The central nervous system manifestations of leukemia

The Journal o[ P E D I A T R I C S

183

The central nervous system mamfestations of leukemia A report of 6 cases with meningeal involvement

J.

M. Steffey, M.D. ~

DES

2r

IOWA

T H AT leukemia can involve the central nervous system is not a new concept. Burns 1 in 1823 recognized and reported a case of leukemia with neurological involvement. Since then numerous other authors have reported such findings. Lightwood, Barrie, and Butler 2 and Dameshek a have commented on the increased incidence of leukemia in recent years. Irrespective of the incidence of leukemia, it would appear that involvement of the central nervous system in this disease is increasing. If so, the probable explanation is the increased survival time of patients with leukemia due to chemotherapy. In 1921 Barker 4 listed "several modes of involvement" of the central nervous system in leukemia, but stated that leukemic infiltration of the leptomeninges was rare. Excluding terminal cerebral hemorrhage, meningeal involvement is probably the most commonly noted central nervous system manifestation of leukemia at the present time.

From the Blank Memorial Hospital [or Children ~Address, Blank Memorial Hospital [or Children, 1200 Pleasant Street, Des Moines 14, Iowa,

INCIDENCE

Sullivan s observed meningeal involvement in 25 per cent of his patients. Other authors ~, 9, 11 have reported a lower incidence (Table I and Table I I ) . Wells and Silver s recorded the highest incidence (52.4 per cent); however, the series included patients with intracranial hemorrhage and over one half of the patients were adults. Liedler and RusselP 1 found neurological complications to be 2 times more frequent in males than in females. Wells s found no significant difference in the incidence in the 2 sexes. PATHOLOGY

Leukemic cells can be found in almost every organ and tissue of the body at postmortem examination? In central nervous system involvement, there appears to be a decided disparity in the clinical manifestations and the pathologic findings, the per cent involvement of the former lagging behind the latter? ~ 6, 20 Clinical pathologic correlation m a y also be lacking, since the central nervous system involvement demonstrable at autopsy m a y not seem to be sufficient to account for the clinical symptoms.

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LitteraP ~ estimated that the neuropathologic changes were present in about 80 per cent of instances, whereas clinical neurological manifestations are observed in only about 20 per cent of patients. Neurological lesions in leukemia include infiltration of the meninges, pial vessels, and the parenchyma of the brain and spinal cord, as well as intracranial and intraspinal hemorrhages. The most common and most serious pathologic finding is that of intracranial hemorrhage. The foremost cause of death in 117 patients reported by Moore ~~ was hemorrhage, the most common site being in the cranium. Of the 23 patients who had massive intracranial hemorrhage, 14 had intracerebral and 9 had subarachnoid hemorrhages. Involvement of the spinal cord and spinal roots seems to be more common in the myelogenous form of leukemia than in the lymphatic form of the disease. In general, involvement of the spinal cord is rare. D'Angio a found only about 1 per cent of 372 children with leukemic involvement of the spinal cord. Littera111 pointed out that the myelopathy in monocytic leukemia is similar to that in pernicious anemia. The cranial nerves are infrequently involved, and, when they are, the seventh nerve is the most common, then the second, eighth, and third in that order of frequency. CLINICAL MANIFESTATIONS The usual clinical picture of meningeal involvement includes headache, vomiting, and nuchal rigidity. These can be attributed to increased cerebrospinal fluid pressure and infiltration of the leptomeninges with leukemic cells. Such cases may be mistakenly diagnosed as septic meningitis? 4 The cerebrospinal fluid changes include: elevated pressure, at times to exceedingly high levels; pleocytosis; increased protein content; and, at times, a decreased sugar content. Papilledema, increased head size, visual disturbance, optic atrophy, and separation of the suture lines are found with increased intracranial pressure. It is unusual for un-

February 1962

Table I. Incidence of meningeal involvement in leukemia

Author Sullivan 5 Moore et al. 1~ Schwab and Weiss12 Lightwood, Barrie, and Butler 2 Steffey

