Journal of Neuro-Oncology 13: 173-175, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Hyperventilation as the initial manifestation of lymphomatous meningitis George Karp and Kenneth Nahum
Division of Hematology/Oncology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School
Key words: hyperventilation, lymphoma, meningitis Summary We present the case of a 57 year old man who developed a B-cell lymphoma which involved his lymph nodes, liver, spleen, bone marrow, and peripheral blood. Shortly after attaining a complete remission with chemotherapy, the patient developed profound hyperventilation with no apparent cardiac or pulmonary cause. After one month, the patient developed a 7th nerve palsy and a subsequent work-up demonstrated that he had lymphomatous meningitis. The hyperventilation resolved completely with intrathecal chemotherapy, although the patient eventually died of widely disseminated lymphoma.
Introduction In patients with non-Hodgkin's lymphoma (NHL), leptomeningeal involvement may occur in up to 9% of cases [1, 2]. Most typically, these patients present with cranial nerve abnormalities. We describe a case of a 57 year old man where hyperventilation alone was the first symptom of disease recurrence and CNS involvement. Because of this unusual presentation, the diagnosis was overlooked until the patient developed cranial nerve findings.
Case report A 57 year old computer analyst presented with increasing lymphadenopathy and fatigue. Three years earlier, he had been diagnosed as having chronic lymphocytic leukemia based on a peripheral blood smear done at another institution. He was treated with two courses of chlorambucil and prednisone because of discomfort caused by cervical adenopathy. He was lost to follow-up for the next three years. At the time of presentation at
Robert Wood Johnson University Hospital, he was noted to have prominent lymphadenopathy in the cervical, axillary, and inguinal areas. His liver and spleen were both enlarged. Peripheral blood smear demonstrated 16% lymphoma cells which were variable in size. Smaller cells had dense nuclear chromatin with nuclear clefting. Larger lymphoma cells had reticular nuclear chromatin with one or two prominent nucleoli. Bone marrow aspirate revealed 91% lymphoma cells and the bone marrow biopsy showed a hypercellular marrow replaced by large cell lymphoma. Flow cytometric analysis demonstrated that these cells were of B-cell origin. On the basis of these studies, a diagnosis of a B-cell lymphoma in a leukemic phase was established. The patient was treated with combination chemotherapy that included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The patient responded dramatically to this regimen with nearly total resolution of his peripheral lymphadenopathy and normalization of hepatic and splenic size by physical examination. After 7 cycles of chemotherapy, however, the patient refused further treatment due to severe nausea and vomiting. A restaging work-up revealed that his peripheral
174 blood smear was normal and his bone marrow aspirate and biopsy were normal except for some small lymphoid aggregates. Eight weeks after his last dose of chemotherapy the patient presented with increasing shortness of breath. Physical examination revealed a respiratory rate of 40, but no pulmonary, cardiac, or neurologic abnormalities. A chest x-ray showed no acute changes and an arterial blood gas revealed a pO2 of 124 mmHg, a pCO2 of 15mmHg, a pH of 7.53 and bicarbonate of 12.1 mEq/l. As it was felt that the hyperventilation might be a manifestation of the patient's anxiety, he was reassured and started on diazepam. The next day the patient noted that he was feeling significantly better and was no longer hyperventilating. Two weeks later the patient was again evaluated and seemed considerably more confortable with a respiratory rate of 22. He was eventually seen by a psychiatrist who recommended that he be managed in the University's stress clinic. However, two weeks later the patient returned with increasing shortness of breath and a respiratory rate of 40. The patient was admitted to the hospital where his physical examination was noted to be unchanged except for the presence of a mild left 7th nerve palsy. Specifically, his lungs were clear, there was no tachycardia, no evidence of thrombophlebitis and no signs of pulmonary hypertension such as an accentuated P2 of the second heart sound. There was no papilledema. The rest of the neurological exam was normal. Chest x-ray, electrocardiogram, and blood gas were unchanged. A C T scan of the brafn was within normal limits. A spinal tap was performed and the cerebrospinal fluid cell count revealed 1,381 white cells per mm 3, all of which were lymphoma cells. CSF glucose was 10 mg/dl, with a serum glucose of 120 mg/dl. CSF protein was 715 mg/dl. It was felt that the patient had lymphomatous meningitis, and an Ommaya reservoir was inserted. After four doses of biweekly intrathecal methotrexate, the patient had only partial improvement of his facial palsy but the hyperventilation completely resolved. The patient was subsequently treated with weekly intrathecal methotrexate, but he eventually developed Staph Aureus meningitis. At the same time, his hematologic picture worsened, with progressive lymphoma in the
bone marrow and peripheral blood. He died two months later of widespread lymphoma. No autopsy was performed.
