qX/VPQJj*^. NEURO-OPHTHALMIC ONCOLOGY NEURO-OPHTHALMIC TOXICITY OF ANTINEOPLASTIC DRUGS w Rosa A. Tang, M.D., Gabriel Pardo, M.D. University oj Texas B. Brain Tumors: BCNU (Carmustine) CCNU (Lomustine) Vincristine(Oncovin) C. Leukemia AML: ALL: Supported m Part by a grant from Research to Prevent Blindness. Inc. I. INTRODUCTION The treatment of cancer has become more innovative in recent years with the addition of new antineoplastic drugs. Advances in supportive care methods give the cancer patient a prolonged survival increasing the patient's exposure to the toxicity of antineoplastic drugs. Most drugs are not only cytotoxic to tumor cells, but also may cause some degree of reversible and/or irreversible damage to healthy tissues including the visual and neurological system. The neuro-ophthalmic toxicity associated with the most common antineoplastic drugs currently in use will be discussed. In many instances a direct cause and effect relationship cannot be clearly established due to concurrent drug treatment which may have an additive effect on the toxicity to the visual system. Neuro-ophthalmic complications in patients receiving antineoplastic drugs can be potentially serious. These can be secondary to the antineoplastic treatment itself, to prior radiotherapy, to a direct or indirect effect of the malignancy, or merely a coincidental event. The toxicity from chemotherapy may be a direct drug-related toxic effect on the eye and central nervous system, a drug-induced metabolic process, a drug-induced ocular or intracranial hemorrhage or infection, or a psychologic effect of the agent. Serious neuro-ophthalmic toxicity may require discontinuation or dose modification. Indirect toxicity may be reversible if the end organ failure is reversible (i.e. drug-induced hepatic or renal failure) or may be irreversible (i.e. intracranial hemorrhage from thrombocytopenia) 1 . Multi-agent chemotherapeutic regimens may increase neuro-ophthalmic toxicity by additive or synergistic effects. Other factors that can also increase this risk are multi-modal therapy (chemotherapy with radiotherapy or immunotherapy), high-dose therapies, and direct administration of the drug to the nervous system (intrathecal, intracarotid, osmotic opening of the blood-brain barrier, or direct intracranial intratumoral therapy). Some may consider drug toxic effects as an iatrogenic complication, a risk associated with the treatment, that may have critical consequences for the affected organ. n. COMMON ANTINEOPLASTIC DRUGS A. Breast Cancer: Tamoxifen (Nolvadex) Cyclophosphamide (Cytoxan, Neosar) Methotrexate (Mexate) 5 Fluorouracil (5 FU, Efudex, Adrucil) Paclitaxel (Taxol) Doxorubicin (Adriamycin) Idamycin (Idarubicin) Cytosine Arabinoside (Cytarabine, Cytosar-UAra-C) Vincristine (Oncovin) Steroids (Prednisone, Deltasone, Prednisolone) CML: Interferon (Roferon-A, Intron-A) Hydroxyurea CLL: Chlorambucil (Leukeran) Cyclophosphamide (Cytoxan) Vincristine (Oncovin) Steroids Pentostatin (Nipent) Thiradabine Promyelocytic: Retinoids (Retinol) D. Lymphoma (Non-Hodgkin's): Cyclophosphamide (Cytoxan, Neosar) Nitrogen mustard (Mechlorethamine, HN2) Doxorubicin (Adriamycin) Vincristine (Oncovin) Steroids Bleomycin (Blenoxane) Methotrexate (Mexate) Interferon (Roferon-A, Intron-A) E. Ovarian Cancer: Cisplatin (Platinol) Carboplatin (Paraplatin) Cyclophosphamide (Cytoxan, Neosar) Paclitaxel (Taxol) F. Lung Cancer: (Small and non-small cell) Carboplatin (Paraplatin) Etoposide (VePesid, VP16) Paclitaxel (Taxol) Cisplatin (Platinol) Vinblastine (Velban) G. Colorectal: 5-EuorouraciI (5FU, Efudex, Adrucil) Folinic acid (Leucovorin) Levamisole (Ergamisol) H. Malignant Melanoma: Interferon (Roferon-A, Intron-A) Interleukin (Proleukin) Dacarbazine (D TIC-Dome) Cisplatin (Platinol) I. Lymphoma (Hodgkin's): Nitrogen Mustard (Mechlorethamine, HN2) Vincristine (Oncovin) Procarbazine (Matulane) Steroids J. Prostate Cancer: Suramin Vinblastine (Velban) 185
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qX/VPQJj*^.
NEURO-OPHTHALMIC ONCOLOGY NEURO-OPHTHALMIC TOXICITY OF ANTINEOPLASTIC DRUGS
w
Rosa A. Tang, M.D., Gabriel Pardo, M.D. University oj Texas
B. Brain Tumors: BCNU (Carmustine) CCNU (Lomustine) Vincristine(Oncovin)
C. Leukemia AML:
ALL:
Supported m Part by a grant from Research to Prevent Blindness. Inc. I. INTRODUCTION
The treatment of cancer has become more innovative in recent years with the addition of new antineoplastic drugs. Advances in supportive care methods give the cancer patient a prolonged survival increasing the patient's exposure to the toxicity of antineoplastic drugs. Most drugs are not only cytotoxic to tumor cells, but also may cause some degree of reversible and/or irreversible damage to healthy tissues including the visual and neurological system. The neuro-ophthalmic toxicity associated with the most common antineoplastic drugs currently in use will be discussed. In many instances a direct cause and effect relationship cannot be clearly established due to concurrent drug treatment which may have an additive effect on the toxicity to the visual system.
Neuro-ophthalmic complications in patients receiving antineoplastic drugs can be potentially serious. These can be secondary to the antineoplastic treatment itself, to prior radiotherapy, to a direct or indirect effect of the malignancy, or merely a coincidental event. The toxicity from chemotherapy may be a direct drug-related toxic effect on the eye and central nervous system, a drug-induced metabolic process, a drug-induced ocular or intracranial hemorrhage or infection, or a psychologic effect of the agent. Serious neuro-ophthalmic toxicity may require discontinuation or dose modification. Indirect toxicity may be reversible if the end organ failure is reversible (i.e. drug-induced hepatic or renal failure) or may be irreversible (i.e. intracranial hemorrhage from thrombocytopenia)1. Multi-agent chemotherapeutic regimens may increase neuro-ophthalmic toxicity by additive or synergistic effects. Other factors that can also increase this risk are multi-modal therapy (chemotherapy with radiotherapy or immunotherapy), high-dose therapies, and direct administration of the drug to the nervous system (intrathecal, intracarotid, osmotic opening of the blood-brain barrier, or direct intracranial intratumoral therapy). Some may consider drug toxic effects as an iatrogenic complication, a risk associated with the treatment, that may have critical consequences for the affected organ.
m . MECHANISMS OF ACTION AND TOXICITY OF ANTINEOPLASTIC DRUGS
Many of the cytotoxic agents used as antineoplastic drugs act at specific phases of the cell cycle and, therefore, have activity only against cells that are in the process of division. The cancers that are most susceptible to cytotoxic effects are those with a large percentage of cells in the process of division (growth fraction). In the same way, those tissues that proliferate rapidly (ocular epitheliums, bone marrow, hair follicles, and intestinal epitheliums) are susceptible to damage by the antineoplastic drugs. Based on what part of the cell cycle they act these agents are classified as phase specific and phase non-specific (Tables 1,2).
The mechanism of action of the most common antineoplastic agents are listed in tables 3 and 4.
The antineoplastic drugs must enter the cell, either by passive diffusion or carrier-mediated transport to produce their desired cytotoxic effects. Once inside the cell, the drug can react with target molecules to disrupt processes that are necessary for cell viability. The mechanisms of action are: DNA synthesis inhibition, damage of DNA or RNA structure, interference with transcription, disruption of mitosis and inactivation of essential amino acids needed for translation. Some of the drugs must undergo either chemical or enzymatic modification to generate the active cytotoxic form2. IV. ANTINEOPLASTIC DRUGS BY GROUP
AND NEURO-OPHTHALM3C SIDE EFFECTS A. Alkylating Agents (Covalent DNA-binding drugs)
1. Nitrogen Mustard (Mechlorethamine. HN2): The usual dose-limiting toxicity is bone marrow depression, which is severe 1 to 2 weeks after the initial injection2.
When administered by intra-carotid artery infusion, an ipsilateral necrotizing uveitis was reported in 3 of 12 patients studied3. A panuveitis detected 5 days to 2 weeks after injection of 97.7 to 150.4 mg. of HN2 progressed to retinal and choroidal atrophy. In one post-mortem study the uveitis was found to be secondary to a necrotizing thromboangiitis of the choroidal vessels, with no involvement of the main ciliary trunks, vortex veins or retinal vascular system.
2. Cyclophosphamide: It is the most commonly used alkylating agent, having a broad application in cancer chemotherapy and in the treatment of other conditions such as rheumatoid arthritis. Cyclophosphamide's dose-limiting toxicity is bone marrow suppression. A major side effect is hemorrhagic cystitis, occurring in about 10% of patients receiving therapeutic doses who are adequately hydra ted. Water intoxication may occur with high dose therapy due to inappropiate ADH secretion2. Non-specific reversible blurred vision lasting from one hour to two weeks without visible ocular pathology was reported in 17% of patients treated with high-dose intravenous (IV) therapy (750 mg/nr on alternate days for 5 days)4. The blurred vision usually lasts less than one hour and can either disappear abruptly or recover gradually during the next several hours. Patients complaining of blurriness were in their second to ninth day of treatment, and upon examination no ocular abnormalities were seen to explain this symptom. Kende postulates that cyclophosphamide can cause miosis as part of the parasympathomimetic effect of the alkylating agents in general and this can cause a shift in visual acuitv5. Keratoconjunctivitis sicca has been reported in up to 50% of patients treated4*5, lasting up to 2 weeks after cessation of therapy. Blepharoconjunctivitis and cataracts are rarely associated with this drug4. Stevens Johnson syndrome was described in a case in which the drug was given in association with steroids5.