[ Year I % 1957 1960 1935 1960 1961

25.0 3.4 2.0 1.0 16.2

treated patients to develop meningeal manifestations; most often chemotherapy has been underway for at least 5 or 6 months. The meningeal symptoms may occur during a hematologic relapse or may, on occasion, herald it. Nonmeningeal neurological manifestations, other than those secondary to cerebral hemorrhage, include cranial nerve palsies, Jacksonian epilepsy, hemiplegia, peripheral neuritis, deafness, proptosis, ptosis, diabetes insipidus, amblyopia, excessive appetite and weight gain, vertigo, paresthesias, hyporeflexia, and tremors of the limbs. Polyradiculitis, paraplegia, and paresthesias are related to cord and nerve root involvement. TREATMENT

Roentgen therapy was employed first in the treatment of meningeal leukemia. D'Angio and colleagues revealed that one half of their patients improved after lumbar puncture alone; presumably, the result of decreasing spinal fluid pressure. However, they found roentgen therapy, whether used with or without spinal puncture, to be the most effective form of therapy. Sansome, is in 1954 was the first to use Table II. Incidence of all types o~ central nervous system involvement in leukemia

Author Wells and Silvers Liedler and Russel ~l Diamond 16 Bass1~ Schwab and Weiss12 Norlander 7 Moore et al. 10 D'Angio 6 Kirshbaum and Preuss9 Brandt 22 Lightwood, Barrie, and Butler 2

I rear 1957 1945 1934 1921 1935 1951 1960 1959 1943 1945 1960

I

%

52.4 35.5 28.5 26.0 22.5 17.5 13.6 10.5 10.0 8.6 4.0

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antifolic acid compounds intrathecalIy. Whiteside 19 employed intrathecal methotrexate in 5 children and recorded good results. He demonstrated that cerebrospinal fluid levels of amethopterin are 30 to 100 times greater after intrathecal administration as compared to similar single massive oral doses. Oral doses of methotrexate or 6mercaptopurine effective in the blood may have levels in the spinal fluid too low to be effective against leukemic ceils in the central nervous system. 2s, 24 Of the 3 methods available for the treatment of leptomeningeal involvement in leukemia---spinal drainage, roentgen therapy, or methotrexate administered intrathecally--the latter was found to be the most effective in the cases herein reported. CASE R E P O R T S

Case 1, L. J. B. (No. 296-368). This white female was diagnosed as having acute lymphatic leukemia at the age of 4~2 years in May, 1958. She was initially treated with steroids and 6-mercaptopurine with prompt hematologic remission. The first neurological complication occurred 22 months after the onset of the illness when she developed a ravenous appetite and marked obesity. The neurological examination, including fundoscopic examination, was negative at that time. Two months later she had headache, blurred vision, and pain in the neck. Again neurological examination was normal. I-Iow 2 ever, when seen one month later because of decreased visual acuity, she had bilateral papilledema and optic atrophy. Bone marrow at this time showed remission. The vision continued to deteriorate and she was completely amblyopic 24 months after the onset of the illness. X-rays of the skull showed marked separation of cranial sutures. Twenty-nine months after the onset of the illness, she developed weakness of the left upper extremity. Physical examination showed bilateral optic atrophy and confirmed the weakness of the left arm. Otherwise, the neurological examination was

