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Cataplexy in variant forms of Niemann-Pick disease.

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Cataplexy in Variant Forms
of Niemann-Pick Disease
Raymond S. Kandt, MD,"tlI Ronald G. Emerson, MD,*tll Harvey S. Singer, MD,*t
David L. Valle, M D , t and Hugo W. Moser, MD*$
A combination of cataplexy and a variant form of Niemaan-Pick disease has occurred in five patients described in
the literature as well as in two of our patients. In our Patient 1, cataplexy was differentiated from epilepsy by
electroencephalographic telemetry and narcolepsy was confirmed by polysomnography. Cataplexy was abolished in
both of our patients by treatment with protriptyline. Four of the seven patients had impairment of vertical eye
movements. All seven patients had a disorder best classified as type C or D Niemann-Pick disease or the Neville,
Wenger, or Wiedemann variant. This appears to be the first identified relationship between cataplexy and a specific
disease.
Kandt RS, Emerson RG, Singer H S , Valle DL, Moser H W : Cataplexy in variant forms of Niemann-Pick
disease. Ann Neurol 12:284-288, 1982
Cataplexy is an abrupt, reversible loss of muscle tone
with maintenance of consciousness, often precipitated by strong emotions, and usually occurring as a
part of the narcolepsy-cataplexy tetrad 1131. We describe seven patients, two of o u r own, who have both
a form of Niemann-Pick disease and cataplexy.
1 was studied by electroencephalographic telemetry during
an attack and subsequently was studied by polysomnography ,
Case Reports
Patient 1
All seven patients were diagnosed as having a variant form
of Niemann-Pick disease 141 because they hail: ( 1 )
hepatomegaly, splenomegaly, or both; ( 2 ) foam cells or
sea-blue histiocytes on examination o f bone marrow or
other tissue; and ( 3 ) characteristic neurological involvemenr. Fibroblast sphingomyelinase acrivity was assayed in
Patients 1 and 2 (Table) using the chromogenic substrate
method of Gal et a1 1121. Additionally, the natural
radiolabeled substrate method of Wengcr [ 231 with extraction carried out as described by Yaniaguchi et al 1261 was
used for Patient I , and the natural ra~iiolabeled substrate
method of Brady et a1 151 for Patient 2. Conjunctival biopsy
was performed o n Patient 1. Patient 3 unclerwent liver and
appendiceal biopsies. With Patient 4 , liver, spleen, lymph
node, and cerebral tissues were examined. Patient 5 had
liver sphingomyelinase activity assayed and spleen sphingomyelin content determined; Patients 6 and 7 are siblings
of Patient 5 .
Laughter-induced loss of postural stability established
the diagnosis of cataplexy [ 2 0 ] in all sevcn patients. Patient
This man of primarily Anglo-Saxon, Caucasian descent was
normal at birth in December, 1058, but developed severe
jaundice. Hepatosplenomegaly was notell at age 3 months.
When h e was 12 years old, his speech became slow and
slurred, motor incoordination developed, and dystonic
posruring was seen. He graduated from high school with
borderline. t o normal intelligence.
Short-term memory deficits arc now prominent, along
with general intellectual decline. He has supranuclear vertical gaze paresis (paralysis of vertical saccades with normal
vestibuloocular reflexes and relative sparing of vertical pursuit), cerebellar speech and ataxia, dysphagia, dystonic gait,
brisk d e e p tendon reflexes and flexor plantar responses, a
mild and variable left hemiparesis, and frontal lobe release
phenomena (snout, root, palmomental reflexes). Findings
supporring the diagnosis of a variant form of Niemann-Pick
disease include bone marrow foam cells and sea-blue histiocytes, low fibroblast sphingomyelinase activity (Table),
and cytoplasmic inclusion bodies with lamellar arrays in
conjunctival cells.
D r o p attacks began when the patient was 12 years old.
They were very infrequent at the beginning, gradually in-
From the 'Department of Neurology ( t Division of Pediatric
Neurology) and the $Department of Pediatrics, rhe Johns Hopkins University School of Medicine and the %JohnF. Kennedy
Institute, Baltimore, MD 21205.
Received June 25, 1981, and in revised form Nov 25. Accepted
for publication Nov 29, 1981.
~
d
d requests
~
Dr
~ M ~ ~John
~~F, Kennedy
~
~ Institute,
,
707 N Broadway, Baltimore, MD 21205.
Material and Methods
Present addresses: 'Departmenr of Neurology (Division of Pediatric Neurology), University of Michigan Medical School, A n n
Arhor, MI 48109; 'iDepartmenr of Neurology, ColumbiaPresbyterian Medical Center, New Y a k , N Y 10032.
284
0364-5 1341821090284-05$01.25 @ 198 I by the American Neurological Association
Fibroblast Sphingomyelinuse Activity a As Asse.c.ced by Three Different Luboratories
Determination
Lab 1"
Lab 2"
Lab 3''
Patient 1
Chromogenic substrate
Natural radiolabeled substrate
78
70.4 k 5.4 (SD)'
...
...
17-20''
...
Patient 2
Chromogenic substrate
Natural radiolabeled substrate
34
...
