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An autosomal dominant syndrome of hemiplegic migraine nystagmus and tremor.

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ined the oculovestibular reflex in patients with hepatic coma and found 4 of 5 1 with absent reflex
horizontal eye motions. Rai, Buxton-Thomas, and
Scanlon [7] described a single patient with hepatic
coma in whom transient ocular bobbing recovered
after treatment of the encephalopathy. These reports
indicate that hepatic coma may affect brainstem tegmental function as well as motor pathways and hemispheric structures.
Eye movement abnormalities have been described
in other “toxic-metabolic” states. Spector, Davidoff,
and Schwartzman [9] described five patients with
total external ophthalmoplegia due to diphenylhydantoin intoxication; one of them (Case 4) had transient bilateral adduction paralysis during the recovery
phase. Other reports document the occasional
presence of abduction paralysis [41 and divergent
strabismus with diphenylhydantoin intoxication [ 11.
Simon [SI has pointed to the frequency of dysconjugate gaze and delayed forced downward deviation of
the eyes in patients with sedative drug overdose.
Dysconjugate gaze is a well-known feature, almost
invariably present in the first stage of anesthesia [S].
Toxic-metabolic conditions thus can affect brainstem
structures and produce dysconjugate gaze, selective
weakness of ocular adduction or abduction, or alteration in the vertical position of the eyes.
Hepatic encephalopathy may, o n rare occasions, be
associated with oculomotor dysfunction more commonly indicative of a structural lesion in the brainstem. Preservation of other functions at the same
level (for example, pupillary reflex, posturing, or respiratory control) and systemic and laboratory evidence of severe metabolic disturbance should point
to a metabolic explanation for the oculomotor dysfunction in such patients.
1. Blair A, Hallpike J, Lascelles P, Wingate D: Acute diphenylhydantoin and primidone poisoning treated by peritoneal dialysis.
J Neurol Neurosurg Psychiatry 31:520-523, 1968
2. Cartlidge N, Bates D, Jones R: Prognostic value of oculovestibular reflex. Br Med J 1:1346, 1978
3. Conomy J, Swash M: Reversible decerebrate and decorticate
postures in hepatic coma. N Engl J Med 278:876-879, 1968
4. Manlapaz J: Abducens nerve palsy in dilantin intoxication. J
Pediatr 55:73-74, 1959
5. Maztia V, Randt C: Amnesia and eye movements in first stage
anesthesia. Arch Neurol 14522-525, 1966
6. Plum F, Posner J: The Diagnosis of Stupor and Coma. Third
edition. Philadelphia, Davis, 1980
7. Rai G, Buxton-Thomas M, Scanlon M: Ocular bobbing in hepatic encephaloparhy. Br J Clin Pract 30202-205, 1976
8. Simon R: Delayed forced down gaze during oculovestibular
testing in sedative drug-induced coma. Neurology (Minneap)
27:346-347, 1977
9. Spector R, Davidoff R, Schwartzman R: Phenytoin-induced
ophthalmoplegia. Neurology (Minneap) 26:103 1-1034, 1976
An Autosomal
Dominant Svndrome
of Hemiplegic Migraine,
Nystagmus, and Tremor
Benjamin Zifkin, M D , Eva Andermann, M D , PhD,
Frederick Andermann, M D ,
and Trevor Kirkham, MB, ChB
A mother and son suffer from hemiplegic migraine
with onset in childhood. Both have nystagmus which
has not changed for many years, but the date of onset is uncertain. They have an asymmetrical tremor,
clinically indistinguishable from essential tremor.
Neuroophthalmological examination revealed inability to produce smooth pursuit, gaze-paretic nystagmus, rebound nystagmus, failure of fixation suppression of the vestibuloocular reflex both horizontally
and vertically, and low gain of the optokinetic system.
These abnormalities, confirmed by electrooculography, are commonly seen in disease of the cerebellum
and brainstem. Treatment with propranolol and
pizotyline lessened the number of episodes of hemiplegia and improved the tremor.
Hemiplegic migraine has been reported in association with nystagmus, retinal degeneration, deafness,
and ataxia in varying combinations in three other
families with autosomal dominant inheritance. These
associated neurological manifestations likely represent
system degenerations rather than the effect of repeated
ischemia imputable to the migraine itself.
