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Cerebrospinal fluid xanthochromia with rifampin.

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TIME
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Sequentiuf total andfiee pla.tnzu curhamazepine leijels oivr a
.36-hoiAr period. The time and surbumuzepine &e.c m e indirzzted hy arrow(. The pPriod of 04jerti1.e rlinirul toxicity
(doiunbent ny~tujimusand ierehellur .\igns) i.i indicated by the
.shaded nreu.
myelography and cisternography. O n e hour later she became lethargic but remained oriented. Neurological examination revealed scanning dysarthria, primary-position
downbeat nystagmus, and diminishcd tone and deep tendon reflexes in all extremities, as well as dysmetria, ataxia,
and impaired rapid alternating movements in the limbs.
After one hour her neurological status had returned to
normal. Carbamazepine, phenytoin, and phenobarbitol
levels at the onset of symptoms were 8.2, 22.2, and 6.7
pgiml, respectively. Metrizamide cisternography accompanied by C T scan with 5 mm sections was normal.
When plasma anticonvulsant levels were undetectable,
and with the patient's consent, carbamazepine was restarted
and plasma levels were measured at various times over the
next two days (Figure). Anticonvulsant levels were determined using high-performance liquid chromatography
(Samuels SD, Ramsay RE, Vasquez D, Sonni R: Micromethod for anticonvulsant determination from whole
blood spotted o n filter paper. Submitted for publication).
T h e unbound fractions were assayed from plasma
ultrafiltrates obtained using Amicon ultrafiltration cones.
O n the morning of the second day the patient developed
symptoms of dysarthtia. downbeat nystagmus in primary
position, limb dysmetria, truncal ataxia, and diminished
deep tendon reflexes two hours after ingesting carbamazepine. At the onset of symptoms her plasma carbamazepine level was 15.0 pgiml; two hours later, when
the symptoms had cleared, it was 15.8 pgiml. T h e corresponding free carbamazepine level was 2.6 pgiml at the
onset of symptoms, with the highest level, 3.1 pgiml, occurring one hour later. T h e percentage of free carbamazepine for all the samples was 15.86
2.65 SD.
Most drug-induced nystagmus is evident in lateral and
upward gaze 141, but i t may occur also with downgaze.
Primary-position downbeat nystagmus has been associated
with structural lesions of the craniocervical junction [ 3 , 41,
while upbeat nystagmus accompanies lesions of the
superior cerebellar vermis o r rectum [Sl. Common toxic
symptoms from carbamazepine are diplopia, drowsiness,
headaches, and ataxia, but these have not always correlated
well with blood levels [ S ] . Sullivan et a1 [7] reported "bilat-
*
228
Annals of Neurology
Vol 12
No 2
August 1982
eral vertical nystagmus o n upgaze" in a patient who had
awakened from coma, at a time when the carbamazepine
level was approximately 10 pgiml. O u r patient, similar to
those reported by Alpert [ I ] , had no evidence of a structural abnormality. All the patients reported by Alpert and
by Sullivan et a1 had taken more than one medication,
whereas the patient reported here developed similar
symptoms when given carbamaz6pine either alone or in
combination with phenytoin and phenobarbital. Pharmacokinetic principles suggest that the brain concentration
o f a drug is proportional to its free serum concentration.
O u r patient's clinical symptoms were indeed more closely
related to the unbound fraction of the drug, occurring with
levels above 2.6 pgiml. T h e protein binding of 84.3% in
o u r patient (normal, 70 to 80%) may explain why plasma
levels well above the therapeutic range were attained before symptoms developed.
Department of Neuvohgy
Veterans Administrution Medical Center
and Uniimtity of Miami
Mrunii, F L 33 125
R eje rences
1. Alpert JN: Downbeat nystagmus due to anticonvulsant toxicity.
A n n Neurol 4:471-473, 1978
2. Berchou RC, Rodin EA: Carbamazepine-induced oculogyric
crisis. Arch Neurol 36:522-523, 1979
3. Cogan BG: Down beat nystagmus. Arch Ophthalmol 80:757768, 1968
4. Daroff RB: Ocular oscillations. Ann Otol Rhino1 Laryngol
86:102-107, 1977
5 . Hoppener RJ, Kuyer A, Meijer JWA, Hulsman J: Correlation
between daily fluctuations of carbunazepine serum levels and
intermittent side effects. Epilepsia 21:341-350, 1980
6. Spector RH, Davidoff RA, Schwartzman RJ: Phenytoininduced ophthalmoplegia. Neurology (Minnezp) 26:103 11034, 1076
7. Sullivan JB Jr, Rumack BH, Peterson RG: Acute carbamazepine toxicity resulting from overdose. Neurology (NY)
31:621-624, 1981
8. Troost BT; Martinez J, Abel JA, Heros RA: Upbeat nystagmus
and internuclear ophthalmoplegia with brainstem glioma. Arch
Ncurol 37:453-456, 1980
Cerebrospinal Fluid
Xanthochromia
with &fampin
Stephen B. Liggett, M D , Joseph R. Berger, MD,
and Jubran Hush, MD
Xanthochromia of the cerebrospinal fluid (CSF) has been
considered a hallmark of subarachnoid hemorrhage. I t may
also be seen in normal newborn infants and in patients with
increased CSF protein, jaundice, carotenemia, or meningeal melanosarcomatosis [ 11. We have observed a yellow
discoloration o f the CSF in rwo patients, imparted by antituberculosis therapy with rifampin.
The first patient, a 28-year-old man with fever, malaise,
and weight loss due to malignant intestinal lymphoma
complicated by IgA heavy-chain disease, was started on
daily doses of isoniazid, 300 mg, ethanibutol, 1,500 mg,
and rifampin, 600 mg, for a presumptive diagnosis of
tuberculosis. Lumbar puncture while antituberculosis
therapy was still being administered demonstrated xanthochromic CSF with an opening pressure of 90 mm H20.