3. Ifosfamide: This agent is administered IV and is used for the treatment of testicular, breast, uterine, cervical, pancreatic, lung and bladder cancers as well as for lymphomas and adult sarcomas6. Its dose-limiting toxicity is bone marrow suppression. Hemorrhagic cystitis has been seen in up to 18% of patients receiving ifosfamide as a single agent, but its concomitant administration with mesna reduces the severity and incidence of this complication. Water retention may be present due to inappropiate ADH secretion. Neurotoxicity has been reported in 30% of patients receiving high-dose ifosfamide therapy. Its spectrum ranges from subclinical EEG changes and mild motor disturbances to seizures and ataxia. Neurotoxicity has been correlated with impairment of both hepatic and renal function2.
There are single case reports of reversible blurred vision, conjunctival hyperemia7 and cranial nerve paresis8. One patient developed a unilateral peripheral facial palsy of acute onset that cleared in 12 hours and had no recurrences with further ifosfamide treatment. Another patient had transient deafness on the fifth day of his only set of treatment.
4. Cisplatin: This is a metal compound that appears to exert its biologic effect by binding directly to DNA. The cis form manifests Afunctional DNA binding activity in its formation of cross-links. This agent is used intravenously currently and was used intraiterialy in many protocols for the
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treatment of brain tumors. Clinical and subclinical hypocalcemia and Hypomagnesemia occur in many patients receiving cisplatin and are related to its effect on the kidney. The major toxic effects of cisplatin are nephrotoxicity, ototoxicity and peripheral neuropathy. These last two effects are dose-limiting and are seen in patients that receive over 500 mg/m2 of cisplatin (after 4 or 5 doses of 120 mg/nr). For ototoxicity the site of injury- is the cochlea and the resulting hearing loss is dose-related and has a reproducible evolution. Hearing impairment is usually bilateral and symmetric and patients may complain of tinnitus and hearing loss in the higher frequencies initially. Children appear to tolerate the ototoxic effect better in that hearing loss occurs at higher doses than adults. However, the younger the child the greater the susceptibility to hearing loss9.
Cisplatin induced peripheral neuropathy is primarily sensory with paresthesias in the distal extremities occuring after a total dose of 500 mg/nr. As the deficit progresses a severe sensory ataxia may occur. Rarelv motor symptoms and an autonomic neuropathy have been reported2'. Biopsy of sural nerves has shown loss of large myelinated fibers, and axonal degeneration. Various other types of CNS toxicity have been described (ie . seizures by Herman, 1980)10 and they appear to be idiosyncratic. Other reports include cerebrovascular occlusions (Doll 19S6)11, myelopathic symptoms (Eeles 1986)'2 and cerebral herniation syndrome which has been related to a pre existent SIADH (Walker 1988)13. Focal encephalopathy with focal or generalized seizures, aphasia and hemiparesis have been described when cisplatin is used at a cummulative dose of 200 mg/m2 A9.
There have been a number of case reports describing the development of cortical blindness after IV cisplatin chemotherapy: 1) The first reported case (Berman and Mann, 1980)10
occurred in a patient with testicular cancer who, after 1 hour course of cisplatin therapy (20mg/m2 daily for 5 days) experienced visual "grayout". Clinically he had no light perception and an optokinetic exam showed no responses. The rest of his neurologic exam was normal except for an EEG which showed focal abnormalities. His visual loss was attributed to an occipital lobe lesion. He was treated with mannitol and dexamethasone with return of his vision within 72 hours. One interesting finding in this patient was that the platinum level in his CSF was equivalent to that of his serum. As mentioned previously, pharmacokinetic studies have shown that cisplatin penetrates poorly into the CSF, possibly suggesting an abnormality in the blood-brain barrier of this patient. 2) Pippitt et al (1981)14 reported a patient with cervical cancer who developed total blindness after her second course of cisplatin (100mg/m2). Ophthalmologic examination was normal. EEG was abnormal and suggested encephalopathy
originating in the occipital lobes. She was diagnosed with cortical blindness and treated with dilantin and dexamethasone. Her vision returned to normal in three weeks. 3) Another case report (Diamond et al, 1982)15 describes the development of an inability to distinguish light and dark in a patient with metastatic fallopian tube cancer after her tenth dose of cisplatin (50mg/m2) and adriamycin. Optokinetic stimulation produced no responses. A VER was performed and showed delayed latency. The rest of the ophthalmologic exam was normal, as was a brain CT scan. The patient eventually had complete return of her visual acuity with retention of a right homonymous hemianopsia. Her vision loss was diagnosed as cortical blindness despite the delayed latency VER, 4) Cohen et al (1983)16 reported the development of left homonymous hemianopsia in a patient with testicular cancer aftert 3 courses of cisplatin treatment with 85 mg/m2. Except for the visual field defect the rest of his eye exam was normal. He was diagnosed with cortical blindness and mild generalizad encephalopathy. Fifteen days after onset the patient had regained his full visual fields. In 1990 Lindeman17 mentioned the possibility of a vascular
event causing the focal encephalopathy based both on the rapid onset and resolution of symptoms and the focal nature of the defect12.In 1993 vanGelder18 postulated that tubular dysfunction caused by cisplatin resulting in renal magnesium wasting and subsequent hypomagnesaemia increases the susceptibility of brain parenchyma to the neurotoxic effects of the drug. When this neurotoxicity leads to epileptic activity in the occipital cerebral cortex, the patient can experience transient blindness either as an epileptic or as a postepileptic (postictal) phenomenon. Both authors found a sudden onset of cortical blindness usually one to two weeks after administration of the drug, that resolved spontaneously by the fifth day of onset of symptoms upon discontinuation of therapy.
Blurred vision or decreased visual acuity have been reported in several patients after intravenous cisplatin therapy (Table 5): 1) Ostrow et al(1978)19 described the development of decreased vision, to the point that fingers could not be distinguished at 6 inches, in a patient after 3 courses of 100mg/m2 of cisplatin IV. Dilated exam showed no evidence of cataract formation, retinal hemorrhage or papilledema. The patient was diagnosed with retrobulbar optic neuritis and the cisplatin was discontinued without any return of visual function. 2) Wiltshaw et al (1979)20 reviewed the use of cisplatin in patients with advanced ovarian cancer and found that after 3 or more courses of the high dose regimen (100mg/m2), they began to observe neurotoxic effects which include blurred
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vision. The drug was immediately stopped with subsequent disappearance of any signs or symptoms of neurotoxicity. 3) Becher et a! (1980)21 described a patient with recurrent bladder cancer who began experiencing bilateral decreased visual acuity after 7 courses of cisplatin (30 mg/d for 5 days). Fundus exam was normal and the suggested diagnosis was retrobulbar neuritis. Visual acuity improved with cessation of therapy. 4) A patient with cisplatin-induced peripheral neuropathy presenting as a myasthenic syndrome was reported by Wright and Droiun (1982)22. The patient also developed visual disturbances manifested as transient episodes of bilateral blurred vision. Ocular exam was normal. The patient experienced lull recovery of vision within 1 month after stopping the drug.
Another component of IV cisplatin-induced ocular toxicity appears to be the development of disc edema, not necessarily accompanied by an alteration in visual function: 1) Ostrow et al (1978, 1980)19-23 described the development of bilateral disc edema in a patient after 3 courses of 60 mg/m2 cisplatin. The patient showed no evidence of central scotomata or decreased visual acuity. The disc edema was alleviated after the cessation of cisplatin and the administration of dexamethasone. A lumbar puncture documented increased CSF pressure of 280 mmH20 with normal CSF chemistry and a CT scan of the head was normal. 2) In the only case reporting postmortem findings of the eyes, Walsh et al (1982)24 described the clinical course of a 3 1/2 year-old child who, after 11 high dose courses of cisplatin (60-120 mg/m2), developed bilateral swelling of the optic disc and venous engorgement by fundus exam. There was no accompanying clinical evidence of increased intracranial pressure or visual changes. Post-mortem examination showed bilateral swelling of the optic nerve heads with almost complete obliteration of the cup, a thickened nerve fiber layer, and slight displacement of the retinal layers from the disc margin. There was no pathologic evidence of increased intracranial pressure or intrinsic brain lesions.
Studies using intracarotid administration of cisplatin for the treatment of brain tumors report that the most serious toxicities encountered were CNS and retinal toxicity. Stewart et al (1982)25 studied the effects of intracarotid cisplatin in 11 patients with intracerebral tumors. Doses ranged from 60 to 100 mg/m2 every 2-8 weeks. One of the patients developed mild blurring of vision in the eye ipsilateral to the infusion site which worsened with subsequent courses of therapy. The patient was diagnosed as having ipsilateral cerebral edema. Another patient developed permanent ipsilateral blindness after the first treatment with cisplatin. It was believed that the patient experienced a cerebral infarct after the therapy as she also
demonstrated aphasia and right hemiparesis. An ERG done on this patient confirmed that her visual impairment was due to retinal damage. A third patient developed bilateral decreased visual acuity, but no further diagnosis was postulated. Postmortem examinations were obtained on 2 patients who had undergone therapv, but there is no report of any retinal findings.
In another study on the intracarotid infusion of cisplatin, Feun et al (1984)26 found that 5 of 35 patients manifested decreased visual acuity occuring ipsilaterally to the treatment side in 3 patients, and bilaterally in the other 2 patients. The authors noted that the retinal toxicity of cisplatin appeared to be dose-related since a higher percentage of patients demonstrated toxic side-effects as the dosage was increased. Dosages at which retinal toxicity was observed ranged from 60 to 100 mg/m2.
In a related study, Tang et al (tables 6, If1 in 1985 reported their findings on the sequentially-measured ERG and VER of patients undergoing treatment with intracarotid cisplatin for brain malignancies. Patient dosages ranged from 60 to 120 mg/m2 every 2-4 weeks. Four weeks after the initial infusion, investigators noted a significant decrease in the b-wave amphtuI of the ERG T d in the plOO amplitude af the VER relative to baseline (pretreatment) values of affected patients. This occured in the eye ipsilateral to the site of injection and correlated with decreased vision in the eye. The effects were irreversible.
