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Diphenylhydantoin effects on thyroid function tests.

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Clinical m d Laboratory Datd
Factor
Patient 1
Patient 2
Age at present
Age o f onset
Mode of onset
Duration of progression
Pattern of involuntary movement
Intensity of
involuntary movement
11
7
21
Insidious
2 Yr
Choreiform, constant
Severe in upper limbs;
mild in lower limbs, head,
and mouth
Hypotonia, congenital deafness
Normal
Normal
None
Normal
Normal
Insidious
9 yr,
Choreiform, constant
Very severe in limbs
and head; mild in mouth
Associated neurological signs
Ophthalmological findings
Psychological findings
Associated nonneurological signs
Electroencephalogram
Blood cytology and chemistry
CSF cytology and chemistry
Kar Y 0 rype
3
. . .
Hypotonia; congenital deafness
Normal
Normal
None
Normal
Normal
Normal
Normal
...
rheumatic fever in these patients, Sydenham’s chorea may
be excluded. O n rare occasions Sydenham’s chorea has
appeared without obvious signs of rheumatic activity, but it
has always been a self-limited disorder. Huntington‘schorea
has been described in children and may appear without a
previous familial history, but the progression of the movement disorder is relentless, and there is marked mental
decay. Other diagnostic possibilities that can be ruled out
are Wilson’s disease, Hdlervorden-Spatz disease, and familial paroxysmal choreoathecosis:
T h e genetic nature of familial nonprogressive chorea has
been established by analysis of the condition in seven pedigrees 13-51. T h e transmission is probably autosomal recessive, although some authors believe it to be aurosomal
dominant with incomplete penetrance. The parents of our
patients were not affected, and no other known relative has
the disease.
The clinical picture points to an abnormality of the striatal
system. Current knowledge of the neurophysiology of
movement disorders makes it probable that the condition is
related to dysfunction of dopaminergic pathways, possibly
as a result of an inherited enzymatic defect.
The importance of recognizing this condition rests on the
psychological and social implications of itsgood prognosis as
well as on its implications for genetic counseling.
References
1. Haerer AF, Currier RD, JacksonJF: Hereditary nonprogressive
chorea of early onset. N Engl J Med 276:1220-1224, 1967
2. Pincus JH, Chutorian A: Familial benign chorea with intention
tremor: a clinical entity. J Pediatr 70:724-729, 1967
3. Nutting PA: Benign, recessively inherited choreo-athetosis of
early onset. J Med Genet 6:408-410, 1969
4. Refsum S: Hereditary nonprogessive involuntary movements
with early onset and intention tremor, without dementia. Acta
Neurol Scand [Suppll 51:489-491, 1972
5 . Chun RWM, Dalay RF, Mansheim BJ, et al: Benign familial
chorea with onset in childhood. JAMA 225:1603-1607, 1973
Diphenylhydantoin
Effects on Thyroid
Function Tests
Robert H. Caplan, MD, Robert Mordon, BS,
Karen Kristoff, BS, and Gary Wickus, P h D
W e determined, respectively, total serum thyroxine as
thyroxine iodine (T4I), triiodothyronine uptake (T3U),and
serum diphenylhydantoin concentration in 17 euthyroid
women and 14 euthyroid men (aged 16-83 years) who
received diphenylhydantoin (200 to 500 mg daily) for from
2 months to 16 years. The free, metabolically active form of
thyroxine (FT,) was estimated indirectly by a free thyroxine
index, calculated by dividing the product of the TJ and T3U
by 100, and by a free thyroxine equivalent, measured by a
modification of the Tetralute method. A euthyroid population of 60 women and 45 men served as controls.
The values for the thyroid function tests (Figure) indicate
that in patients taking diphenylhydantoin the mean T,I is
reduced 30% and the mean free thyroxine index and free
thyroxine equivalent are reduced 25%. i n these patients,
approximately 33% of the results of the free thyroxine
index test, our primary screening test for thyroid dysfunction, were in the hypothyroid range. T h e T3U was slightly
increased. Serum diphenylh ydantoin concentrations ranged
from 0.4 to 3.6 m$dl. There was no obvious correlation
between the results of the thyroid function tests and the
diphenylh ydantoin concentration or duration of trearment.
From the Departments of Medicine and Clinical Chemistry, Gundersen Clinic,Ltd, and La Crosse Lutheran Hospital, Lacrosse, WI.
Accepted for publication Nov 8, 1976.
Address reprint requests to Dr Caplan, 1836 South Ave, La Crosse,
WI 54601.
Notes and Letters 603
THYROXINE 1741)
.1’
T3 UPTAKE(T3U)
PLRCtRT
w/dl
45
I
14 0
12 0
FREE THYROXINE
EOUIVALENT(FTE)
UNITS
FREE THYROXINE
INDEX ( F l l )
UNITS
14-
18
16
14
I2
iz
I6
+ , 0; ,
IO8
b
4
20
p<oos
p<OOS
CONTROL
OPH
CONTROL
DPH
Cerebral Hemorrhage
in Amyloid Angiopathy
=
CONTROL
Serum thyroxine iodine, triiodothyronine (Ti) uptake, free
thyroxine index, and free thyroxine equivalent i n control
and diphenylhydantoin (DPHFtreated patients.
Vertical brackets indicate ihe mean 2 SD. Group
comparisons were made with Student’s t-test.