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within normal limits. At this time the bone marrow showed hematologic relapse. During the last 9 months of the illness the patient had multiple lumbar punctures performed. The pressure ranged from 205 to 515 mm. of water; cell count was 3 to 2,300 cells per cubic millimeter, predominantly lymphocytes; protein, 45 to 103 my. per cent; glucose, 24 to 63 my. per cent. Over a 6-month period she was given 6 intrathecal injections of methotrexate, 5 my. each. She was also treated with x-ray therapy, 90 roentgens to the calvaria. Although the pleocytosis and increased pressure responded to the intrathecal methotrexate, she remained blind to the time of death. She died 32 months after the onset of the illness. At the time of autopsy, ~ the optic nerves appeared pale and hypoplastic with a focal area of softening at the optic chiasm. Sections of the optic nerve revealed a profuse dense leptomeningeal and perivascular leukemic infiltration. The pituitary gland was unremarkable. There was patchy, focal profuse infiltration of the Ieptomeninges by leukemic cellular elements with rare infiltration within the intracerebral VirchowRobinson spaces. Case 2, M. P. O. (No. 707-272). This white male was 5 8 9 years of age when the diagnosis of acute Iymphatic leukemia was made. During the course of the disease, he was treated with corticosteroids, 6-mercaptopurine, cytoxan, and methotrexate. One year after the onset of the illness he developed vomiting and headaches. There was no nuchal rigidity; however, the disc margins were blurred. A lumbar puncture was done, and the opening pressure was 300 mm. with 517 cells, of which 91 per cent were lymphocytes and 9 per cent neutrophils; glucose was 24 my. per cent; and protein, 26 rag. per cent. Bone marrow aspiration showed relapse of the leukemia. Skull films showed separation of the coronal and lambdoidal sutures. He was given 2 ~Autopsy findings include only those of the central nervous system.

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Steffey

intrathecal injections of methotrexate, 5 rag. on each occasion, 2 days apart. All neurological symptoms subsided promptly. Sixteen months after the onset of the illness the patient again complained of headache and vomiting. Physical examination revealed papilledema. The results of the lumbar puncture were similar to the previous findings except for a normal glucose content. Methotrexate was given intrathecaIly as before. Again the bone marrow showed relapse. Five months elapsed and he again developed symptoms of headache and vomiting. A lumbar puncture again showed an elevated pressure. He was treated with intrathecal injections of methotrexate 5 mg. on 3 consecutive days. The bone marrow showed hematologic relapse. Three months later the bone marrow was in remission, and the patient was asymptomatic. A lumbar puncture was within normal limits. He did not have any central nervous system symptoms in the last 8 months of the illness. He died on June, 1961, 2 ~ years after the onset of the illness. At the time of autopsy, there was thickening and clouding of the cerebral leptomeninges. The ventricular system was normal. Both cerebral and cerebellar sections showed a dense, moderately profuse, omnipresent leukemic cellular infiltration of the leptomeninges. There was abrupt demarcation of the leukemic infiltration at the margin of brain substance; a sparse intracerebral leukemic infiltrate limited to occasional superficial Virchow-Robinson spaces was present. Case 3, D. M. F. (No. 300-925). In September, 1958, this 5-year-old white male was diagnosed as having chronic myelogenous leukemia. During the course of the illness he was treated with roentgen therapy, 6-mercaptopurine, and steroids. Eleven months after the onset he developed a right facial paralysis after an ear infection. He continued to have difficulty with the ear and the facial paralysis throughout the remainder of life. The bone marrow at that time showed hematologic relapse.

February 1962

Eighteen months after the onset of the illness while being treated with 6-mercaptopurine and steroids, the patient complained of headaches. Physical examination revealed the fundi to be within normal limits. However, there was a right facial paraIysis. Shortly after this the patient had an episode characterized by lethargy, nonresponsiveness, and deviation of the eyes to the right. A lumbar puncture was performed which seemed to relieve these symptoms and findings almost immediately. He was treated over the next 5 weeks with 3 intrathecal injections of methotrexate with improvement. He returned 2 months later, 21 months after the onset of the illness, with the complaint of headache and vomiting. A lumbar puncture confirmed central nervous system involvement, and he was treated with 3 intrathecal injections of methotrexate every other day. Four days after the last injection he was asymptomatic. He died 3 months later, 24 months after the onset of the illness. During the last 6 months of this patient's illness he had many lumbar punctures performed. The findings were as follows: pressure 160 to 600 ram. of water; cell count, 64 to 2,400 with protein, 43 to 55 rag. per cent; sugar, 22 to 90 mg. per cent; no bacteria were seen; and India ink stain for torula was negative. Autopsy findings revealed minimal clouding and thickening of the Ieptomeninges. There was no leukemic infiltration of the meninges demonstrated microscopically. Case 4, L. L. S. (No. 243-719). This 3year-old girl was diagnosed as having acute lymphatic leukemia in December, 1954. During the course of the disease she was treated with 6-mercaptopurine, steroids, and azaserine. She did well for 9 months then she began to complain of headaches and vomiting, mostly in the morning. The physical examination was within normal limits except for bilateral papilledema. Peripheral blood count was within normal limits. A lumbar puncture revealed a pressure of 400 ram. with the child relaxed. There were 176 cells present, 10