Similar findings were reported by Miller (1985)28 in 1 of 11 patients treated with intracarotid cisplatin and 4 of 11 patients receiving a combination of BCNU and cisplatin (Table 8). The local effect of this drug may be reduced by using a supraophthalmic carotid infusion catheter29"32. The retinopathy may result from toxic effects similar to those of other metallic compounds such as copper, iron, mercury and cobalt on the photoreceptors and retinal pigment epithelium28.
In regards to optic nerve toxicity. Tang's study (1985)27
showed that no patients developed bilateral involvement. Maiese (1990)33 reported 5/6 patients that had progressive optic nerve toxicity following infra-ophthalmic intra-arterial cisplatin. The patients received 60 mg/m2 of cisplatin every month for 3 to 10 treatments. Ototoxicity was evident in 2/6 patients. All the patients with optic nerve toxicity experienced bilateral involvement. The incidence or severity of the optic nerve toxicity was not dependant on the cummulative dose of cisplatin. In two of these patients, VER prolongation preceded acuity loss by at least 4 months, and this test was recommended to monitor the patients34. The mechanism of toxic neuronal injury is not well defined and may be secondary to an idiosyncratic effect of cisplatin.
In Kupersmith's series (1988)35 3/5 patients with infraophthalmic injection of cisplatin developed clinical visual loss in the ipsilateral eye. Two patients had
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vaso-occlusive events manifested as retinal infarcts, diffuse retinal ischemia and necrosis , and the third one developed a retrobulbar optic neuropathy. Patients who received supraophthalmic artery injection had no ocular toxicity35. One patient reported by Miller (198S)28 developed an acute
I cavernous sinus syndrome following the second intracarotid infusion of cisplatin, consisting of a partial third and sixth nerve paralysis, including pupillary involvement, as well as dysesthesia and hypesthesia in the distribution of the first and second divisions of the fifth nerve. Shimamura (1990)
j repeated a case of unilateral optic atrophy and homonymous hemianopia from involvement of the optic tract in a patient who had a supraophthalmic injection of cisplatin32.
Optic nerve or retinal toxicity as well as ototoxicity may initially develop on the treated side and progress to bilateral involvement with subsequent treatments34 for reasons not
i well understood. The ill effects of this drug are potentiated when used in conjunction with other antineoplastic drugs28-30,32-36. Risk factors for the development of ocular toxicity may be the same as for peripheral neuropathy: female gender and older age since ocular toxicity is not
i observed in young males4. 1 Two animal studies in the literature report briefly on the
ocular toxicity of cisplatin. In an abstract, Clark et al (1980) reported the light microscopic and electron microscopic
: results of cisplatin toxicity on the peripheral and central nervous system of rats. Sprague-Dawley rats received
I intraperitoneal injections of cisplatin either chronically (0.5 mg each week to a total of 7-10 mg) or acutely (1 mg every
i 1-2 days). Histologic examinations revealed abnormal axons and axonal degeneration in the optic disc, retrolaminar optic nerve, spinal cord, and peripheral nerves. Axons were
j focally enlarged and filled with degenerating organelles and ! disorganized neurofilaments. The myelin sheaths I surrounding the focal areas of damage were thin. The | authors claimed that the doses tested in the rats were I equivalent to human doses. Peyman et al (1984)37 evaluated j ^ toxic ^ non-toxic doses of various antineoplastic drugs, j including cisplatin, after intravitreal injection into albino
rabbits. Histopathologic changes were reported as a general I finding for all the drugs tested, and were not specific to any
one agent. Gross retinal changes were evident 3 days after i intravitreal injection of a drug and were described as whitish j reactions in the retina, surface hemorrhages, and optic I atrophy. At appropriate doses, light microscopy showed
damage only to the photoreceptor outer segments and the pigment epithelium. The dose range tested for cisplatin was 0.1-3.0 mg. The highest non-toxic intravitreal dose of cisplatin as determined by an ERG and retinal histology was found to be 0.1 mg.
Experiments conducted by R. Tang and C. Garcia (1986 { unpublished data) in an attempt to develop an animal model
| i T e - c m ^ f f f i H j 6Y\
for cisplatin induced ocular toxicity used a monkey and rabbits as follows:
The retinas of a diabetic female cynomologus monkey after right internal carotid artery infusion of cisplatin were examined with electron microscopy. Damage ocurred in the eye ipsilateral to the site of injection. All layers of the retina appeared to have suffered diffuse ischemic damage. Both the outer and inner nuclear layers contained cells with clumped chromatin and some had frankly pyknotic nuclei. The plexiform layers demonstrated a "swiss cheese" appearance due to numerous vacuoles and swollen vesicles. Mitochondria in the inner segments of the photoreceptor cells were markedly swollen with disorganized cristae. The photoreceptor cell outer segments showed no remarkable damage.
Pigmented rabbits were injected intravitreallv with cisplatin in doses of 0.02 ug, 0 2 ug, 2.0 ug, and 20 ug. Fundus exams and ERG's were performed on days 2 and 5 post-injection. Two eyes were tested at each dose with the exception of the 0.1 ug and 0.2 ug doses. With the highest dose tested (20 ug), fundus exams on day 2 post-injection showed vascular changes, primarily in the form of vessel irregularity, accompanied by slight paleness of the retinas. After 5 days definite retinal pallor was noted with punctate hemorrhages. No ERG recording was present on day 2 and 5 post-injection in either eye tested at this dose. The next dose tested (2 ug) produced equivocal results. In one animal there was no grossly abnormal findings on fundus exam 2 days post-injection, but the ERG was non-responsive. Five days after injection the retina of the same animal appeared pale and again had no response on the ERG. The eye of another animal which received the same dose of cisplatin showed no retinal changes and no changes in the ERG on either day 2 or day 5 post-injection. With the rest of the dosages tested no changes were noted in the fundus exams or in the ERG's at days 2 and 5 post-injection. Light and electron microscopic studies of all of the rabbit retinas revealed similar findings to that of the monkey studied.
5. Chlorambucil: This agent is commonly used to treat chronic lymphocytic leukemia4. Its dose-limiting toxicity is bone marrow depression2.
Ocular toxicity is rare with keratitis being the most common problem. One isolated case report mentions diplopia, papilledema and retinal hemorrhages in association with eosinophilia in a patient 3 months after discontinuation of the drug38. No other central nervous system abnormalities were detected and signs and symptoms resolved completely without further treatment.
6. Nitrosoureas: BCNU (Carmustine) and CCNU (Lomustine) are used in primary CNS tumors, melanoma, lymphomas, lung, colon and gastric cancer. Their toxicity is delayed causing thrombocytopenia and leukopenia2 as their main toxic effect.
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Intracarotid injection of BCNU, usually given in combination with cisplatin, may be complicated by retinal toxicity. Miller reported 8/10 patients with sight loss due to retinal changes. Four of these patients developed fundus abnormalities 8 to 12 weeks after receiving 600-800 mg of intr arterial BCNU combined with cisplatin in all but one patient28. In the other 4 patients the symptoms and ocular changes started later. Once visual loss began it was progressive and severe in all of Miller's cases.
In our study30 done at MD Anderson Cancer Center, 4/18 patients with intracerebral malignant neoplasms developed ipsilateral visual loss after receiving from 3 to 7 total courses of combined intrarterial BCNU and cisplatin treatment (Table 9). Mild abnormalities in the ERG and VER preceded the visual clinical deterioration by several weeks and were felt to have predictive value in regards to visual loss and fundus abnormalities later. Severe ERG and VER changes correlated with the degree of visual loss and fundus changes. The fundus abnormalities consisted of marked retinal pigment epithelial changes in addition to arteriolar attenuation and sheathing. Fluorescein angiography showed patchy areas of hyper and hypofluorescence as well as focal areas of periarterial and perivenous leakage.
In our series30 one patient had improvement of vision over a three month period when therapy was stopped. In the other 3 patients the vision loss was irreversible or progressive. The doses at which toxicity was noted was BCNU 120 mg/m2 and cisplatin 75 mg/m2.
Many patients in these reported series had received cranial irradiation prior to the chemotherapy, and this factor may have been an added risk to develop toxic complications.
Based on the toxicity data it is recommended to limit the dose of BCNU to 100 mg/m2 and cisplatin to 60 mg/m2 when used intra-arterially. Also using less alcohol to disolve the BCNU or selective supra-ophthalmic catheterization may help obviate the retinal toxicity39.
The mechanism of BCNU retinopathy is presumably one that occurs at the endothelial level of the retinal and choroidal vasculature. This may explain the time delay that occurs between the administration of the drug and the first
^evidence of retinal toxicity (usually weeks)28. In summary, an ipsilateral delayed neuroretinal toxicity
occurs in up to 70% of the patients treated intra-arterially and approximately half of them will progress to no light perception40. Retinal abnormalities include arterial narrowing and RPE changes. The ERG shows rod and cone dysfunction in a high percentage of these patients.
Vaso-occlusive changes manifested as choroidal thrombi, central retinal artery occlusion and retinal hemorrhages with associated visual loss were reported in 65% of patients treated intra-arterially about six weeks after the start of therapy28 35 .
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Only one report has documented progressive loss of vision over a 29-week period after a single intra-arterial dose of 500 mg of BCNU40. This patient had immediate blurry vision after intracarotid injection, developing disc and macular edema followed by enlarged extraocular muscles 6 weeks later. The patient had clear signs of rubeosis 29 weeks after the initial injection40.
Greenberg reported 4/6 patients who developed ipsilateral retinal exudates and hemorrhages 3 weeks after the second or third course of intracarotid infusion. From these, three patients progressed to blindness of the involved eye41. In another paper he reported a new monocular pattern-shift VER abnormality seen with focal retinal damage in a patient with a right parietal malignant melanoma treated with 3 pulse doses of unilateral intra-arterial carotid BCNU to a cummulative dose of 750 mg/m2 4 1 A . A report by Shingleton reveals that in addition to the exudates and hemorrhages, 10 patients developed optic disc edema 2 to 14 weeks after the second or third course of treatment42. Pickrell postulates a toxic vasculitis affecting the posterior ciliary circulation with infarction of the prelaminar portion of the optic nerve as the etiology of unilateral optic nerve swelling seen in a patient 5 weeks after a second intracarotid infusion of BCNU43.
