Central neurogenic hyperventilation (CNH) has been defined by Plum and Swanson as a syndrome comprising normal arterial oxygen tension (PaOJ, decreased arterial carbon dioxide tension (PaCOJ, and respiratory alkalosis in the absence of cardiac or pulmonary abnormalities that would stimulate a compensatory hyperpnea. We report here an awake patient with CNH associated with lymphomatoid granulomatosis (LC) confined to the central nervous system.
A 41-year-old white male electrician presented to his local hospital with a three-day history of uncontrollable rapid breathing. His past medical history revealed a grand mal seizure one year prior to this admission which was not evaluated. At the outside hospital, the patient was awake and alert. Arterial blood gas levels obtained breathing room air revealed pH, 7.62; Pa02, 120 mm Hg; PaC02, 7 mm Hg with a bicarbonate of 12 mEq/L. His white blood cell (WBC) count was 26,600/cu mm with a hemoglobin of 17.1 g/dl. The patient underwent a lumbar puncture which revealed glucose 52 mg/dl, protein, 90 mg/dl, and 15 cells (87 percent lymphocytes). Computerized tomography (CT) of the brain revealed multiple small contrast enhancing lesions. He was treated with chloramphenicol and tobramycin. Three days later, the patient was found to be confused and his mentation was slow. He was transferred to the University Medical Center for further evaluation.
Physical examination revealed a temperature of 36.7°C with a pulse rate of 85 beats per minute and a blood pressure of 110/70 mm Hg. The patient was found to be breathing rapidly with a respiratory rate of 26 per minute. He was awake and alert but had a flat affect. He was oriented to person, but he had a decrease in immediate memory. His coordination was poor. The reflexes were all intact and four plus bilaterally. His plantar reflexes were flexor bilaterally. His admission chest roentgenogram was normal. Arterial blood gas levels breathing room air revealed pH, 7.55, Pa02,113 mm Hg, and PaC02, 16 mm Hg. A repeat spinal fluid examination revealed 10 WBCs (100 percent lymphocytes), protein, 109 mg/dl; glucose, 44 mg/dl; and a negative VDRL. Sedation with morphine sulfate failed to control the hyperventilation. Repeat blood gas values obtained 24 hours later revealed pH, 7.67; Pa02, 124 mm Hg; PaC02, 6 mm Hg; bicarbonate, 7 mEq/L; and the anion gap was 11 mEq/L. Repeat chest roentgenogram was normal. Because of the severe alkalosis, the patient was intubated, mechanically ventilated, and paralyzed with pancuronium bromide. A CT scan of the brain revealed decreased left frontal density with diffuse irregular contrast enhancement of both hemispheres that was greatest in the frontal areas (Fig 1). No mass lesion was seen.
A brain biopsy was obtained on the seventh hospital day which revealed an angiocentric infiltrate of mononuclear cells focally extending into the brain substance consistent with lymphomatoid granulomatosis (Fig 2). An outside pathology consultant felt that the lesion revealed focal evolution to a large cell malignant lymphoma resembling immunoblastic sarcoma. A tracheostomy was preformed on the tenth hospital day. Mechanical ventilation was continued, and treatment with prednisone (1 mg/kg per day) and cyclophosphamide (2 mg/kg per day) was started on the tenth hospital day. Marked recovery of neurologic function was noted on the 18th hospital day. The patient was gradually weaned off the pancuronium and off of the ventilator on the 18th hospital day with improvement in hyperventilation. The tracheostomy was closed on the 21st hospital day. When the diagosis of lymphoma was entertained, the patient had a CT scan of the chest and abdomen which were normal. Serum quantitative immunoglobulins revealed a mild elevation of IgG and IgA. Repeat CT scan of the brain on the 32nd hospital day revealed decreased densities in the left frontal lobe, and disappearance of the diffuse, bilateral contrast enhancing lesions. The patient was started on whole brain radiation therapy. At the time of discharge, five weeks from the date of admission, arterial blood gas values breathing room air revealed pH, 7.50; Pa02, 85 mm Hg; and PaCOz, 30 mm Hg.