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per cent of these being lymphocytes and 90 per cent neutrophils. The protein was 20 rag. per cent. Skull films were normal. The symptoms of headache and morning vomiting persisted as did the papilledema. Seven weeks after the onset of headache and vomiting, the liver and spleen were found to be enlarged for the first time. The peripheral smear showed lymphocytosis, immature lymphocytes, and inadequate platelets. The bone marrow was in relapse. A few days later, there were multiple retinal hemorrhages in addition to papilledema. Treatment with cortisone and 6-mercaptopurine brought about a clinical remission. Previous findings of retinal hemorrhages, papilledema, and symptoms of increased intracranial pressure disappeared completely. However, this remission lasted only a few weeks, and on Jan. 12, 1956, she died, 13 months after the onset of the illness. Autopsy findings revealed leukemic involvement of the subarachnoid area of the cerebellar hemispheres. Other portions of the central nervous system were not involved. Case 5, R. C. K. (No. 190-537). This 6year-old boy first become ill in July, 1955, with a fever and anemia. The diagnosis of acute lymphatic leukemia was made in October, 1955. During the illness he was treated with corticosteroids, 6-mercaptopurine, and aminopterin. The first neurological symptoms appeared 18 months after the onset of the leukemia in January, 1957, at which time he complained of headache and vomiting. Fundoscopic examination showed bilateral papilledema. He was treated with prednisone and continued to take aminopterin and 6-mercaptopurine. After 2 months of treatment with this regimen the eye grounds were normal. In September, 1957, the patient again developed headaches, and fundoscopic examination showed bilateral papilledema. A lumbar puncture was done, and this seemed to relieve the symptoms. At this time he was in hematologic remission. Three months later he returned with headache and vomiting. Physical examination

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showed marked papilledema with hemorrhages near the right disc, nuchal rigidity, and fever. A lumbar puncture confirmed the impression of central nervous system involvement. Symptoms improved after the lumbar puncture. He also received roentgen therapy to the skull. He was again seen in April, 1958, 30 months after the onset of the illness, because of headache. Bilateral papilledema was noted. He was found to be in hematologic remission. X-ray therapy to the skull was repeated. In June, 1958, he returned with symptoms of increased intracranial pressure, and he was treated with 1 mg. of methotrexate, intrathecally. Lumbar puncture findings carried out on numerous occasions showed a pressure never less than 600 mm. of water; ceils, 51 to 420 per cubic millimeter; protein, 16 to 53.5 mg. per cent; glucose, 3 to 46 mg. per cent. He died 3 years after the onset of the illness due to massive gastrointestinal hemorrhage. Postmortem findings showed dense infiltration of the arachnoid tissue and subarachnoid space by leukemic cells, without recognizable infiltration of the cortex. Case 6, P. K. K. (No. 307-182). This 5year-old white female was diagnosed as having acute lymphatic leukemia in March of 1959. The last time she was seen at the age of 7 years, she was still living but in hematologic relapse. The leukemia has been treated with 6mercaptopurine, methotrexate, and corticosteroids. The first central nervous system symptoms became manifest slightly over 2 years after the onset of leukemia. Presenting symptoms were headache and vomiting, mostly in the morning. At the time she developed these symptoms she had been taking prednisone and methotrexate. On fundoscopic examination there was bilateral papilledema. The blood count was within normal limits except for a reduction in platelets. A spinal fluid examination was performed. The pressure was not taken because the child was struggling. The fluid