Intraarterial infusion (carotid artery) may cause periorbital edema, orbital pain, and chemosis as acute local secondary effects.
Rare toxic effects include orbital abnormalities with local vasodilation and arteriovenous shunting as well as pain and fibrosis of the extraocular muscles4,28-40-44. Glaucoma secondary to orbital vascular congestion or rubeosis, vitreous opacification, conjunctival hyperemia, corneal edema and/or opacities is seen rarely4'28,45,46. Optic neuritis, atrophy or edema, diplopia, internal ophthalmoplegia, and nystagmus associated with a cerebellar syndrome have been described in isolated reports28,43,46-47. A case of a dilated fixed pupil was presumed to be secondary to damage to the ciliary nerve, with no other third nerve involvement28. These latter complications are mentioned as descriptive case reports without detailed explanation as to their evolution or treatment. ' 7. Busulfan: This agent is used to treat chromc myelogenous leukemia. The dose-limiting effect are bone marrow depression and pulmonary toxicity2.
The most frequent ocular side effect is posterior subcapsular cataract (PSC) formation with a polychromatic sheen presumably due to decreased DNA synthesis in the lens epithelium4'47. PSC is seen months or years after therapy with 2-6 mg/day. Up to 10% of patients develop definite PSC and 30% early PSC although the incidence increases with duration and total dose. Keratoconjunctivitis sicca has been reported rarely4.
8- Procarbazine: It is used in combination drug therapy of patients with advanced Hodgkin's disease. The major
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toxicity is a dose-related, reversible bone marrow depression with leukopenia and thrombocytopenia. It is neurotoxic in 10% to 20% of the patients, and may manifest as altered levels of consciousness (from mild drowsiness to profound stupor), transient mental changes (hallucinations, agitation, manic psychosis), reversible paresthesias, and/or ataxia2.
Ocular side effects are rare and include photophobia with keratitis, inability to focus, retinal hemorrhages, nystagmus diplopia, and disc edema38. These complications are mentioned in isolated case reports without detailed explanation of the pathophysiology or treatment. B. PYRIMIDINE ANTAGONISTS
1. 5 - Fluorouracil: It is used to treat colorectal, breast, head and neck, gastric, and pancreatic cancers. Systemic toxic effects include bone-marrow suppression, mucosal ulceration, and diarrhea. Neurotoxicity is present in 2-7% of the patients as a cerebellar syndrome characterized by incoordination, gait ataxia, slurred speech and nystagmus. The highest incidence of neurotoxicity is seen with treatment schedules of IV doses (bolus) greater than 15 mg/kg one or more times per week. Continous infusion with doses as high as 14 g/24 hrs. is not associated with significant neurotoxicity2.
A coarse nystagmus in all directions of rapid onset but reversible upon stopping or lowering the dosage was described in 4 patients receiving intravenous 5-FU. The nystagmus seems to be secondary to the toxic effect of the drug on cerebellar and vestibular structures. Convergence and divergence msufficiency can be seen previous to the development of the cerebellar syndrome, and they also improve by decreasing the dosage9. The toxic cerebellar syndrome is unrelated to hematologic or gastrointestinal toxicities. The cerebellar toxicity is of acute or subacute onset and virtually always reversible within one week after 5-FU is stopped or the dosage is reduced45. This neurotoxicity represents dose limiting toxicity in some protocols (less than 20 mg/kg avoids it)9. These signs may reappear when treatment is reinstituted. This syndrome must be differentiated from metastatic involvement of the cerebellum and from the subacute carcinomatous cerebellar degeneration syndrome48 (paraneoplasic). An organic brain syndrome of confusion, disorientation, and cognitive deficits is rarely seen2. Three cases have been reported in which a limitation of the action of the medial rectus was observed. One of the patients recovered in 5 weeks and the other two died shortly after treatment was given49. A case of optic neuropathy with disc edema has also been reported without specific details as to its long term evolution50. Conjunctivitis and/or keratitis are the most frequent ocular toxic effects4'51. Approximately 50% of patients develop corneal epithelial defects which resolve in several weeks (usually 2 to 3 weeks) after cessation of therapy. Other complications include blepharitis, punctal-canalicular
stenosis, ankyloblepharon, blepharospasm, lid necrosis, and pigmentation of the eyelids51*53. These side effects may be secondary either to local irritation due to DNA synthesis inhibition of the epithelium of conjunctiva, cornea and tear ducts, or reaction to induced decrease in basal tear secretion. The longstanding conjunctival irritation and excessive tearing can lead to lower lid skin atrophy and tightening, that can be reversible in early stages but with continued usage can cause ectropion. C. SUGAR MODIFIED ANALOGS
1- Cvtosine Arabinoside (Cvtarabine. ara-C): It is used to treat acute myelogenous leukemia and refractory lymphoma". High-<iose protocols are under investigation for treatment of advanced non-Hodgkin's lymphoma and chronic myelocytic leukemia. The main systemic toxicities are leukopenia and thrombocytopenia. High-dose regimens can induce significant neurologic toxicities, including seizures, peripheral neuropathy and a cerebellar syndrome. Severe cerebellar dysfunction seen at doses of 48 g/nr per treatment cycle or higher is the major dose-limiting toxicity2. Rarely neurotoxicity has been observed at low doses. The diagnosis of Ara-C cerebellar syndrome is a clinical one. CSF is usually normal and MRI may reveal diffuse cerebellar atrophy. Neuropathologic studies have shown that Purkinje's cells are the target for Ara-C toxicity. The overall incidence of cerebellar toxicity ranges fron 6% to 50%9 (Table 10). First symptoms, including nystagmus and mild gait ataxia, are evident in 3 to 8 days after the first dose, and precede major cerebellar symptoms by about 24 hours9. Cerebellar syndrome with nystagmus was reported in 8% of the patients studied by Herzig55. High dose Ara-C toxicity is age dependant. Of 418 patients treated with high dose Ara-C no patient less than 50 years-old developed severe symptoms, whereas 19% of patients older than 50 years developed severe symptoms55. Lateral gaze nystagmus to the right was seen in a patient studied by Hwang56. It started 12 hours after treatment and resolved in three days. Optic neuropathy is rare and has been described with intrathecal therapy57.
Superficial punctate keratitis, subepithelial deposits, central punctate opacities, microcysts, mild stromal edema, and striae in Descemet's membrane have all been described as toxic ocular effects 58- 5 9 in 38% to 100% of patienfs . They appear after 5-7 days of high-dose Ara-C along with pain, lacrimation and photophobia. The severity of the ocular symptoms and signs is related to dose and duration of therapy, with high concentration found in tears. Ocular toxicity may be secondary to nonselective inhibition of DNA synthesis, to which the corneal epithelium is particularly susceptible due to its rapid cell replication. Prophylaxis with topical prednisolone used during administration ofcytosine arabinoside prevents keratitis4. Kaufman found that the corneal abnormalities disappear gradually during three weeks
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after cessation of therapy with symptoms resolving after several days57. D. PURINE ANALOGS
Fludarabine, cladribine, and pentostatin are adenosine (Ado) derivatives active against a broad spectrum of lymphoid and hematologic malignancies. They all have similar toxicities including myelosuppression, immunosuppression, and sporadic neurotoxicity60.
With high dose therapy severe toxicity is common with all three drugs. This is dose (intensity) - dependent, often delayed for weeks to months after therapy and generally irreversible. With the standard dose therapy, severe toxicity is rare and presents with similar frequency (15%) with all three drugs, most often occur while on therapy and are generally transient and reversible. Dose is clearly the strongest predictive factor for neurotoxicity although the duration of exposure may be an additional factor. At the current recommended doses the neurotoxicity is minimal. Development of moderate or severe neurotoxicity should prompt discontinuation of the drug. This usually happens when the purine analogs are used at higher than recommended doses. The neurotoxicity manifestations include: Paraparesis, quadriparesis, Guillian-Barre, Brown-Sequard, headaches, dizziness, proximal motor weakness, seizures, tremor, somnolence, blurred vision, cortical blindness, lethargy, cerebellar dysfunction with ataxia, peripheral motor neuropathy, among others60.
1- Fludarabine (FAMP. Fludara): This agent is veiy effective in chronic lymphocytic leukemia. Moderate to severe myelosuppression has been observed with its use2.
Chun described 14 patients who developed severe CNS toxicity. Thirteen of these patients had received high doses of FAMP (greater than 96 mg/m2/day per 5-7 days per course). Only one patient treated with low doses developed similar problems (dose less than 125 mg/m2/course). The CNS toxicity was characterized by visual loss due to optic neuropathy which developed eventually in most cases. This complication had a delayed onset and progressive clinical course and appeared to be dose related. Of 36 patients treated with high doses of FAMP two developed cortical blindness, one experienced photophobia, one patient complained of diplopia transiently prior to visual loss (no details of motility exam given), and one patient had a transient peripheral facial palsy61.
A progressive encephalopathy preceded the fatal outcome of all patients but one and is believed to be related to progressive demyelination of the CNS, found on post-mortem studies of these patients. The precise mechanism responsible for the demyelination after FAMP is unknown50.
2. Cladribine (CdA. Leustatin. Raritah): Of 29 patients with refractory acute leukemia treated with CdA (0.3-0.5 mg/kg per day for 7-14 days) twelve developed paraparesis
or quadriparesis which was delayed, beginning several weeks after completion of CdA treatment. Work up for other etiologies for these findings was negative. Partial reversibility was seen in most patients after several months. There is one case of amaurosis which was transient and seen when CdA was used by one hour bolus infusion at a dose of 12.5-15 mg/nr/day. At the currently used doses of CdA, reports of neurotoxicity are extremely rare and include: confusion, mood changes, dizziness, and headaches. The NCI Group C protocol for CdA in hairy cell leukemia included 932 patients (1992-1993). Neurotoxicity was reported in 182 cases being severe in 10 cases only60.