The syndrome of hemiplegic migraine, tremor, and
ocular smooth pursuit system disorder seen in this
family appears to be inherited as a single autosomal
dominant trait, although more than one autosomaf
dominant gene may be involved.
Zifkin B, Andermann E, Andermann F, Kirkham T:
An autosomal dominant syndrome of hemiplegic
migraine, nystagmus, and tremor.
Ann Neurol8:329-332, 1980
Various combinations of neurological deficits associated with familial hemiplegic migraine have been described. We report a mother and son with hemiplegic
migraine, essential tremor, nystagmus, and a disorder
of the ocular smooth pursuit system, a syndrome
From the Department of Neurology and Neurosurgery, McGill
University and the Montreal Neurological Hospital and Institute,
Montreal, Que, Canada.
Received Dec 3, 1979, and in revised form Feb 20, 1980. Accepted for publication Feb 23, 1980.
Address reprint requests to Frederick Andermann, MD, Montreal
Neurological Hospital and Institute, 3801 University St,
Montreal, Que, Canada H3A 2B4.
0364-5 134/80/090329-04$01.25 @ 1979 by Frederick Andermann
S y n d r o m e of h e m i p l e g i c m i g r a i n e ,
T r e m o r of h e a d
M e n t a l r e t a r d a t i o n , paralysis
which to our knowledge has not previously been described.
18 19
nyrtogmus a n d tremor
E x a m i n e d , f o u n d to b e n o r m a l
T w o f e m a l e s , normal b y history
Fig I . Pedigree of Kindred C.
Case Histories
Patient 1
The proband (111-15 in Fig 1) is a right-handed 22-year-old
French-Canadian male. At 12 years of age, six weeks after
he had sustained a brief period of unconsciousness following a head injury, he noted black spots before his eyes
lasting one hour, followed by numbness and weakness beginning in the left foot and rapidly involving the entire left
side of his body and face. The weakness and paresthesias
lasted four hours and were followed by severe, constant
bifrontal headache with nausea, vomiting, and photophobia, which abated without treatment after about twelve
hours. Following this episode similar attacks occurred
about three times monthly, involving either side of the
body and face. Transient right-sided weakness was associated with dysphasia.
Examination at age 16 years showed horizontal gazeparetic nystagmus, constant fine head tremor, and moderately severe postural and fixation tremor of the hands. The
tremor, best demonstrated when he held a filled glass, had
all the clinical characteristics of essential tremor. H e was
treated with propranolol, 40 mg orally twice daily.
The tremor improved, but one year later he developed
acute right hemiplegia and homonymous hemianopia, dysphasia, drowsiness, and severe left hemicranial headache.
Nystagmus and tremor persisted. Arteriography during the
hemiplegic attack (Fig 2) showed narrowing of the left
middle cerebral artery branches in the sylvian region. A C T
scan was normal. An electroencephalogram showed slow
Annals of Neurology
Fig 2.(Patient I ) Left internal carotid angiogrurn showing
narrowing of the left middle cerebral artery and its Srancbes.
Vol 8 No 3 September 1980
waves over the left hemisphere and background asymmetry. A radioisotope circulation study suggested moderate reduction of blood flow to the left hemisphere with no
focal uptake.
Ethanol and papaverine were given intravenously with
prompt improvement in his hemiplegia, the hemianopia
and dysphasia resolving over three days. Propranolol and
dipyridamole were given orally. Before and just after beginning therapy he suffered two 45-minute episodes of
hemiparesthesia and hemiparesis, first right- and then leftsided, each followed by severe headache. The right
hemiparesis was also associated with incomplete hemianopia and dysphasia. He has taken propranolol and pizotyline since, and has had only two brief episodes of
hemiplegic migraine in four years.
Neuroophthalmological examination showed normal visual acuity, pupillary reactions, visual fields, and fundi.