Discussion
The development of a leukemic phase in a patient with large cell-lymphoma (the predominant cell type in the bone marrow of this patient) often heralds a rapid worsening of the course of the patient. Survival is often less than two months [3, 4]. Although the majority of patients succumb to disseminated visceral disease, a small but distinct minority will develop central nervous system complications secondary to direct involvement by lymphoma. In one study, 5% of 1039 patients with NHL developed CNS lymphoma, and of these, 44% were patients with diffuse large cell lymphoma [1]. Levitt et al. [2] found that 9% of 592 patients with NHL developed CNS involvement. In these series, leptomeningeal involvement represented 66--78% of the total number of CNS cases [1, 2]. In Levitt's study, it was felt that bone marrow involvement was a relative risk factor for the development of CNS lymphoma [2]. Cranial nerve palsies appear to be the most common presenting sign in this group of patients. Other associated symptoms or signs include paresthesias, headaches, drowsiness, backache, and confusion [1, 2, 5-7]. We are unaware of any previous reports where hyperventilation was a sign or symptom of CNS involvement by lymphoma. In 54 patients with carcinomatous (as opposed to leukemic or lymphomatous) meningitis, no patient manifested any respiratory abnormality [8, 9]. The mechanism of hyperventilation in lymphomatous meningitis is unclear, but may be related to an increase in intracranial pressure. In patients with lesions of the brainstem, hyperventilation may result despite low arterial CO2 tensions and adequate oxygenation, and may represent a release from the reflex mechanism of respiratory control [10]. Potential mechanisms such as pulmonary edema and lactic acidosis have also been suggested in tumor patients [11, 12]. Although hyperventilation has been described in patients with infectious men-
175 ingitis, it is usually not as pronounced as in our patient [13]. In conclusion, hyperventilation may be a rare presenting sign of a malignant meningitis. Clinicians caring for cancer patients should maintain a high index of suspicion in order to facilitate a rapid diagnosis and the institution of appropriate palliative therapy.
6.
7.
8.
References 9. 1. Herman TS, Hammond N, Jones SE, Butler J J, Bryrne Jr. GE, McKelvey EM: Involvement of the central nervous system by non-Hodgkin's lymphoma. Cancer 43: 390-397, 1979 2. Levitt LJ, Dawson DM, Rosenthal DS, Moloney WC: CNS involvement in the non-Hodgkin's lymphomas. Cancer 45: 545-552, 1980 3. Mintzer DM, Hauptman SP: Lymphosarcoma cell leukemia and other non-Hodgkin's lymphomas in leukemic phase. Am J Med 75: 110-120, 1983 4. Fram R J, Skarin AT, Rosenthal DS, Pinkus G, Nadler LM: Clinical, pathologic and immunologic features of patients with non-Hodgkin's lymphoma in a leukemic phase. Cancer 52: 1220-1228, 1983 5. Wilder-Smith E, Roelcke U: Meningopolyradiculitis
10. 11. 12.
13.
(Bannwarth syndrome) as primary manifestation of a centrocytic-centroblastic lymphoma J Neurol 236: 168-169, 1989 Cash J, Fehir KM, Pollack MS: Meningeal involvement in early stage chronic lymphocytic leukemia. Cancer 59" 798800, 1987 Heimans J J, Wijermans PW, Polman CH, Huijgen PC, Ossenkoppele G J, van Kamp G J: Longterm meningeal involvement as the only clinical manifestation of low grade malignant non-Hodgkin's lymphoma. J Neuroonc 9: 275277, 1990 Gonzalez-Vitale JC, Garcia-Bunuel R: Meningeal carcinomatosis. Cancer 37: 2906-2911, 1976 Olson ME, Chernik NL, Posner JB: Infiltration of the leptomeninges by systemic cancer. Arch Neurol 30: 122137, 1974 Adams RD, Victor M: Principles of neurology, 4th ed., McGraw-Hill, New York 282, 1989 Plum F: Mechanisms of 'central' hyperventilation, Ann Neurol 11: 636-637, 1982 North JB, Jennett S: Abnormal breathing patterns associated with acute brain damage. Arch Neurol 31: 338-344, 1974 Bannister R: Brain's clinical neurology, 6th ed., Oxford University Press, London 471, 1985
Address for offprints: G. Karp, Division of Hematology/Oncology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, CN-19, New Brunswick, NJ 08903, USA
Clinical Study
Hyperventilation as the initial manifestation of lymphomatous meningitis George Karp and Kenneth Nahum
Division of Hematology/Oncology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School
Key words: hyperventilation, lymphoma, meningitis Summary We present the case of a 57 year old man who developed a B-cell lymphoma which involved his lymph nodes, liver, spleen, bone marrow, and peripheral blood. Shortly after attaining a complete remission with chemotherapy, the patient developed profound hyperventilation with no apparent cardiac or pulmonary cause. After one month, the patient developed a 7th nerve palsy and a subsequent work-up demonstrated that he had lymphomatous meningitis. The hyperventilation resolved completely with intrathecal chemotherapy, although the patient eventually died of widely disseminated lymphoma.