3. Pentostatin (Nipent): It is a purine analog used for treatment of hairy cell leukemia. Toxicities are varied and somewhat unpredictable. Lymphopenia is often encountered, leading to potentially serious infections. Acute renal failure and neurological toxicities (including seizures and coma) are less common but can be life-threatening2.
Conjunctivitis, eye pain, blepharitis, cataracts, diplopia, exophthalmos, lacrimation, optic neuritis, and retinal detachment have all been seen in patients beign treated with this drug but no clear cause-effect has been established62. E. VINCA ALKALOIDS
1. Vincristine: It is used in the treatment of leukemias (ALL, CLL), lymphomas, primary brain tumors, sarcomas, and breast carcinoma. The principal side effect that limits the use of this agent in cancer treatment is neurotoxicity, which is age and dose related and is manifested by a peripheral, mixed sensory-motor neuropathy. The earliest and most consistent finding has been the loss of deep tendon reflexes, followed by paresthesias in the fingers and toes which may progress, depending on dose and schedule, to profound muscle weakness and sensory impairment. Paresthesias will typically resolve upon discontinuation of the drug , but the loss of the tendon reflexes (mainly the Achilles) may be permanent. Autonomic neuropathy often occurs early in the course of vincristine administration, resulting in abdominal pain, constipation, paralytic ileus, urinary retention, and orthostatic hypotension2.
Cranial nerve palsies including oculomotor, abducens or facial are seen in up to 50% of patients. Bilateral ptosis was seen by Albert in 14/20 patients, recti and oblique paresis in 13/20, lagophthalmos with seventh nerve palsy in 6/20 (4 unilateral and 2 bilateral) and corneal hypesthesia in 2/20 patients63. The incidence is dose-related. Patients who developed cranial nerve palsies received a mean total dose of 17.7 mg of vincristine (2.6 to 136 mg) over an average of 10 months (range 2-44 weeks). Cranial nerve paresis resolved in about 90% of patients in 2-24 weeks (mean 11 weeks) after cessation of therapy 4-63. Patients with hepatic dysfunction have a higher incidence of cranial nerve palsies secondary to impaired vincristine deactivation4.
Optic neuropathy has been described and it can either resolve or progress to optic atrophy64,65, but it is a diagnosis of exclusion since it can be produced by the underlying disease or as a radiation effect. Post-mortem studies have shown demyelination of the optic nerve posterior to the lamina cribosa, as well as a decrease in the number of ganglion cells and nerve fiber layer. Norton found unilateral optic neuropathy in 2 patients. Both of them complained of orbital pain six days after the administration of the drug. One of them developed a central scotoma, color vision impairment and relative afferent pupillary defect. The other patient had a paracentral scotoma and prepapillary vitreous haze with a pale disc 15 weeks after injection. The abnormalities improved 2 months after the drug was discontinued64. Bilateral optic atrophy was seen by Shurin in a patient who developed decreased visual acuity, diplopia, constricted visual fields and central scotomas in both eyes. Visual acuities were 20/80 OD and 20/400 OS. Eight months later there was pallor of the optic nerves with visual acuity of20/50 OU55 Optic neuropathy can resolve partially or completely off therapy, with residual disc pallor4.
Induced night blindness, reported in one case, is identical to recessively inherited stationary night blindness. This finding is thought to occur in patients with an altered blood-retinal barrier secondary to the underlying disease and/or concurrent radiation therapy. In the case described the dark adaptation curve was monophasic, lacking a scotopic branch; rhodopsin kinetics were normal; spectral threshold data revealed residual rod-mediated vision; and the ERG b-wave was grossly depressed with a normal a-wave. The mechanism appeared to be interference with synaptic transmission between photoreceptors and their second order neurons by disruption of neuronal microtubules. Photoreceptors were otherwise functionally normal. Although well documented, this isolated phenomenon needs further case reports for substantiation4.
Few cases of transient cortical blindness in children receiving intravenous vincristine without preceding radiation therapy have occurred. Byrd reported this complication in a patient 7 days after drug administration. Recovery was full after 72 hours66. The average recovery time for most cases reported has been 1 to 14 days4.
2. Vinblastine; It is used in the treatment of Hodgkin's lymphoma, where it has been used in place of vincristine, providing similar antitumor activity with less neurotoxicity. Vinblastine is also used in the treatment of non-Hodgkin's lymphoma, prostate, breast,testicular and ovarian cancer. The major toxicity caused by this drug is myelosupression. The neurotoxic symptoms are similar to those of vincristine but they are less common and less severe2.
Wilson studied the use of vinblastine by continuous arterial infusion in 26 patients. They developed erythema of the forehead in the cutaneous area supplied by the
ophthalmic artery, with no vesiculation and that rapidly faded leaving an inconspicuous brownish discoloration of the skin. Transient ptosis and paresis of one or more of the extraocular muscles was common, and in only one case was this permanent. Pain in the eye was likewise frequent but this was generally mild and of brief duration61.
3. VePesid_(VP 16, Etoposide): This agent is a topoisomerase inhibitor used in testicular cancer and small cell lung carcinoma. The major toxicity is myelosupression, primarily leukopenia with some thrombocytopenia2. There are isolated reports of optic neuritis and transient cortical blindness62. F. FOLIC ACID ANTAGONISTS
1- Methotrexate: It is used clinically at low doses (lymphoma, ALL), high doses (30 to 250 mg/kg in brain tumor and osteogenic sarcoma), or intrathecally (meningeal metastases)68,69. It is the drag of choice for gestational choriocarcinoma. It can also be used for uveal carcinoma and as an immunosuppressor in conditions such as chronic uveitis, psoriasis and rheumatoid arthritis. Leucovorin has been used as rescue to replace depleted folate pools in normal cells so that DNA synthesis may resume and hence decrease toxicity4. Intrathecal and high-dose administration of methotrexate may be accompanied by neurotoxicity. Acute manifestations include headache, nausea, disorientation, and symptoms of increased intracranial pressure. Subacute toxicity may be seen within a few weeks as motor deficits. Long-term delayed toxicity can arise in the form of encephalopathy (Table 11). Methotrexate neurotoxicity may be mediated by depletion of cerebral reduced folates; inhibition of cerebral protein or glucose metabolism; injury to cerebral vascular endothelium resulting in increased blood-brain barrier permeability; and/or inhibition of catecholamine neurotransmitter synthesis. Most of the drug is excreted unchanged by the kidney and thus an impaired renal function increases the risk of toxic reactions2.
Ocular toxicity with high dose therapy includes somewhat-immediate periorbital edema, photophobia, ocular pain and burning associated to keratitis, seborrheic blepharitis,̂ conjunctivitis, and decreased reflex tear production which' resolve rapidly and spontaneously when drag is discontinued and are not consider dose-limiting toxic effects4,70"72. This is seen in about 25% of cases, 2-7 days after initiation of therapy, resolves within 1 week after cessation of therapy and reccurs with reinstitution of therapy4. When given in association with mannitol and intravenous cyclophosphamide it has been reported to produce macular edema followed by permanent pigmentary changes73. Both thejnagwloLasd methotrexate delivered via the carotid artery have direct
"" access to the ipsTIateral choroidal and retinal circulations. TEe average interval from the time of the tirittreatment to the time of examination of 9 patients that underwent six or more treatments was thirteen months. All had significant
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retinal pigment epithelium changes that were exclusively localized to the posterior pole, in the fovea! and parafoveal regions. No patient had severe visual loss and most visual symptoms were mild with scotomas in two patients. EOG and ERG performed in one patient were normal Fluorescein angiography in one patient showed progressive hyperfluoresence emanating from the level of the retinal pigment epithelium (RPE). No leakage from the retinal vasculature was noted. These RPE abnormalities probably represent direct toxicity of the methotrexate, potentiated by the blood-retinal barrier disruption. The ocular changes seen in these patients were of minimal functional significance, even after as many as 13 treatment sessions and is considered an acceptable toxic effect of this form of therapy73.
With intrathecal administration Boogerd reported one case of axonal degeneration and demyelination of optic nerves and chiasm, along with similar abnormalities in the brainstem and spinal eordJeading_to death. The patient complained of blurry vision 3 weeks after treatment. Examination at this point revealed normal fundus, pupillary reactions and motilhy. By the fifth week the patient Z blind in both eyes and mild pallor of the optic nerves was seen shortly before death71. A careful differentiation with optic neuropathy as a manifestation of meningeal carcinomatosis, radiation induced neuropathy or paraneoplastic syndrome is necessary. G. ANTI ESTROGENS rtpwh> tjgdLfitfS
1. Tamoxifen: This nonsteroidal estrogen antagonist competitively binds to cytoplasmic estrogen receptors arresting the cell in G1 phase. It is active as an adjuvant hormonal therapy in the treatment of breast carcinoma.
Keratopathy (central, whorl-like, subepithelial opacities), optic neuritis and cystoid macular edema, have been described in isolated reports. Several authors have found retinal white refractile opacities superficial to the blood vessels in the paramacular and foveal areas74"89 (Table 12). These deposits have not been substantially associated with visual loss as we demonstrated in our recent study90 where 3/274 patients had retinal deposits with normal vision. No retinopathy was found with a total dose less than 23.7 gms. ' Most of the toxicity of tamoxifen seems to be related to the antiestrogenic properties of the drug. Given the chemical composition of tamoxifen and its chemical structure similarity to other toxic agents with cationic amphophilic properties such as chloroquine. amiodarone and
jjAmg^hpid complex in the lysosomes of the cornea and retina, most likely at the level of the retinal pigment epithelium. This chemical similarity lets us also speculate "**
"That its toxicity may be dose related rather than idiosyncratic90. In one case reported of post-mortem exam the macular lesions measured 3-10u and the paramacular
lesions 30-35u in diameter. These woe confined to the nerve fiber and inner plexiform layer with positive staining for glycosaminoglycans76.