1 88

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Steffey

contained 930 cells, the majority of which were mononuclear cells. Glucose was 31 mg. per cent, and protein, 37 mg. per cent. Culture was negative. She was treated with 5 mg. of methotrexate twice, with a 2-day interval. There was clinical improvement, and the cells in the spinal fluid decreased. She was seen 4 months after the first central nervous system symptoms because of a headache. A lumbar puncture showed elevated pressure (480 ram. water) and the cell count was elevated; protein and sugar were normal. Culture was negative. Methotrexate, 5 mg. was given intrathecally with symptomatic improvement. The bone marrow aspiration confirmed the suspicion of hematologic relapse. The patient has been seen since this time because of acute gastrointestinal hemorrhage, however, she has had no more central nervous system symptoms. COMMENTS

From December, 1954, through June, 1961, at Raymond Blank Memorial Hospital for Children, 37 cases of leukemia were treated. Of these, 6 developed neurological complications of meningeal involvement representing an incidence of 16.2 per cent. There were 3 males and 3 females. Five had acute lymphatic leukemia, and 1, chronic myelogenous leukemia. The usual age at which the neurological symptoms appeared was 6 to 7 years of age. However, in one case symptoms appeared at 3 9 ~ years. The

average duration of antileukemic therapy before the development of neurological symptoms was 1 8 ~ months. The length of survival from the time of the onset of central nervous system symptoms to the time of death ranged from 3 months to 22 months, the average being 12 months (Table I I I ) . All 6 of the children reported had headache and vomiting as initial symptoms of meningeal involvement. All had increased spinal fluid pressure and increased cell counts in the spinal fluid. The sugar level varied but was usually on the low side and the protein content tended to be increased. Case 1 represented a girl who developed hypothalamic obesity and blindness as the first neurological complication of leukemia. Other similar cases have been reported, as Also it is of interest that this girl had weakness of the left arm which resolved spontaneously, and for which no neurologic lesions could be demonstrated at postmortem examination. Whether this girl's rather pro.longed survival could possibly be related to the intrathecal injection of methotrexate and whether earlier intrathecal methotrexate would have salvaged sight are pure speculations. Case 3 developed 3 types of neurological complications. The meningeal involvement which was characterized by the usual manifestations, which were relieved by methotrexate, intrathecally. The facial nerve paresis was either due to infection or leukemic infiltration of the seventh nerve in the area

Table I l L Summary of cases reported

Age

Sex

L. J. B.

4%2

M. P.O. D.M.F.

589 5

F M M

L. T.S. R. C.K. P. K.K.

3 6 5

F M F

Type o[ leukemia

Acute lymphatic Acute lymphatic Chronic myelogenous Acute lymphatic Acute lymphatic Acute lymphatic

Time [rom onset o[ Survival disease until alter onset Survival first CNS o[ CNS involvement symptoms (in months) (in months) (in months)

Bone marrow at time o[ first CNS symptoms

No. o[ intrathecaI methotrexate in)ections

32 28 24

20 12 18

12 16 6

Remission Relapse Relapse

6 7 6

13 36 29 ( Still living)

9 18 24

4 18 Alive

Remission Remission Relapse

0 1 3

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of the middle ear, which could not be determined at autopsy, but in either instance was most likely related to the leukemia. The other complication was that of a strokelike episode with deviation of eyes and anisocoria for which lumbar puncture alone appeared to be beneficial. The first symptoms patient 4 developed were those of nervous system involvement, viz., headache and vomiting. With clinical remission of the leukemia the neurological symptoms abated. Patient 5 was treated prior to the time methotrexate was readily available but seemed to receive satisfactory symptomatic relief from lumbar puncture alone. In the cases presented it seems that the patients received more benefit from 3 injections of 5 mg. of methotrexate, intrathecally given, every other day, than from single injections of the same dose given as symptoms reappeared. The most consistent pathologic finding in these cases was infiltration of the leptomeninges with leukemic cells. In m a n y instances, however, the autopsy findings did not adequately explain the clinical findings. SUMMARY