The faint yellow color was appreciated only when the sample was viewed against a white background. CSF studies
revealed 1 white cell per cubic millimeter (a mononuclear
leukocyte), no red cells, protein of 42 mgidl, glucose of 67
mgidl, and negative VDRL. Serum bilirubin was 0.8 m d d l
with a direct bilirubin of 0.4 mgldl. Serum albumin was 2.9
gmidl. Two days after discontinuation of antituberculosis
therapy, the CSF became clear and colorless.
The second patient was a 55-year-old woman with
chronic renal failure and epilepsy who presented with
fever, malaise, and a left upper lobe pulmonary infiltrate
due to reactivation of tuberculosis. Daily therapy with
isoniazid, 300 mg, pyridoxine, 10 mg, and rifampin, 600
mg, was initiated and phenytoin at 400 mg daily was continued. Two days later, impaired mental clarity (subsequently determined to be secondary to phenytoin intoxication) prompted lumbar puncture. Opening pressure was
120 mm H,O and the CSF was faint yelllow with 1 white
cell (a mononuclear leukocyte) and 1 red cell per cubic
millimeter, glucose of 68 mgidl, protein of 35 mgidl, and
negative VDRL. Total and direct bilirubin at the time of
lumbar puncture were 1.0 and 0.7 mgidl, respectively.
Serum albumin was 2.4 mg/dl. After three weeks of
therapy, rifampin was discontinued because of suspected
hepatotoxicity. At repeat examination the CSF w a s clear
and colorless.
The rifamycins, particularly rifampin, are well known to
impart an orange-red color to body fluids such as sweat,
urine, feces, saliva, and tears. This orange-red color is a
direct consequence of the concentration of rifampin o r its
metabolites. Therapeutic CSF levels are seen in meningitis
[ 2 , 41, and CSF rifampin levels as high as 3.5 m d m l have
been reported [4].
Though rifampin levels in CSF were not determined in
our patients, the temporal relationship of CSF xanthochromia to rifampin therapy was clear. Additionally, there
was no evidence of recent subarachnoid hemorrhage, jaundice, carotenemia, or elevated CSF protein.
Conceivably, spectrophotometric analysis of CSF can
serve as an alternative t o direct chemical assay in distinguishing rifampin from other causes of CSF xanthochromia. Rifampin exhibits maximal absorption at 237 nm
with substantial absorption between 300 and 400 nm as
well as in higher ranges [ 5 ] . The products of blood breakdown, methemoglobin, oxyhemoglobin, and bilirubin,
have maximal absorption peaks generally between 400 and
500 nm 131.
Rifampin is 90% protein bound, and in our patients low
serum protein levels may have resulted in increased availability of free rifampin, enabling it t o cross the blood-brain
barrier in sufficient quantity to result in xanthochromia despite the absence of meningeal inflammation. Rifampin
therapy should be added to the list of conditions known to
produce CSF xanthochromia.
Depurtment o f Neurnloo
University of Miumi School of Medicine
Miami. FL 33 I01
References
1. DeJong R N : Examination of the cerebrospinal fluid. In DeJong
RN (ed): T h e Neurologic Examination. Fourth edition.
Hagerstown, M D , Harper & Row, 1979, p p 766-767
2. D'Oliveira JJG: Cerebrospinal fluid concentrations of rifampin
in meningeal tuberculosis. Am Rev Respir Dis 106:432-437,
1972
3. Kjellin KG, Soderstrom CE: Diagnostic significance of CSF
spectrophotometry in cerebrovascular diseases. J Neurol Sci
23:359-369, 1974
4 . Larbaoui D, Boulahbal F, Air-khaled A, e t al: Etude ties tacx
seriques er rachidiens de rifampicine (R.AMP). Arch Inst Pasreur Alger 50,51:17 1-181, 1972-73
5 . World Health Organization: IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals ro Humans.
Geneva, World Health Organization, 1980, pp 243-244
Mania-Induced Remission
of Tardive Dyskinesia in
Manic-Depressive Illness
William J. Weiner, MD,' and Thomas R. Werner, MDf
It has been suggested that improvement in lingual-facialbuccal dyskinesias and limb chorea may be related to alterations in mood [5]. Recently, Cutler et a1 [ l ] reported two
cases of dyskinesia in manic-depressive illness in which the
patients had lingual-facial-buccal dyskinesia and axial
chorea in the depressed state and no abnormal movements
during mania. We report an additional patient in whom the
presence of dyskinesias depended on the state of the
psychiatric illness.
A 38-year-old white man had onset of manic-depressive
illness at age 35 with an initial episode of mania characterized by insomnia, psychomotor hyperactivity, pressure
of speech, intrusiveness, flight of ideas, sexual preoccupation, and exhibitionism. The illness was initially managed
with haloperidol, chlorpromazine, and thioridazine. After
approximately eight months of neuroleptic use, the patient
developed dyskinetic choreiform movements of his right
shoulder and both arms. In subsequent years he has
had recurrent manic episodes that have necessitated the
use of continued lithium, electroconvulsive therapy, and
neuroleptics. The dyskinesias have become worse, and at
present consist of bilateral upper extremity chorea, respiratory dyskinesias, retrocollis, and axial dystonic posturing. The movements sometimes have been violent
enough to result in spontaneous rib fractures. During his
nonmanic phase the patient cares for himself at home, but
he has not resumed his professional activities.
Over the last four years this man has had six recurrent
manic episodes. Three to six days prior to each onset of
Notes and Letters
229
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