2. Nafoxidine: Is an antiestrogenic agent rarely used in the treatment of breast cancer. Few patients taking this medication for over three years developed bilateral cataracts4, but a strong definite association has not been documented. H. CORTICOSTEROIDS
Systemic corticosteroids are widely used by oncologists either alone or in combination with other antineoplastic agents. Corticosteroids are administered to cancer patients for three basic purposes: 1) in high-dosage for a tumor cell killing effect; 2) in moderate dosage as adjunctive therapy for such purposes as reducing edema, treating hypercalcemia, managing thrombocytopenia, and symptomatic palliation of patients with severe hematopoietic depression; and 3) in low dosage as a physiologic replacement2. Corticosteroids have a direct lymphocytolytic effect on leukemias and lymphomas cells and beneficial anti-inflammatory effects in primaiy and metastatic brain tumors thereby reducing tumor swelling91-92.
The most common ocular side effect is the development of bilateral posterior subcapsular cataracts with administration which lasts more than one year with a daily dose of more than 10 mg of prednisone or its equivalent93,94. Other complications include decreased visual acuity, acute myopia, subconjunctival and retinal hemorrhages, myopathic extraocular muscle palsy, exophthalmos, ptosis, scleral discoloration and thinning, increased intraocular pressure and glaucoma, opportunistic infections (mainly Candida endophthalmitis, CMV retinitis, and toxoplasmosis), and pseudotumor cerebri4-93'95. I. ANTI MICROBIALS (NON-COVALENT
DNA BINDING) 1. Doxorubicin (Adriamvcin): It has a very broad range
of clinical usefulness, being active against carcinomas of the breast, bladder, endometrium, lung, ovaries, stomach, thyroid, sarcomas, and lymphoid and myelogenous tumors. Its use is limited by the development of myelosupression which is dose-related and occurs in 60% to 80% of patients. Cardiotoxicity can manifest as acute electrocardiographic changes and a delayed progressive cardiomyopathy2.
Ocular side effects include excessive lacrimation at the time of IV infusion, with blepharospasm and periorbital edema seen with a severe keratoconjunctivitis in about 25% of patients38-96. This is a transient problem responsive to symptomatic therapy, although it is usually only present while the patient is being infused intravenously.
2. Suramin: This agent is used in the treatment of metastatic prostate cancer, acute leukemias and adrenocortical tumors2.
A toxic keratopathy has been found in 16.6% of the patients, who complain of foreign body sensation and are found to have corneal epithelial deposits which resolve in a
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fewweeks upon discontinuation of the dmg. Some of them have bluny vision secondary to hyperopic shift of one diopter in their refractive error97, J. IMMUNO THERAPY ^
1. Interferon: There are three types available: alpha, beta and gamma. It is used in the treatment of melanoma, refill celTcaremoma, mulSpIe^Boma, Kaposi's sarcomaTcHronic" iroiicienc^ mdas" an anti-angiogenic drug to treat choroidal neovascularization.
Tftlgirdoses, mterteron is neurotoxic and the ahnofmalities seen in the EEG resemble those in diffuse encephalitis98. A persistent neurotoxicity has beeiTidentified long affer 'the treatment with interferon-alpha has concluded. The patients may present with copitive symptoms (confusion, impaired memory), behavioral changesOethargy, hypersomnia), and affective disorders. The pattern of deficits has been consistent with frontal-subcortical dysfunction". In six patients receiving high-dose interferon for ALS, 3 developed mild disc edema which was reversible with cessation of therapy4.
One case of oculomotor nerve paralysis, two cases of eyelashes hypertrichosis, one of acute corneal allograft rejection and one case of papilledema have been reported100. These are descriptive cases without a detailed explanation as of their mechanism or evolution. In 1993 we reported501 10 patients treated with alfa interferon (subcutaneous, intravenous or intramuscular) for various systemic disorders who developed a vaso-occlusive retinopathy characterized by cotton-wool spots, retinal capillary non-perfusion, retinal hemorrhages, retinal edema, vascular occlusions, microvascular abnormalities, and vascular leakage. In most patients (9/10) the retinal changes were reversible without permanent visual loss98,100"104. In 1994 a group from Japan reported 62 cases of chronic hepatitis patients treated with interferon of 3 different types. Seventy percent of their patients showed retinopathy after 6 months of therapy and these did not correlate with the type of interferon used. They found that pre-existing diabetes is a risk factor, as 92% of diabetic patients (12 out of 13) developed interferon induced retinal changes. These cases also improved upon discontinuation of the drug. This group entertains an autoimmune pathogenetic mechanism with immunologic activation of the complement system not dependent on anti-interferon antibodies as the most likely pathogenetic mechanism of this vaso-occlusive retinopathy105.
2. Interleukin 2: IL-2 is a biological response modifier. Possible antitumor mechanisms are activation of natural killer (NK) and lymphokine-activated killer (LAK) cells, proliferation of activated T cells and induction of secondary cytokines (T cells, monocytes, macrophages). Dose related side effects include chills, fever, anorexia, vomiting, rash and myalgias resembling a flu-like syndrome. These develop a
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treatment. Hepatotoxieity with intrahepatic cholestasis is a limiting factor as well as hypothyroidism presumably on an autoimmune basis. Cardiac arrhythmias, pulmonary interstitial edema ("vascular leak syndrome") and systemic hypotension have also been noted106.
Dose dependent neuropsyehiatrie effects include disorientation, palinopsia, auditory and visual hallucinations106,107 , behavioral changes and cognitive impairment. These tend to occur at the end of the course of treatment and reverse with cessation of therapy. Stupor and coma have been reported in association with brain metastasis after IL-2 administration presumably on the basis of worsening of pre-existing cerebral edema107. Some authors believe that alterations in the permeability of the blood-brain barrier by the IL-2 may explain the CNS toxicity. Some other possible mechanisms are arrhythmias and hypotension.
Neuro-ophthalmic toxic effects include scintillating scotomas, transient homonymous defects, amaurosis fiigax, and transient vertical diplopia similar to the transient neurologic deficits found in migraine106"108. These complications stop upon discontinuation of the drug.
3. Levamisole (EreamisoH: This immunomodulator is used in conjunction with 5 -FU to treat colon cancer stage Duke C. Its toxic effect is manifested as a flu-like syndrome. Of 463 patients enrolled in clinical trials, 10 patients developed central nervous system symptoms such as dizziness, ataxia, depression, confusion, memory loss, weakness and headache. Cases of encephalopathy-like syndrome associated with demyelination as well as peripheral neuropathy have been reported . Onset can be acute or subacute and it improves upon discontinuation of the drug62.
Ocular problems include blurred vision, photophobia, lacrimal duct stenosis and conjunctivitis in isolated reports62. K. RETINOIDS
Since the development of cancer is fundamentally a process of loss of cellular differentiation, the chemoprevention of cancer with retinoids represents a physiological rather than cytotoxic approach to arresting or reversing the process of carcinogenesis. Retinoids can suppress tumor promotion and modify some properties of fully transformed malignant cells, restoring anchorage-dependent growth, increasing cellular adhesiveness, and inducing multiple phenotypic changes. The exact mechanism of action of retinoids is still unclear, but it has been finally recognized that retinol and its metabolite, retinoic acid, exert their primary molecular action by activating and simultaneously repressing specific genes109.
1 • Retinol, Retinoic acid: Patients with acute differentiation-induced
few hours after administration in the fifth to eleventh day o
, l/K. - y t ^ c S t & d o e s i .
promyelocyte leukemia achieve complete remissions after treatment with all-trans-retinoic acid (tRA)110.
We have seen two patients that developed papilledema atotRAtreatment for acute promyelocyte leukemia which
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were felt to have leptomeningeal disease and leukemic infiltration of the optic nerve respectively. Both patients had headaches, severe optic nerve swelling with normal vision and minimal visual field deficits. No other chemotherapy or radiation treatment was given to these patients. Neuroimaging as well as CSF studies were consistent with a diagnosis of pseudotumor cerebri, which resolved within 3 weeks and 6 weeks upon discontinuation of the tRA administration and institution of alternate chemotherapy (Tang, 1993).
Patients with a history of succesfully treated head and neck cancers have a reduced incidence of second malignancies when treated prophylactically with cis-retinoic acid (cRA). An ongoing study at MD Anderson Cancer Center (Tang, 1994) using 9-cis retinoic acid for advanced malignancies has not shown any evidence of neur^phthalmic toxicity in a 12 month follow up. A phase H trial ofcRA and interferon-A in squamous cell carcinoma of the skin reported overall and complete response rates of 73% and 27%, respectively. Similar results with this combination have been observed in cervical carcinoma109. The side effects of retinoids are those of hypervitaminosis A, and include symptoms related to increased intracranial pressure caused by increased production of cerebrospinal fluid (pseudotumor cerebri)110. Some patients may have neuropsychiatry manifestations such as severe depression and psychosis109.
Other ocular abnormalities include conjunctivitis and corneal opacities109,11
2- Fenretidine (4-HPR): There is limited clinical experience with this drug, but it has been well tolerated in
women taking 200 mg. daily for one year as adjuvant therapy for breast cancer110.
Reversible xerophthalmia and nyctalopia have been reported at higher doses and may be related to lower plasma retinol levels in patients receiving fenretidine 1 1 0 Fifteen patients on fenretidine for cervical or bronchial dysplasia followed by us for 14 months with clinical and electrophysiologic studies have not experienced any neuro-ophthalmic problems (Tang, 1994). V. CONCLUSIONS
Neuro-ophthalmic toxicity is a real entity and can potentially limit the dosage of antineoplastic drugs. For most drugs high dose or combination therapy is more likely to produce neuro-ophthalmic complications than standard oral or intravenous therapy. Any part of the eye or adnexa can be affected. Differentiating the visual complications of therapy from other ocular complications of the cancer, intercurrent radiotherapy and opportunistic infections can be challenging. As cancer patients are treated more aggressively, receiving more antineoplastic drug in dose and type,living longer, and as new agents are developed for use in new protocols, neuro-ophthalmic complications of antineoplastic drugs will increase and become more complex to elucidate. The recognition and treatment of antineoplastic drugs induced neuro-ophthalmic toxicity may well be more frequent and present as an important clinical challenge to oncologists, neurologists and ophthalmologists alike.