Introduction In patients with non-Hodgkin's lymphoma (NHL), leptomeningeal involvement may occur in up to 9% of cases [1, 2]. Most typically, these patients present with cranial nerve abnormalities. We describe a case of a 57 year old man where hyperventilation alone was the first symptom of disease recurrence and CNS involvement. Because of this unusual presentation, the diagnosis was overlooked until the patient developed cranial nerve findings.
Case report A 57 year old computer analyst presented with increasing lymphadenopathy and fatigue. Three years earlier, he had been diagnosed as having chronic lymphocytic leukemia based on a peripheral blood smear done at another institution. He was treated with two courses of chlorambucil and prednisone because of discomfort caused by cervical adenopathy. He was lost to follow-up for the next three years. At the time of presentation at
Robert Wood Johnson University Hospital, he was noted to have prominent lymphadenopathy in the cervical, axillary, and inguinal areas. His liver and spleen were both enlarged. Peripheral blood smear demonstrated 16% lymphoma cells which were variable in size. Smaller cells had dense nuclear chromatin with nuclear clefting. Larger lymphoma cells had reticular nuclear chromatin with one or two prominent nucleoli. Bone marrow aspirate revealed 91% lymphoma cells and the bone marrow biopsy showed a hypercellular marrow replaced by large cell lymphoma. Flow cytometric analysis demonstrated that these cells were of B-cell origin. On the basis of these studies, a diagnosis of a B-cell lymphoma in a leukemic phase was established. The patient was treated with combination chemotherapy that included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The patient responded dramatically to this regimen with nearly total resolution of his peripheral lymphadenopathy and normalization of hepatic and splenic size by physical examination. After 7 cycles of chemotherapy, however, the patient refused further treatment due to severe nausea and vomiting. A restaging work-up revealed that his peripheral
174 blood smear was normal and his bone marrow aspirate and biopsy were normal except for some small lymphoid aggregates. Eight weeks after his last dose of chemotherapy the patient presented with increasing shortness of breath. Physical examination revealed a respiratory rate of 40, but no pulmonary, cardiac, or neurologic abnormalities. A chest x-ray showed no acute changes and an arterial blood gas revealed a pO2 of 124 mmHg, a pCO2 of 15mmHg, a pH of 7.53 and bicarbonate of 12.1 mEq/l. As it was felt that the hyperventilation might be a manifestation of the patient's anxiety, he was reassured and started on diazepam. The next day the patient noted that he was feeling significantly better and was no longer hyperventilating. Two weeks later the patient was again evaluated and seemed considerably more confortable with a respiratory rate of 22. He was eventually seen by a psychiatrist who recommended that he be managed in the University's stress clinic. However, two weeks later the patient returned with increasing shortness of breath and a respiratory rate of 40. The patient was admitted to the hospital where his physical examination was noted to be unchanged except for the presence of a mild left 7th nerve palsy. Specifically, his lungs were clear, there was no tachycardia, no evidence of thrombophlebitis and no signs of pulmonary hypertension such as an accentuated P2 of the second heart sound. There was no papilledema. The rest of the neurological exam was normal. Chest x-ray, electrocardiogram, and blood gas were unchanged. A C T scan of the brafn was within normal limits. A spinal tap was performed and the cerebrospinal fluid cell count revealed 1,381 white cells per mm 3, all of which were lymphoma cells. CSF glucose was 10 mg/dl, with a serum glucose of 120 mg/dl. CSF protein was 715 mg/dl. It was felt that the patient had lymphomatous meningitis, and an Ommaya reservoir was inserted. After four doses of biweekly intrathecal methotrexate, the patient had only partial improvement of his facial palsy but the hyperventilation completely resolved. The patient was subsequently treated with weekly intrathecal methotrexate, but he eventually developed Staph Aureus meningitis. At the same time, his hematologic picture worsened, with progressive lymphoma in the
bone marrow and peripheral blood. He died two months later of widespread lymphoma. No autopsy was performed.