The subject of central nervous system manifestations of leukemia is presented, and the literature reviewed briefly. Six cases of meningeal involvement complicating the course of leukemia are recorded and discussed. Five of these patients were treated with methotrexate, intrathecally, with relief of clinical manifestations. The intrathecal administration of methotrexate in doses of 5 mg. appeared to be more effective in relieving symptoms and eliminating abnormal spinal fluid changes than did spinal fluid drainage and/or roentgen therapy. Three intrathecal injections of methotrexate on alternate days seemed to be more efficacious and of more lasting benefit than one injection given as symptoms reappeared. The explanation for the increased incidence of leukemic infiltration of the central nervous system would appear to be the pro-

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longation of life by antileukemic drugs. Six of 37 children with leukemia (16.2 per cent) in this series developed this complication. Early recognition and prompt treatment m a y prevent undesirable results of prolonged increased intracranial pressure, including blindness. Whether prophylactic intrathecal injections of methotrexate at monthly intervals would yield better results than treatment when the complication has developed merits further investigation. REFERENCES

1. Burns, A.: Observation of the Surgical Anatomy of the Head and Neck, p. 386, F. Lucas, Jr., E. j. CoMe, and Cushing and Jewett, Baltimore, 1823. 2. Lightwood, R., Barrie, H., and Butler, N.: Observations of One-Hundred Cases of Leukemia in Childhood, British J. Med. 1: 747, 1960. 3. Dameshek, William: Leukemia, Maryland State M. J. 9: 244, 1960. 4. Barker, L. F.: Neutrophilic Myelocytes in the Cerebrospinal Fluid of a Patient Suffering From Myeloid Leukemia and Their Significance for the Diagnosis of Myeloleukemic Infiltration of the Leptomeninges, South. M. J. 14: 437, 1921. 5. Sullivan, M. P.: Intracranlal Complications of Leukemia in Children, Pediatrics 20: 757, 1957. 6. D'Angio, G. H., Evans, A. E., and Mitus, A.: Roentgen Therapy of Certain Complications of Acute Leukemia in Childhood, Am. J. Roentg. 82: 541, 1959. 7. Nordlander, N. B.: Eosinophilic Leukemia. Infiltration of the Gasserian Ganglion, Acta med. scandinav. 139: 146, 1951; 8. Wells, C. E., and Silver, R. T.: The Neurologic Manifestations of the Acute Leukemias: A Clinical Study, Ann. Int. Med. 46: 439, 1957. 9. Kirshbaum, J. D., and Preuss, F. S.: Leukemia. A Clinical and Pathologic Study of One Hundred and Twenty-three Fatal Cases in a Series of 14,400 Necropsies, A. M. A. Arch. Int. Med. 71: 777, 1953. 10. Moore, E. W., Thomas, L. B., Shaw, R. K., Freireich, E. J.: The Central Nervous System in Acute Leukemia, A. M. A. Arch. Int. Med. 105: 451, 1960. 11. Litteral, E. B., and Malamud, N.: Leukemia with Predominant Neurologic Manifestations, Neurology 5; 740, 1955. 12. Schwab, R. S., and Weiss, S.: The Neurological Aspect of Leukemia, Am. J. M. Sc. 189" 766, 1935. 13. Dock, G., and Warthin, A. S.: A New Case of Chloroma With Leukemia, Tr. Am. Physicians 19: 64, 1904.