Tables 13 and 14 summarize the most frequent neurologic, visual, and neuro-ophthalmic toxic manifestations of common antineoplastic drugs.
C E L L C Y C L E A N D A N T I N E O P L A S T I C D R U G S
S -DNA synthesis G2 -Premitotic interval
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' 1 ABLE 1 PHASE SPECIFIC AGENTS
G, - phase: Production of enzymes needed for DNA synthesis Asparaginase Steroids Tamoxifen
Bilateral optic disc swelling with venous engorgement. Post mortem: Both heads swollen with almost complete obliteration of cup Thickening of NFL and crowding of the peripapillary retina with slight displacement of retinal layers away from the edge of the optic disc. Dx: Not stated.
Inability to fix. Transient blurred VA OH worsening throughout the day with an episode of diplopia (new glasses improved vision somewhat). Note: pt also had peripheral neuropathy Dx: Not stated; Myasthenia ??
Decreased vision in left VFs QU. initially followed by poor depth perception. Fundus & cranial nerves were normal. VFs showed a dense left homonymous hemianopsia (note: pt had mild encephalopathy) Dx: Cortical blindness
60 mg m' day 1 and 8 even- 3 weeks
100 mg'm1 month
3 weeks after 3rd course
2 weeks after 3rd course
30 nig day x 5 every 4 weeks After 7 courses; intensified afler 8
20 mgmvVday x 5
100 mgW'month
85 mg every 3 weeks
After initial cycle
13 days after 2nd course
Several hours after 10th course
50 mg'm2 2 weeks after 1st course
Dexamethasone during 4th course / Adriamvcin resolved Note: 6 months later given eddp again with no recurrence Zinc { for low serum levels) / No visual improvement reported
Improvement 6 months after eddp cessation
Dexamelttasone and Mannitol / Recovery in 72 hours
Phenytoin and dexamethasone (also heparin for suspected infarcts) / Regained vision within 10 hours
Partial return of vision over next several weeks. Persistent right homonymous hemianopsia but complete return of VA after 8 mo.
120 mg' m1 for 5 courses; then 10 months after starting eddp 60 mg m2 for 6 more courses
Vinblastine Bleomycin
Adriamycin Droperidol
Adriamycin given with last 6 courses
Complete recovery in 1 month Cyclophosphamide
85 mg'm1 by continuous 7 days after completion of 3rd IV Hydration only / full VFs 15 days Vinblastine infusion over 24 hours course after onset of VA problems Bleomycin approximately every month
H KD KD
TABLE 6 RESPONSE DATA IN 35 PATIENTS*
INTRACAROTID CISPLATIN IN BRAIN TUMORS (After Tang et al, 1985)
TUMOR TYPE RESPONSE
~ Patients Improved Stable Failed Not examined Glioblastoma Astrocytoma
Grade II-III diosarcoma Meningosarcoma Melanoma Oat Cell of Lung Adenocarcinoma of Lung Extragonadal Germ Cell Trophoblastic Tumor Undifferentiated Carcinoma
Unknown Primary
TOTAL 35 13 10
*M.D. Anderson Cancer Center
TABLE 7 TOXICITY IN 35 PATIENTS*
INTRACAROTID CISPLATIN IN BRAIN TUMORS (After Tang et al, 1985)
DOSE DPP (mvm1)
Total no. of courses Toxicity (no. of courses)
Nausea,vomiting Renal Myelo suppression Central Nervous System
Seizures Motor weakness Agitation Encephalopathy Coma
Orbital Pain Retinal (decreased vision)
Auditory Hypomagnesemia
60 75 90 100 120
83 18 1
8 7 1 2 1 2
3 1 3 2 1 1 1 1 1 2 3 1 1 2 4
*M.D. Anderson Cancer Center
TABLE 8 VISUAL OUTCOME FOLLOWING BCNU+CISPLATIN
(After Miller et al, 1985)
Total Dose (mg/m1) Patient # BCNU Cisplatin Visual Acuity Time (months)
Usually dose limiting Rarely dose limiting Common, with i.t. therapy (commercial preservative implicated) 15% 15%
15% 2 per 1,500 per year
Dose related or Idiosvnc (ON)
Accidcntal overdose
Usual doses
Dose related
Dose related
Increases with large doses
Related to high doses (> 2 mg) and cumulative doses Dose related
Large i.t doses or prolonged therapy
Dose related Dose rclalod
Dose related
Delayed / Usually irreversible
Immediate onset / rapid recovery Delayed (days - weeks) 2 days / up to 2 \\ ks Delayed (wks) / progressive Immediate to 1 wk / reverses in 1-6 wks 3-8 days/ up to 2 wks recov er, 1-2 wk / 1-3 mo
XIL RETINOIDS 1. Rctinol/Rfitinoic acid Promyelocitic
leukemia Pseudotumor cercbri
2. Fenretinide (4-HPR) Breast CA Cervical dyspl.
Xerophthalmia Nyctalopia
206
THERAPEUTIC REVIEW, JOELMINDEL, EDITOR
Reporting Adverse Drug Reactions: Characteristics and Procedures of Three Organizations JOEL MINDEL, MD, PHD
Department of Ophthalmology, ML Sinai School of Medicine, New York, New York
Abstract. Three organizations in the U.SA. ask health care providers to report adverse effects of drugs in their patients: The Food and Drug Administration; United States Pharmacopeia; and the National Registry of Drug Induced Ocular Side Effects and Drug Interactions, In a comprehensive Table, the characteristics and procedures of these three organizations are summarized, <Surv Ophthalmol 38:455-455, 1994)
Key words, adverse effects of drugs * Food and Drug Administration • United States Pharmacopeia * National Registry of Drug Induced Ocular Side Effects and Drug Interactions
In an effort to increase the reporting of ad-verse drug reactions, the Food and Drug Admin-istration has simplified its reporting forms (one replaces five) and has given its program a new name, MED Watch. The FDA has asked that the medical journals promote MEDWateh and re-mind their readers of MEDWateh's goal, to en-sure the safety of medications and medical de-vices. Survey of Ophthalmology is taking this opportunity to review the differences between, and similarities of, the three major organizations in the United States interested in receiving notifi-cation of ophthalmic therapeutic mishaps: Food
and Drug Administration; United States Phar-macopeia; National Registry of Drug Induced Ocular Side Effects and Drug Interactions.
Reporting of adverse drug reactions by health care professionals is voluntary. A reporting phy-sician may wish to send copies of the completed FDA form to all three agencies. The FDA empha-sis is on serious adverse reactions; the National Registry is interested in all adverse reactions; and the US Pharmacopeia v^nts reports on po-tential as well as real adverse reactions (see "In-formation Desired" in Table).
2
ereserves
Text Box
THERAPEUTIC REVIEW. JOEL MINDEU EDITOR
Reporting Adverse Drug Reactions: Characteristics and Procedures of Three Organizations JOEL MINDEL, MD, PHD
Department of Ophthalmology, ML Sinai School of Medicine, New York, New York
Abstract. Three organizations in the U.SA ask health care providers to report adverse effects of drugs in their patients: The Food and Drug Administration; United States Pharmacopeia; and the National Registry of Drug Induced Ocular Side Effects and Drug Interactions. In a comprehensive Table, the characteristics and procedures of these three organizations are summarized. (Surv Ophthalmol 58:455-455, 1994)
Key words, adverse effects of drugs * Food and Drug Administration • United States Pharmacopeia • National Registry of Drug Induced Ocular Side Effects and Drug Interactions
In an effort to increase the reporting of ad-verse drug reactions, the Food and Drug Admin-istration has simplified its reporting forms (one replaces five) and has given its program a new name, MEDWatch. The FDA has asked that the medical journals promote MEDWatch and re-mind their readers of MEDWatch's goal, to en-sure the safety of medications and medical de-vices. Survey of Ophthalmology is taking this opportunity to review the differences between, and similarities of, the three major organizations in the United States interested in receiving notifi-cation of ophthalmic therapeutic mishaps: Food
and Drug Administration; United States Phar-macopeia; National Registry of Drug Induced Ocular Side Effects and Drug Interactions.
Reporting of adverse drug reactions by health care professionals is voluntary. A reporting phy-sician may wish to send copies of the completed FDA form to all three agencies. The FDA empha-sis is on serious adverse reactions; the National Registry is interested in all adverse reactions; and the US Pharmacopeia v^nts reports on po-tential as well as real adverse reactions (see "In-formation Desired" in Table).
2 0 7
REPORTING ADVERSE DRUG REACTIONS
TABLE 1 Summary of Characteristics and Procedures of Organizations Seeking Reports of Advene Drug Reactions
Organization Program Name
Food and Drug Administration1
MED Watch US Pharmacopeia3
Practitioners" Reporting Network (USP PRN)
National Registry''
Information desired
Who reports?
Enforcement power
Reporting method
Confidentiality
Serious adverse reactions (defined as death, life threatening, hospitalization, disability, congenital anomaly or re-, quiring medical or surgical interven-tion to prevent permanent impair-ment) from drugs, biologteals and devices.
All product problems from drugs, biolo-gical: and devices.
Voluntary from health care profession-als.
Mandatory from manufacturers and dis-tributors (within 15 days if product on market less than 3 years, otherwise an-nually).
Yes
Written form only (mail or fax)
Patient confidentiality— Yes Health care professional —Yes May tell manufacturer (for follow-up
purposes) unless requested not i« do
All actual and potential adverse reactions from drugs, radiopharmaceuticals, biologicals and devices.
All product problems from drugs, biolo-gicals and devices.
Voluntary from health care profession-als.
No
Medication Error Form or Dntg Product Problem Form or fax or telephone 800-4-USPPRN (800-487-7776). Represen-tative 9:00 AM-4:30 PM, M-F.
Answering machine all other times.
Patient confidentiality —Yes Health carc professional—Yes
All Mctual reactions from drugs and bio-logical* (but not devices).
Reactions arc limited to those affecting the visual system or produced by treat-ing the visual system.