Lymphomatoid granulomatosis is characterized by an angiocentric, angiodestructive infiltrate of atypical lympho-reticular cells predominantly affecting the lungs, skin, central nervous system, and kidneys that was first described in 1972. Disease presenting in or confined to the central nervous system is rare, although central nervous system involvement occurs in 23 to 30 percent of patients with LG. The disease process can evolve into a malignant lymphoma if not vigorously treated with a combination of cyclophosphamide and prednisone. Combination chemotherapy of the resultant malignant lymphoma with several drug regimens has been unsuccessful in achieving remission. A recent reevaluation of the syndrome has suggested that a diagnosis of malignant lymphoma or malignant lym-phoproliferative syndrome can be made instead of lymphomatoid granulomatosis if multiple samples of tissue are examined.
Central neurogenic hyperventilation has been reported in association with primary brainstem astrocytoma, and malignant cerebral reticulosis. Our review of the literature failed to reveal a similar case of central hyperventilation due to lymphomatoid granulomatosis of the central nervous system with or without transformation to lymphoma.
Acute respiratory alkalosis decreases cerebral blood flow, shifts the oxygen hemoglobin dissociation curve to the left, and increases anaerobic metabolism of glucose in the brain.uOur patient remained awake despite a PaCOz of 6 mm Hg and pH of 7.67. Our patient continued to hyperventilate in spite of sedation and required total paralysis to correct his severe respiratory alkalosis. The hyperventilation resolved, and the patient was successfully weaned off the pancuronium and the respirator after eight days of cyclophosphamide and prednisone therapy for lymphomatoid granulomatosis.
The histologic findings in our patient revealed lymphomatoid granulomatosis. Bone marrow examination and CT scans of the chest and abdomen showed no evidence of lymphoma. The initial CT scan of the brain (Fig 1) revealed contrast enhancement similar to that of a case reported previously by Sackett et al. One patient with systemic LG who developed a central nervous system immunoblastic sarcoma five months after initial diagnosis has been reported.
Plum and Swanson, in their analysis of nine patients with central neurogenic hyperventilation, demonstrated an increase in minute alveolar ventilation from one and one-half to four times the normal resting level with profound hypocapnia and arterial alkalosis without anoxemia. The respiratory response to reflex and chemical stimuli were preserved. Autopsies demonstrated medial pontine destruction in five subjects, with indirect damage to this area in the sixth. Extraneural abnormalities were insufficient to explain fully the respiratory change. This suggested that the structures in the medial pontile reticular formation of man are at least indirectly inhibitory to respiration. Central neurogenic hyperventilation occurs when the lesion in the medial pontile tegmentum prevents descending inhibitory impulses from reaching the medullary respiratory centers. This results in the uninhibited stimulation of the medullary respiratory centers by the lateral pontile reticular formation and laterally placed descending neural pathways. Since the tissue obtained in our patient was a cerebral biopsy, we cannot clearly state whether any pontile lesion existed. The diffuse irregular contrast enhancement seen on the CT scan suggests that the process may have been widespread enough to involve the brainstem.
In summary, a patient with lymphomatoid granulomatosis and focal transformation to lymphoma limited to the central nervous system presented with severe central neurogenic hyperventilation. The hyperventilation resolved as the underlying pathology was treated with prednisone and cyclophosphamide. Ultimately, whole brain irradiation was administered for the lymphoma since the disease process was confined to the brain.
Figure 1. Computerized tomography of brain before (A, left) and after contrast (B, right) shows diffuse contrast enhancement of both hemispheres greatest in the frontal areas.
Figure 2. Section of cerebrum demonstrates a polymorphic angio-centric infiltrate of mononuclear cells (hematoxylin-eosin, original magnification x 250).