These results agree with those of other studies [ l , 21.
Investigators also report decreased m4measured directly
by equilibrium dialysis [ 3 ] and decreased total
triiodothyronine (T3)concentration [ 11in patients receiving
long-term treatment with diphenylhydantoin.
Most studies of diphenylhydanroin-treated patients
[1-4], including our own, indicate that the patients are
clinically euthyroid. Basal metabolic rate, thyroid radioactive iodine uptake, and cholesterol concentrations are also
normal [4].
T h e abnormally elevated thyrotropin concentrations [l, 21 and exaggerated thyrotropin response to
thyrotropin-releasing factor [ 11 expected in hypothyroid
patients have not been demonstrated.
T h e mechanism by which diphenylhydantoin reduces
both total and free T4 and total T, is not clear. Although
pharmacological concentrations of the drug displace T4from
thyroxine-binding globulin in vitro, the slight increase in
T3U does not explain the 30% reduction in TJ.Furthermore, displacement of T4from thyroxine-binding globulin
should suppress hypothalamic-pituitary function and result
in a new steady state in which serum thyrotropin and TJ are
reduced but the free thyroxine index is restored to normal.
Until the mechanism by which diphenylhydantoin affects
thyroid function is resolved, we emphasize that euthyroid
subjects receiving this drug may have low T41and low free
thyroxine indexes and equivalents. Treatment with thyroid
hormone is not indicated in the absence of pituitary failure
or an abnormally high thyrotropin concentration.
References
1. Hansen JM, Skovsted L, Birk Lauridsen U, et al: The effect of
diphenylhydantoin on thyroid function. J Clin Endocrinol
Metab 39785-789, 1974
2. Stjernholm MR, Alsever RN, Merritt CR: Thyroid-function
tests in diphenylhydantoin-treated patients. Clin Chem
21:1388-1392, 1975
3. Chin W, Schussler GC: Decreased serum free thyroxine concentration in patients with diphenylhydantoin. J Clin Endocrinol
Metab 28:181-186, 1968
4. Oppenheimer JH, Fisher LV, Nelson KM, et a1 Depression of
the serum protein bound iodine level by diphenylhydantoin.J
Clin Endocrinol Metab 2 1:252-262, 1961
604 Annals of Neurology Vol 1 No 6 June 1977
K. Jellinger, MD
Cerebral amyloid angiopathy, unrelated to generalized
amyloidosis, is a frequent but inconstant finding in patients
with Alzheimer’s disease and senile dementia [l-31. Recently this vascular abnormality has been stressed as a cause
of nonhypertensive hemorrhage in the aged [3-51 and of
hereditary cerebral hemorrhage in younger persons [61. The
usual cortical type of malignant hypertensive angiopathy is
rare in the elderly, whether or not hypertension is present,
but simultaneous involvement of the pia-cortical vessels by
hypertensiveandcongophilic angiopathy does occur [2,5,71.
W e examined the frequency of cerebral hemorrhage due
to amyloid angiopathy in a nonselected autopsy series of
demented patients over age 55. Of these 1,010 patients,
5 3% had the anatomical features of presenile and senile
degeneration, 23 % had cerebrovascular diseasc without
senile changes, and 14% had amixture ofsenile and vascular
changes. Among these patients were 7 with cerebrovascular
amyloidosis and 8 with combined amyloid and hypertensive
vasculopathy. In the subjects with combined amyloid and
hypertensive vasculopathy one occasionally found, in the
same vascular channel, hyalin degeneration in one segment
and amyloid deposits extending into the brain parenchyma
along another.
Ten of the 15 patients with cerebrovascular amyloidosis
(with or without accompanying hypertensive vasculopath y)
had multiple miliary hemorrhages, and 8 had massive
hemorrhages distributed in the various lobes of the brain.
These 8 represented 2 % of a total of 400 consecutive
autopsied cases of nontraumatic cerebral hemorrhage.
These data, as well as the recent reports cited, emphasize
that cerebral amyloid angiopathy is a rare but important
cause of intracranial hemorrhage in the aged.
References
1 . Gerhard L, Bergener M, Hornyaun S: Angiopathie bei Alz-
heirner’scher Krankheit. 2 Neurol 201:43-61, 1972
2. Mandybur TI: The incidence of cerebral amyloid angiopathy in
Alzheimer’s disease. Neurology (Minneap) 25: 120-126, 1975
3. Ulrich G, Taghavy A, Schmidt H: Zur Nosologie und Atiologie
der kongophilen Angiopathie (Gefassform der cerebralen
Amyloidose). 2 Neurol 206:39-59, 1973
4. Torack RM: Congophilic angiopathy complicated by surgery
and massive hemorrhage. Am J Pathol81:349-366, 1975
5 . Torvik A: Aspects of pathology of presenile dementia. Acta
Neurol Scand 46:Suppl 43:19-31, 1970
6. Gudmundsson G, Hallgrirnsson J, Jonasson TA, et al: Hereditary cerebral haemorrhage with amyloidosis. Brain 95:387404, 1972
7. Jellinger K: Cerebrovascularamyloidosis with cerebral hemorrhage. J Neurol 214:195-206, 1977
From the Department of Neurology and L. B. Institute of Clinical
Neurobiology, Lainz-Hospital, 1, Wolkersbergenstrasse, A 1130
Vienna, Austria.
Accepted for publication Nov 12, 1976
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