Voluntary from health care profession-als.
No Modified FDA report form or telephone
503-494-5686. Representative 8:30 AM-5:00 PM M-F.
Answering machine all other times.
Patient confidentiality — Yes Health carc professional —Yes
Interaction
Financial support
Provides to USP PRN only product de-fect information, on a weekly basis.
Provides information to National Regis-try annually.
Federal funds.
All report information forwarded daily to FDA.
US Pharmacopeia Medical Device and Laboratory Product Problem Report-ing Program under contract to FDA.
US Pharmacopeia funds. Drug manufacturers' subscriptions. FDA funds.
Does not routinelv provide information to FDA or l:SPC.
American Academy of Ophthalmology. Ophthalmology Department of the
Oregon Health Sciences University.
Data dissemination to health care providers
Feedback to health care providers submitting re-ports
Data dissemination to man-ufacturers
Medical Bulletin sent to one million health care providers, including all physicians, four times a year.
Thank you letter with another blank form enclosed.
Follow-up information may be requested if a cluster of reports.
Notified approximately every two weeks of re|>oiis on their products; more fre-quently if there is a cluster of reports.
Drug Product Quality Rri'iru> sent monthly to those reporting events and prob-lems, to anyone requesting being placed on mailing list and to profes-sional journals.
Ixtter of acknowledgement stating all follow-up information alxiut that re-port received front FDA or manufac-ture!.
Placed on mailing list for Drug Product Quality Review.
Will be told if others report similar prob-lems if so requested.
Subscribing drug manufacturers (see above Financial Support) receive daily detailed information.
Non-subscribers notified on a daily basis only that problem has been reported; quarterly, each manufacturer sent a list of its products that were reported.
Submitted to ophthalmologic and gener-al medical journals for publication.
Textbook: Drug Muted Ocular Sid? Ef-fects and Drug Intrractimis. (FT Fraun-felder, author).
Physician may speak directly with execu-tive director and receive advice on how to handle problem and, in broad terms, information about similar cases.
Rare requests for follow-up data.
If trend emerges, medical director of drug company may be contacted.
'Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857
'United States Pharmacopeia 12601 Twinbrook Parkway Rockville, MD 20852
'National Registry of Drug Induced Ocular Side Effects and Drug Interactions
Casey Eye Institute 3375 Southwest Terwilliger Boulevard Portland, Oregon 97201
Reprint address: Joel Mindel, M.D., Department of Ophthalmology, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029.
208
MEDWATCH MEDICAL PRODUCT* ItPQKTINC FtOCIAM
K»U»0Mr (UB)
events and product problems
o*
Patient information 2. AgaatUma
0f JPINMlt! or Date o» btolh:
3. Sa*
Q l a m a t a
• mala
4. WaJfiht
ft*
Kgs Adverse event or product problem
; Q M v t m m / m * andtar • Productprobtafi*(».p„drtacaJnMftjndior*) Oulcomaa attrttoutad lo wfrtraa avant ~ " (shack aN that apply) • dmbUty
Q daath | | eonoTwtti anomaJy
f l H M h m a l m r n a ¥ m m " m O n 9 M n a * i_i » m i « M i » v parmanant impairtnanttiamaga • ho»pttal7a»>ofi - k m i or prototiqad • othar.
IMMPlt
itoaerflw «v*nt or probtwn
4. Data of this raport 1222222
t M o v a n t laataAatooratofy data, mdudno dataa
O t h f n t w i n l history, inriudinf praaadatlnfl madtoal ooodWona (a.g., atargias. raca, pregnancy. arooWng and aieotwl UM, hapatiertanal dy«»ur>dk*>, sic.)
Mall to: MEDWATCH ^ 5600 F i she r s U n a 1-«XKFOA-O17» RockviHa, 110 20652-0717
- 967,1991. 2. Pratt WB, Ruddon RW, Ensminger WD, et al: The anticancer drugs. Second edition.
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NOTES
2 1 1
ereserves
Text Box
NEUROLOGICAL COMPLICATIONS OF ORGAN TRANSPLANTATION Patch ell, R: Neurological complications of organ transplantation. Ann Neurol1994;36:688-703.
Reviewed by: Andrew G, Lee MD, Rosa Tang MD.
1. Incidence of neurological complications 30-60% 2, Neurological complications common to all transplant types
a. Direct immunosuppressive agent effects i. Cyclosporine
(1) most common agent used for anti-rejection (2) mechanism
(a) inhibits lymphokine production & release <b) selectively inhibits helper & cytotoxic T cells (c) blocks antigen-induced T-cell activation
(d) higher risk of CNS toxicity (i) previous cranial radiation (ii) hypocholesterolemia (iii) hypomagnesemia (iv) B-lactam antibiotics (v) high dose steroids (vi) hypertension (vii) uremia
(e) Treatment (i) decrease dose or eliminate drug
(ii) most side effects reversible ii. FK 506
(1) chronic immunosuppression (2) similar mechanism of action to cyclosporine (3) side effects similar to cyclosporine but less common (4) most reversible after drug withdrawn
iii. Corticosteroids (1) affect both cellular & humoral immunity (2) exposes pt. to risk of opportunistic infection (3) neurological effects
(a) myopathy (i) 2-3 weeks post therapy (ii) proximal muscle weakness (iii) most severe in hip girdle (iv) resolves after 2-8 months
(b) steroid psychosis (c) spinal cord or cauda equina compression
(iv) Neuroimaging 1) mild to moderate cerebral edema
(v) usually resolves slowly, up to 2 weeks (vi) resolves even without stopping drug!
v. antithymocyte and antilymphoblast globulins (1) polyclonal antisera against thymocytes of lymphs (2) serum sickness occassionally (3) neurological effects
(a) rare (b) may occur with cross reaction with CD3 antigen (c) similar effects to OKT3
<2> X 3
vi. azathioprine (1) antimetabolite (2) suppresses both cell-mediated & humoral immunity (3) myelosuppression (4) hepatotoxicity (liver failure may cause neurologic effects) (5) no direct neurological effects
CNS infections i. 5-10% incidence in transplant patients ii. 44-77% of CNS infections result in death iii. Organisms
(1) wide variety (2) 80% of CNS infections from 3 organisms!!
4) Cryptococcus (c) third period: 6 mos after transplant
(i) lingering effects of previous infection (ii) opportunists from chronic suppression (iii) nonimmunosuppressed infection rate
c. De novo lymphoproliferitive disease i. Posttransplant lvmphoproliferative disorder (PTLD)
(1) 15-20% of PTLD develop CNS disease (2) 85% of cases CNS = only detectable site in CNS cases (3) pathogenesis
(a) EBV infection <b) containe EBV DNA (c) express EBV gene products (d) activation of polyclonal B-cells (e) unchecked EBV proliferation (f) eventually unchecked malignant clone (g) cytogenetic event (h) similar to chromosomal translocation in Burkitt's ds
(4) Why does virally induced PTLD occur in CNS ? (a) immunologically priveleged site (b) CNS infections different & less intense than systemic
(5) Clinical features same as primary CNS lymphoma (a) tumors arise deep in brain (b) around perivascular spaces (c) involvement of subependymal white matter (d) multicentric in 22-50% (c) 25% have leptomeningeal spread (0 Altered mental status common (multicentric) (g) Seizures less common than primary brain tumors (h) diagnosis by stereotactic biopsy
(6) Treatment (a) reduction in immunosuppression (b) antiviral therapy (c) conventional chemotherapy and radiotherapy (d) anti-B-cell antibodies, interferon-alpha
(7) Prognosis poor: overall survival 31% Seizures i. 6-36% of transplant patients ii. etiology
CD drugs = most common cause (esp. cyclosporin, OKT3) (2) metabolic derangements (3) hypoxic-ischemic injury (4) infections (5) infarction (6) tumors
iii. anticonvulsant therapy (1) induce hepatic cytochrome oxygenase p450 system (2) variable effect on cyclosporine levels
3. Neurological complications specific to transplant types a. Types
i. complications from underlying disease ii. problems from transplant procedure itself iii. side effects of immunosuppression iv. posttransplant problems specific to type of transplant
b. Kidney transplants i. 30% develop neurological complications ii. Underlying disease
iii. Procedure (1) femoral or lateral femoral cutaneous n. injury (2) spinal cord ischemia
iv. immunosuppression (1) reversed T-cell subsets & increased CDS, decreased CD4 (2) susceptible to viral infections, CMV & EBV
v. Specific renal transplant complications (1) 9% have cerebrovascular events
(2) acute rejection encephalopathy Bone marrow transplant (BMT) i. 60-70% of allogenic BMT have neurological complications ii. neurologic complications = death in 5-10% patients iii. underlying disease
(1) recurrent CNS leukemia up to 13% (2) neoplastic meningitis (3) prior radiation and chemotherapy CNS damage
iv. procedure (1) low dose total body radiation (2) cognitive dysfunction in long term survivors
v. immunosuppression (1) more severely immunosuppressed than other transplants (2) granulocytopenic for 1 month (3) infections
iii. immunosuppression (1) PTLD second only to cardiac transplant (2) neurotoxic effect of cyclosporine higher
(a) hypercholesterolemia (b) hypertension
iv. specific complications (1) central pontine myelolysis (CPM) (2) CPM in 7-13% autopsy transplant patients (3) infrequent in renal or cardiac transplant (4) clinical
(a) demyelination in the pons (b) extrapontine demyelination can occur (c) associated with rapid correction hyponatremia (d) rise in seium sodium in liver transplants (blood
replacement after blood loss) (e) altered MS or coma (f) pseudobulbar palsy (g) quadriplegia
f. Pancreas transplant i. 60% neurological complications ii. underlying disease
(1) severe diabetes with end organ damage (2) renal failure (3) peripheral or autonomic neuropathy (4) carpal tunnel syndrome increased frequency
iii. procedure (1) neurological complications rare (2) postoperative stroke
iv. immunosuppression simliar to liver or heart G. Steroids - cytotoxic drugs
1. Visual loss due to " leopard" fundus (Gass 1992)
