
          Isolated skin involvement
        • b.
          Seizures early after presentation
        • c.
          Isolated dementia
        • d.
          Bone marrow involvement
        • e.
          High serum lactate dehydrogenase (LD) level
      When IL presents with isolated skin involvement, the prognosis is relatively favorable because of earlier recognition and more indolent clinical behavior. Central nervous system involvement manifested by seizures shortly after presentation or dementia, widespread systemic involvement including the bone marrow, delayed treatment, and a high LD level, which represents tissue necrosis, are recognized poor prognostic factors in IL.
      Abdominal computed tomography showed a solid mass (2 cm) in the lateral aspect of the right kidney. An ultrasound-guided biopsy yielded tissue that proved to be diffuse large cell lymphoma. A bone scan disclosed areas of increased signal in both hemithoraces, both kidneys, and axial and appendicular skeleton. The LD level was elevated at 370 U/L (112-257 U/L).
      • 5.
        Which one of the following therapeutic modalities is most appropriate for our patient at this time?
        • a.
          Plasmapheresis
        • b.
          Bone marrow transplantation
        • c.
          Cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisone (CHOP) chemotherapy with or without whole-brain radiotherapy
        • d.
          Whole-brain radiotherapy
        • e.
          Pulse corticosteroid therapy
      Since our patient has a systemic disease, a systemic treatment should be offered. Clinicians considering treatment options do not have published prospective clinical trials to guide their choice. Plasmapheresis may be an alternative in patients in whom the therapeutic goal is to ameliorate neurologic symptoms.
      • Harris CP
      • Sigman JD
      • Jaeckle KA
      Intravascular malignant lymphomaiosis: amelioration of neurological symptoms with plasmaphercsis.
      Bone marrow transplantation may represent an option for patients in whom chemotherapeutic regimens fail.
      • Rose C
      • Staumont D
      • Jouet JP
      Successful autologous bone marrow transplantation in intravascular lymphomatosis [letter].
      Since IL disseminates in the vessel walls, use of intravenous agents has a theoretic advantage. Anthracycline-containing regimens are effective in large cell non-Hodgkin lymphoma and could be used in IL, A comparison of these regimens has established CHOP as the standard of care in other diffuse large cell variants of non-Hodgkin lymphoma.
      • Fisher RI
      • Gaynor ER
      • Dahlberg S
      • et al.
      Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma.
      Because of the multifocal nature of this disease, systemic treatment with combination chemotherapy with or without whole-brain radiotherapy may be the most appropriate approach in this patient. Whole-brain radiotherapy may control sudden neurologic deterioration in a patient undergoing chemotherapy or may be used as adjuvant treatment after aggressive systemic chemotherapy, but it is inappropriate as a single therapy. Response to corticosteroid administration may be substantial but is usually partial and brief and may delay the establishment of the correct diagnosis and the institution of combination chemotherapy.
      The bone marrow biopsy specimen was normal. The patient received 6 cycles of CHOP chemotherapy and whole-brain irradiation (50 Gy). After 5 months of treatment, most of the CNS lesions and the renal lesion had resolved considerably. Two months later, the patient was admitted to the hospital because of new neurologic focal signs, renal insufficiency, and hypercalcemia. An evaluation revealed new abdominal lymphadenopathy and recurrence of disease in the CNS. The bone marrow biopsy showed large cell lymphoma. Palliative care was instituted. Seven months after diagnosis, the patient died at home.