Discussion
The development of a leukemic phase in a patient with large cell-lymphoma (the predominant cell type in the bone marrow of this patient) often heralds a rapid worsening of the course of the patient. Survival is often less than two months [3, 4]. Although the majority of patients succumb to disseminated visceral disease, a small but distinct minority will develop central nervous system complications secondary to direct involvement by lymphoma. In one study, 5% of 1039 patients with NHL developed CNS lymphoma, and of these, 44% were patients with diffuse large cell lymphoma [1]. Levitt et al. [2] found that 9% of 592 patients with NHL developed CNS involvement. In these series, leptomeningeal involvement represented 66--78% of the total number of CNS cases [1, 2]. In Levitt's study, it was felt that bone marrow involvement was a relative risk factor for the development of CNS lymphoma [2]. Cranial nerve palsies appear to be the most common presenting sign in this group of patients. Other associated symptoms or signs include paresthesias, headaches, drowsiness, backache, and confusion [1, 2, 5-7]. We are unaware of any previous reports where hyperventilation was a sign or symptom of CNS involvement by lymphoma. In 54 patients with carcinomatous (as opposed to leukemic or lymphomatous) meningitis, no patient manifested any respiratory abnormality [8, 9]. The mechanism of hyperventilation in lymphomatous meningitis is unclear, but may be related to an increase in intracranial pressure. In patients with lesions of the brainstem, hyperventilation may result despite low arterial CO2 tensions and adequate oxygenation, and may represent a release from the reflex mechanism of respiratory control [10]. Potential mechanisms such as pulmonary edema and lactic acidosis have also been suggested in tumor patients [11, 12]. Although hyperventilation has been described in patients with infectious men-
175 ingitis, it is usually not as pronounced as in our patient [13]. In conclusion, hyperventilation may be a rare presenting sign of a malignant meningitis. Clinicians caring for cancer patients should maintain a high index of suspicion in order to facilitate a rapid diagnosis and the institution of appropriate palliative therapy.
6.
7.
8.
References 9. 1. Herman TS, Hammond N, Jones SE, Butler J J, Bryrne Jr. GE, McKelvey EM: Involvement of the central nervous system by non-Hodgkin's lymphoma. Cancer 43: 390-397, 1979 2. Levitt LJ, Dawson DM, Rosenthal DS, Moloney WC: CNS involvement in the non-Hodgkin's lymphomas. Cancer 45: 545-552, 1980 3. Mintzer DM, Hauptman SP: Lymphosarcoma cell leukemia and other non-Hodgkin's lymphomas in leukemic phase. Am J Med 75: 110-120, 1983 4. Fram R J, Skarin AT, Rosenthal DS, Pinkus G, Nadler LM: Clinical, pathologic and immunologic features of patients with non-Hodgkin's lymphoma in a leukemic phase. Cancer 52: 1220-1228, 1983 5. Wilder-Smith E, Roelcke U: Meningopolyradiculitis
10. 11. 12.
13.
(Bannwarth syndrome) as primary manifestation of a centrocytic-centroblastic lymphoma J Neurol 236: 168-169, 1989 Cash J, Fehir KM, Pollack MS: Meningeal involvement in early stage chronic lymphocytic leukemia. Cancer 59" 798800, 1987 Heimans J J, Wijermans PW, Polman CH, Huijgen PC, Ossenkoppele G J, van Kamp G J: Longterm meningeal involvement as the only clinical manifestation of low grade malignant non-Hodgkin's lymphoma. J Neuroonc 9: 275277, 1990 Gonzalez-Vitale JC, Garcia-Bunuel R: Meningeal carcinomatosis. Cancer 37: 2906-2911, 1976 Olson ME, Chernik NL, Posner JB: Infiltration of the leptomeninges by systemic cancer. Arch Neurol 30: 122137, 1974 Adams RD, Victor M: Principles of neurology, 4th ed., McGraw-Hill, New York 282, 1989 Plum F: Mechanisms of 'central' hyperventilation, Ann Neurol 11: 636-637, 1982 North JB, Jennett S: Abnormal breathing patterns associated with acute brain damage. Arch Neurol 31: 338-344, 1974 Bannister R: Brain's clinical neurology, 6th ed., Oxford University Press, London 471, 1985
Address for offprints: G. Karp, Division of Hematology/Oncology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, CN-19, New Brunswick, NJ 08903, USA