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14. Bass, M. H.: Leukemia in Children With Special Reference to Lesions in the Nervous System, Am. J. M. Sc. 162: 647, 192l. 15. Howell, A., and Gouch, J.: Acute Lymphatic Leukemia With Facial Diplegia and Double Abducens Palsy, Lancet 1: 723, 1932. 16. Diamond, I. B.: Leukemic Changes in the Brain, Arch. Neurol. & Psychiat. 32: 118, 1934. 17. Viets, H. J., and Hunter, F. T.: Lymphoblastomatous Involvement of the Nervous System, Arch. Neurol. & Psychiat. 29: 1246, 1933. 18. Sansome, G.: Pathomorphosis of Acute Infantile Leukemia Treated With Modern Therapeutic Agents; "Meningoleukemia" and Frolich's Obesity, Ann. paediat. 183: 33, 1954. 19. Whiteside, J. A.: Intrathecal Amethopterin in Neurological Manifestations of Leukemia, A. M. A. Arch. Int. Med. 101: 279, 1958. 20. Tr6mner, E., and Wohlwill, F.: Ueber Erkrankungen des Nervensystems, insbesondere der Hirnnerven, bei Leukgmie, Deutsche Ztschr. f. Nervenh. 100: 233, 1927. 21. Leidler, F., and Russel, W. O.: The Brain in Leukemia; A Clinicopathologic Study of 20 Cases With a Review of the Literature, Arch. Path. 40: 14, 1945. 22. Brandt, S.: Alterations leucemiques de systeme nerveux, Acta psychiat, et neurol. 20: 107, 1945. 23. Elion, G. B,, Bieber, S., and Hitchings, G. It.: The Fate of 6-mercaptopurine in Mice, Ann. New York Acad. Sc. 60: 297, 1954. 24. Hamilton, L., and Elion, G. B.: The Fate of 6-mercaptopurine in Man, Ann. New York Acad. Sc. 60: 304, 1954. 25. Burchenal, J. H., Murphy, M. L., and Tan, C. T. C.: Treatment of Acute Leukemia, Pediatrics 18: 643, 1956. 26. Bassoe, P.: Leukemic Infiltration in the Spinal

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27.

28. 29. 30. 31.

32.

33.

34. 35. 36. 37. 38.

Canal as a Cause of Paraplegia, J. Nerv. & Ment. Dis. 47: 180, 1918. Bernard, J., and Seligemann, M.: A Study of Sixty-one Leukemias Treated with 6-mercaptopurine (and 6-MP plus Azaserine), Ann. New York Acad. Sc. 60: 305, 1954. Blaschy, R.: Polyneuritisghnliches Krankheitsbild bei Leuk~imie, Miinchen, reed. Wchnschr. 76: 2166, 1929. Gritchley, M., and Greenfield, J. G.: Spinal Symptoms in Chloroma and Leukemia, Brain 53: 11, 1930. Firkin, B., and Moore, C. V.: Clinical Manifestations of Leukemia, Am. J. Med. 28: 764, 1960. Freidrich, E. J., Thomas, L. B., Frei, E,: A Distinctive Type of Intracranial Hemorrhage Associated With "Blastic Crisis" in Patients With Leukemia, Cancer 13: 146, 1960. Fried, B. M.: Leukemia and the Central Nervous System With a Review of 30 Cases From the Literature, Path. & Lab. Med. 2: 23, 1926. Gilbert, E. F., and Rice, E. C.: Neurologic Manifestations of Leukemia; Report of Three Cases in Children Simulating Acute Bacterial Meningitis, Pediatrics 19: 801, 1957. Gauld, W. D.: Leukemia Presenting With Neurological Manifestations, Lancet 2: 939, 1948. Hill, E.: Papilledema and Intracranial Complications of Leukemia, Am. J. Ophth. 15: 1127, 1932. Munroe, E. E. H.: Acute Myeloid Leukemia Simulating Meningitis, J. A. M. A. 74: 603, 1920. Murphy, J. P., and Brody, B. S.: Nerve Root Infiltration in Myelogenous Leukemia, J. A. M. A. 115: 1544, 1940. Oulle, C.: Ascending Polyradiculitis in Acute Leukemia, Nord. reed. 49" 645, 1953.