Ocular smooth pursuit was broken into small saccades
horizontally and vertically. There was marked gaze-paretic
nystagmus on horizontal gaze, the slow phase showing an
exponential decrease in velocity. Marked rebound nystagmus occurred on return to the midline from eccentric horizontal gaze that had been maintained for 20 seconds. Fixation did not suppress the vestibuloocular reflex either
vertically or horizontally. The gain of the pursuit and
optokinetic systems was low. Saccadic eye movements
were normal. These findings were confirmed using electrooculography.
Patient 2
This patient (11-6 in Fig 1) is the 48-year-old mother of the
proband. At 12 years of age, following a minor head injury,
she had her first episode of hemiplegic migraine, with black
spots in all visual fields, hemiparesthesias, hemiparesis, and
severe hemicranial headache associated with nausea, vomiting, photophobia, and phonophobia. Episodes subsequently occurred once or twice monthly, unrelated to her
menses, though fatigue and emotional stress increased their
frequency. Each attack lasted about two hours and involved
either side of the body. This pattern continued until she
was 31 years old. In the past 17 years only two such
episodes have recurred, both recently. Tremor of the head
and arms has been present for many years, but the time of
onset is uncertain. It has always been worse in the right
arm, and she uses the left hand for such tasks as holding a
Examination showed pronounced tremor of the head and
postural and fixation tremor of both arms, particularly the
right. The left corner of the mouth did not move as well as
the right. Neuroophthalmological examination and electrooculography showed the same abnormalities as in her
son. A CT scan was normal. No further attacks have occurred while she has been taking propranolol and
pizotyline. Her tremor is improved.
Kindred C
A maternal aunt of the proband (11-5 in Fig l), now deceased, is said to have had a tremor of the head. A maternal
uncle has frequent severe headaches but no episodes of
hemiparesis, nystagmus, or tremor. No other family members are known to be affected.
Three families similar to this o n e have been described. Ohta e t al 121 reported familial hemiplegic
migraine with persistent cerebellar manifestations
developing over years in patients who had had several hemiplegic attacks; disorders of gait and stance
and incoordination of the limbs were prominent, and
horizontal nystagmus was present; no resting or
postural tremor was noted. T h e authors attributed
the persistent deficits to ischemia d u e to vasospasm
occurring during the hemiplegic migraine.
Young et a1 131 reported eleven cases of migraine
in four generations of one- family. Four persons suffered hemiplegic migraine, all with associated permanent deficits. Two had retinitis pigrnentosa and
sensorineural deafness as well as nystagmus o n both
lateral and upward gaze; one was also ataxic. T h e
other two had nystagmus but no ataxia. T h e authors
concluded that recurrent severe migraine was not responsible for the fixed neurological deficits but that
several associated genetically determined conditions
were present in this family.
Codina e t a1 I11 reported hemiplegic migraine in
eight members of a Spanish family, three of whom
had nystagmus o n horizontal gaze and instability on
Romberg testing. Electrooculography suggested central brainstern dysfunction. No note was made of
tremor. T h e authors suggested that the neurological
signs found in these three patients were d u e to a
“system dysgenesis” associated with herniplegic migraine.
Familial hemiplegic migraine with essential tremor
and the disordered smooth pursuit noted in o u r patients has not been described previously. Though the
constellation of neurological signs in these families
differs somewhat, there is a resemblance among the
four kindreds. All have members with hemiplegic
migraine and nystagmus; tremor, unsteadiness, signs
of cerebellar dysfunction, retinitis pigmentosa, and
deafness appear to be less consistent components of
the syndrome.
T h e ocular findings in our patients may be due t o
cerebellar or brainstem disease [4];the neurophysiological basis for these conclusions was unknown
when the previous cases of hemiplegic migraine
and nystagmus were reported. Neither patient had
signs or symptoms of episodic brainstem o r cerebellar ischemia associated with the attacks of hemiplegia, and arteriography and C T scanning did not
show lesions in these locations. We suggest that the
abnormalities of ocular movement coordination associated with familial hemiplegic migraine in our patients, and inherited with it, represent an isolated
system degeneration rather than sequelae of prolonged vasoconstriction.
T h e tremor in our patients has the characteristics
Brief Communication: Zifkin et al: Familial Hemiplegic Migraine 331
of essential tremor. The age of onset is uncertain,
neither mother nor son relating it to the attacks of
hemiplegia. Thus it is unlikely that the tremor and
nystagmus are related to vasoconstriction-induced
damage to brainstem and cerebellar structures sustained during the hemiplegic migraine attacks, as has
been suggested [ 2 ] .
