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Unusual Sites of Malignancies

CASE 2. Central Neurogenic Hyperventilation As a Complication of Richter's Syndrome

Departments of Internal Medicine III, Clinical Chemistry, Radiology, and Neurology, Ludwig Maximilians Universität, Munich, Germany
Department of Pathology, Julius Maximilians Universität, Würzburg, Germany
Department of Internal Medicine I, Universität Köln, Köln, Germany

A 75-year-old man with a 3-year history of B-cell chronic lymphocytic leukemia (CLL) presented with a reduced performance status and tachypnea for 3 days. He was restless and anxious, but awake and fully oriented. Vital signs were normal except for a respiratory rate of 40/min. Physical examination and routine laboratory tests including blood cell counts, serum glucose, creatinine, lactate, liver function tests, and thyroid-stimulating hormone, did not reveal any abnormal findings besides the features of a typical CLL (Fig 1A). However, arterial blood gases showed the following: pH 7.7; PaO₂, 135 mmHg; PaCO₂, 7.3 mmHg; base deficit, –11.7 mEq/L; and standard bicarbonate, 9.5 mEq/L; consistent with a severe, chronic respiratory alkalosis with incomplete metabolic compensation. In a diagnostic work-up, pulmonary and cardiac causes of hyperventilation were excluded by chest x-ray, ECG, and echocardiography. None of the patient's drugs was known to be associated with hyperventilation. A psychogenic hyperventilation was excluded, as symptoms persisted during sleep. Cerebral computed tomography scan excluded high intracranial pressure and bleeding. Magnetic resonance imaging (MRI) showed discrete signal alterations within the pons and medulla oblongata on T2-weighted images, but no further evidence for intracerebral mass effect or infiltration (Fig 2). Examination of the CSF demonstrated the following: protein, 173 mg/dL; glucose, 9 mg/dL; and leukocytes, 2/mm³. Albumin CSF-serum ratio was 22.6, indicating severe disturbance of the blood-brain barrier. The CSF cytogram showed 6% neutrophils, 22% lymphocytes, 28% monocytes, and 44% large blastoid cells (Fig 1B). The latter cells were CD19+, CD20+, CD5+, immunoglobulin M+, and monoclonal for SK+, corresponding to the known CLL. Microbiological tests were negative. The findings suggested the diagnosis of central neurogenic hyperventilation (CNH) due to CNS infiltration of a transformed CLL. Midazolam, 5 mg intravenously, resulted in immediate reduction of respiratory rate, but the effect was transient, and repeated administration was necessary. The patient received intrathecal cytosine-arabinoside, methotrexate and dexamethasone, and intravenous prednisolone. With this treatment, the respiratory rate went down to normal within 4 days. However, the patient developed bilateral peripheral facial nerve palsy, dysarthria, and orofacial dyskinesia that did not respond to high-dose intravenous methotrexate. He subsequently refused any further treatment and died from progressive lymphoma within several weeks. An autopsy was denied by the patient's family.

View larger version (89K): [in this window] [in a new window]   Fig 1.

View larger version (126K): [in this window] [in a new window]   Fig 2.

Transformation into an aggressive large-cell lymphoma, referred to as Richter's syndrome, occurs in 3% to 5% of CLL patients.1 Whereas infiltration of the brain or meninges by typical B-cell CLL is common, only seven cases of Richter's syndrome with cerebral involvement have been reported.2

CNH was first described in 1959.3 The syndrome is commonly seen in deeply comatose patients with serious CNS injuries, but is a rare finding in patients awake, where it is most frequently caused by an intracerebral malignancy. It is characterized by sustained hyperventilation persisting during sleep, a marked decrease in PaCO₂, elevated PaO₂, and severe respiratory alkalosis. Absence of any respiratory stimulus is mandatory for the diagnosis. So far, 19 cases of patients with tumor-induced CNH have been published, and 10 of these patients suffered from CNS lymphoma.4 To our knowledge, this is the first report on CNH caused by Richter's syndrome. Several pathogenetic mechanisms have been suggested, including the infiltration of the pons by tumor cells without destruction of the tissue architecture.5 This might lead to medial pontine dysfunction and unopposed stimulation of respiratory centers in the medulla.4 CNS lymphoma are known to develop extensive microscopic infiltration of the brain that may lead to unspecific T2 hyperintensity or may not be detected on MRI.6 In our patient, the presence of large blasts within the CSF and the discrete MRI findings in the pons suggested an infiltration of this area as an explanation for the development of CNH. Symptomatic treatment consists of repeated or continuous intravenous administration of midazolam, propofol or morphium, or mechanical ventilation. In CNH caused by intracerebral lymphoma, intravenous steroids, chemotherapy, and local irradiation were effective for specific therapy.4,7 If lymphoma cells are demonstrated within CSF, intrathecal chemotherapy seems to be helpful. However, the prognosis of CNH is grave, since in the majority of published cases, the patients have died within a few months from diagnosis.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Dighiero G, Travade P, Chevret S, et al: B-cell chronic lymphocytic leukemia: Present status and future directions—French Cooperative Group on CLL. Blood 78: 1901-1914, 1991[Free Full Text]

2. Cramer SC, Glaspy JA: Efird JT, et al: Chronic lymphocytic leukemia and the central nervous system: A clinical and pathological study. Neurology 46: 19-25, 1996[Abstract/Free Full Text]

3. Plum F, Swanson AG: Central neurogenic hyperventilation in man. Arch Neurol Psychiatr 81: 535-549, 1959

4. Chang CH, Kuo PH, Hsu CH, et al: Persistent severe hypocapnia and alkalemia in a 40-year-old woman. Chest 118: 242-245, 2000[Free Full Text]

5. Shibata Y, Meguro K, Narushima, et al: Malignant lymphoma of the central nervous system presenting with central neurogenic hyperventilation: Case report. J Neurosurg 76: 696-700, 1992[Medline]

6. Lai R, Rosenblum MK, DeAngelis LM: Primary CNS lymphoma: A whole-brain disease? Neurology 59: 1557-1562, 2002[Abstract/Free Full Text]

7. Krendel DA, Pilch JF, Stahl RL: Central hyperventilation in primary CNS lymphoma: Evidence implicating CSF lactic acid. Neurology 41: 1156-1157, 1991

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schmid, C. Articles by Hallek, M. Search for Related Content PubMed PubMed Citation Articles by Schmid, C. Articles by Hallek, M. Social Bookmarking                            What's this?