      DISCUSSION

      Intravascular lymphomatosis, previously thought to be a malignant proliferation of vascular endothelium, is a rare form of diffuse large cell non-Hodgkin lymphoma confined within lumina of blood vessels. Histologically, the tumor cells consist of large mononuclear cells resembling large cell lymphoma cells, confined to medium-sized arterioles, venules, and capillaries. These cells stain with lymphoid markers, such as the leukocyte common antigen CD45 and B-cell phenotypes, but T-cell variants have been described. Fewer than 200 cases have been reported in the world literature. Men and women are afflicted with equal frequency, with age of onset ranging from infancy to the eighth decade of life. Intravascular lymphomatosis has a predilection for involving the CNS and skin but may disseminate widely and infiltrate vessels of all other organs. Occasionally, as in our patient, extravascular large cell lymphoma masses are seen. New techniques using polymerase chain reaction amplification may be able to detect small malignant clonal B-cell populations on bone marrow biopsy.
      • DiGiuseppe JA
      • Hartmann DP
      • Fréter C
      • Cossman J
      • Mann RB
      Molecular detection of bone marrow involvement in intravascular lymphomatosis.
      Fever, an erythematous macular-papular or nodular rash, and prominent neurologic signs are present in up to 85% of patients. Since IL results in neoplastic proliferation in small caliber vessels, disturbed vascular flow or thrombotic events may cause abrupt-onset focal deficits. However, dementia usually dominates the neurologic presentation. The spectrum of neurologic manifestations includes headache, visual hallucinosis, seizures, myoclonus, cranial nerve palsies (especially of the third, sixth, seventh, and eighth cranial nerves), gait disturbances, myelopathy, radiculopathy, and neuropathy.
      • Chapin JE
      • Davis LE
      • Kornfeld M
      • Maridler RN
      Neurologic manifestations of intravascular lymphomatosis.
      An MRI may show multifocal, usually contrast-enhancing confluent periventricular or parenchymal lesions, or diffuse leptomeningeal enhancement, sometimes even demonstrating such changes before the onset of clinical symptoms.
      • Williams RL
      • Meltzer CC
      • Smirniotopoulos JG
      • Fukui MB
      • Inman M
      Cerebral MR imaging in intravascular lymphomatosis.
      Histologic confirmation is the only specific means for diagnosing IL. Skin biopsy, when there is a clinically apparent rash, has a sensitivity of about 85%. Brain biopsy may have only a 50% yield, and a repeated biopsy may be required. Immunostaining is necessary,
      • Williams RL
      • Meltzer CC
      • Smirniotopoulos JG
      • Fukui MB
      • Inman M
      Cerebral MR imaging in intravascular lymphomatosis.
      Other clinically involved organs may provide suitable targets for biopsy and tissue confirmation. Organs reported to yield abnormal biopsy specimens include lung, kidney, liver, gallbladder, prostate, adrenal gland, sural nerve, bone marrow, spleen, and muscle.
      Brain tissue for diagnosis is obtained by using a stereotactic approach. The differential diagnosis includes infectious cerebritis or meningoencephalitis, multiple subcortical infarcts, vasculitis, neurosarcoidosis, and demyelinating disease when the characteristic clinical, neuroimaging, and CSF findings are present. Angiocentric T-cell (lymphomatoid granulomatosis) should also be considered. In almost one half of the reported patients in the world literature, diagnosis was made on postmortem examinations. If no treatment is given, median survival is less than 6 months.
      Retrospective series suggest that aggressive systemic chemotherapy may achieve complete remission. In patients in whom complete remission has been reported, a combination of anthracycline-based regimens and corticosteroids was used.
      • DiGiuseppe JA
      • Nelson WG
      • Seifter EJ
      • Boitnott JK
      • Mann RB
      Intravascular lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherapy.
      • Demirer T
      • Dail DH
      • Aboulafia DM
      Four varied cases of intravascular lymphomatosis and a literature review.
      Patients receiving local treatments had a brief survival. Adjuvant radiation may be used, especially whole-brain treatment in patients with a rapidly deteriorating neurologic course despite systemic chemotherapy. A case of successful (30-month disease-free survival) autologous bone marrow transplantation after CHOP failure has been reported.
      • Rose C
      • Staumont D
      • Jouet JP
      Successful autologous bone marrow transplantation in intravascular lymphomatosis [letter].

      ACKNOWLEDGMENT

      We thank Dr Daniel M. Jacobson, Marshfield Clinic, Department of Neurology, for his thoughtful review of the submitted manuscript.

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        Intravascular malignant lymphomaiosis: amelioration of neurological symptoms with plasmaphercsis.
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        Successful autologous bone marrow transplantation in intravascular lymphomatosis [letter].
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        Molecular detection of bone marrow involvement in intravascular lymphomatosis.
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        Neurologic manifestations of intravascular lymphomatosis.
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