The syndrome of hemiplegic migraine, tremor, and
ocular smooch pursuit system disorder seen in our
family appears to be inherited as a single autosomal
dominant trait, although more than one autosomal
dominant gene may be involved. Though the various
neurological signs expressed in the four families may
represent pleiotropic manifestations of a single autosomal dominant gene, more than one autosomal
dominant mutation may be implicated.
Pending clarification of the biochemical defect,
further clinical reports are required to define the full
spectrum of this syndrome. Genetic linkage studies
should prove useful in determining whether one or
more autosomal dominant genes are involved.
Presented in part at the Thirteenth Canadian Congress of Neurological Sciences, Vancouver, BC, Canada, June 1978.
We thank Susan Zeesman for assistance in preparation of the manuscript.
Codina A, Acarin PN, Miguel F, Noguera M: Migraine hkmiplkgique associke i un nystagmus. Rev Neurol (Paris)
1243526530, 1971
Ohta M, Araki S , Kuroiwa Y Familial occurrence of migraine
with a hemiplegic syndrome and cerebellar manifestations.
Neurology (Minneap) 17:813-817, 1967
Young GF, Leon-Barth CA, Green J: Familial hemiplegic migraine, retinal degeneration, deafness, and nystagmus. Arch
Neurol 23:201-209, 1970
Zee DS, Yee RD, Cogan DG, et al: Ocular motor abnormalities in hereditary cerebellar ataxia. Brain 99:207-234,
Ultrai&&ture of
Leukocyte Inclusions
William R. Markesbery, MD, Richard 0. Robinson, MD,
Peggy V. Falace, MD, and Michael D. Frye, BS
Ultrastructural study of leukocytes from 7 patients
with mucopolysaccharidosis (MPS) I, 11, or 111 demonstrated a variety of membrane-bound inclusions in 34
to 68% of lymphocytes and larger mononuclear cells.
The most common inclusions were membrane-bound
vacuoles containing faintly osmiophilic material, but
a variety of clear vacuoles, dense granular inclusions,
and myelin figures were also seen. Fingerprint profiles
were present in small percentages in MPS I1 and 111,
indicating that they are not as specific as previously
considered. Granulocytes, lymphocytes, and larger
mononuclear cells from a patient with MPS VII
showed many small and larger membrane-bound vacuolated inclusions, some of which contained large
dense granules. The presence of alterations in a readily
accessible tissue such as blood indicates that ultrastructural study of leukocytes may be a useful adjunct
in guiding further biochemical studies in MPS, especially in early or obscure cases.
Markesbery WR, Robinson RO, Falace PV, Frye MD:
Mucopolysaccharidoses: ultrasuucture of leukocyte
inclusions. Ann Neurol 8:332-336, 1980
The mucopolysaccharidoses (MPS) are inherited
lysosomal storage disorders characterized by accumulation of mucopolysaccharides (glycosaminoglycans) in various organs. Through correlation
of clinical, radiological, genetic, and biochemical
studies, they have been classified into at least seven
distinct major types [ 141. A variety of cytoplasmic inclusions have been described in lymphocytes, monocytes, and granulocytes in the different types of MPS
by light microscopic studies [l, 7, 9, 13-17, 19, 21,
221; however, little has been written about the ultrastructure of these inclusions.
This report describes the ultrastructural appearance and frequency of inclusions in leukocytes of patients with Hurler syndrome (MPS I), Hunter syn-
From the Departments of Pathology, Neurology, and Pediatrics
and the Sanders-Brown Center on Aging, University of Kentucky
Medical Center, Lexington, KY.
Received Nov 9, 1979, and in revised form Feb 19, 1980. Accepted for publication Feb 23, 1980.
Address reprint requests to William R. Markesbery, MD, Department of Neurology, University of Kentucky College of
Medicine, Lexington, KY 40536.
0364-5 134/80/090332-05$01.25 @ 1979 by William R. Markesbery
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autosomal, hemiplegic, migraine, syndrome, dominantly, nystagmus, tremors
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