...
...
25.2
19.9
"Expressed as percentage of control.
"George Thomas, J. F. Kennedy Institute, Baltimore, M D .
"David Wenger, University of Colorado Medical Center, Denver, CO.
dRoscoe Brady, National Institutes of Health, Bethesda, M D .
'The discrepancy between results from laboratories 1 and 2 is unexplained. Both values represent the mean of four determinations. When
cells that had been cultured in laboratory 2 were retested in laboratory 1, the value with natural substrate was 4976, suggesting that the
discrepancy relates, at least in part, to culture conditions.
Fi g 1 . Patient 1 undergoing E E G telemetry. Note muscle artifacts on E E G tracing during laughter.
creasing to three or four episodes per day by age 20. His
mother clearly recalled the onset of cataplexy when he was
12. She had said something humorous; he laughed and
abruptly "slid down the wall." Within seconds he had recovered completely without intervening incontinence, unconsciousness, or subsequent drowsiness.
There has been no definite history of excessive daytime
sleepiness, hallucinations, or sleep paralysis. He has had no
seizures. Routine electroencephalograms (EEGs) have not
demonstrated sleep-onset rapid eye movement (REM) periods or epileptogenic discharges. The patient was admitted
for telemetry. While watching a television comedy, he
began to laugh. H e abruptly lost muscle tone in his neck,
and his head fell backward (Figs 1, 2). H e recovered completely within 10 seconds and described what had happened to him, but when asked again approximately one
minute later, he did not recall any of the events. Cataplexy
was abolished by protriptyline, 20 mg orally at bedtime.
Subsequently, polysomnography demonstrated the typical
findings of narcolepsy, with multiple episodes of sleeponset REM periods and also rhythmical nocturnal myoclonus of the legs.
Patient 2
Fig 2 . CataPLexyoccurring moments after the laughter in Figure 1 . Note absence of seizure discharges or muscle artifacts.
This 9-year-old white girl without parental consanguinity
o r French or Jewish ancestry had a normal perinatal course
except for mild jaundice. Hepatosplenomegaly was noted
at age 6 weeks. Evaluation of the hepatosplenomegaly
when she was 2 years 11 months old revealed decreased
fibroblast sphingomyelinase activity (Table), but her
neurological history and examination were normal. Bone
marrow aspiration showed foamy macrophages with lightblue cytoplasm. During the following year the patient developed a broad-based, ataxic gait, intellectual deterioration, and a prominent intention tremor. Over the next few
years, new findings have included supranuclear vertical
gaze paresis, use of head thrusting to change lateral direction of gaze, jerky
pursuit movements, intermittent
bowel ahd bladder incontinence, difficulty swallowing,
hyperactive gag reflex, very little spontaneous speech, a
few beats of cogwheeling at the wrists, and dysdiadochokinesia.
Starting after the patient was 7 years old, humorous
Kandt et al: Cataplexy in Niemann-Pick Disease
285
events have caused her body to go limp; she slumps to the
floor with preserved consciousness and absence of subsequent drowsiness. If lifted up, she remains standing.
These cataplectic episodes occur several times daily.
Routine EEGs d o not show sleep-onset REM or seizure
discharges. Polysomnography was attempted but was impossible because the patient refused to tolerate the electrodes. Prorriptyline was started at a dosage of 5 mg orally
at bedtime. Cataplexy, which had occurred two or three
times per day, was abolished, and her behavior at school
improved. Prior to the protriptyline, the patient typically
grunted and thrashed about in bed for 30 to 40 minutes
each night; this behavior also stopped with the institution
of protriptyline. She has never had seizures. There have
been no other concomitants of narcolepsy.
convulsive nature began during the last half year of the patient’s life.
Patient 6 (Patient 3 of Wiedemann et al [Z])
This boy, the brother of Patients 5 and 7 , had the
“Wiedemann” variant of Niemann-Pick disease with the
onset of intellectual and motor deterioration ar age 2 years.
Hepatosplenomegaly and bone marrow foam cells were
present. Laughter-induced loss of postural stability began
when the patient was 8 years old and occurred frequently.
There were no seizures at any time. Sphingomyelinase activity and tissue sphingomyelin content were not assayed.
Patient 7 (Patient 4 of Wiedemann et al 1.231)
Additional Patients from the Literature
Patient .3 (Patient 7 of Neville et a1 [IT])
This 3-year-old boy with the “Neville” variant of
Niemann-Pick disease had cessation of intellectual development at age 2x years. Shortly thereafter he had the
onset of “seizures,” which began as a “sudden abnormal
laugh, followed by momentary loss of consciousness” occurring three times daily and sometimes accompanied by a
single flexion of the trunk. Examination showed hepatosplenomegaly, hypotonia, ataxia, and intention tremor.
At 355 years he developed a supranuclear defect of
vertical eye movements. T h e EEG showed a “moderate
diffuse abnormality with fast activity in the posterior
temporal regions.” Foam cells were present in the liver and
bone marrow. Liver sphingomyelinase activity was normal,
but liver sphingomyelin levels may have been increased
slightly. N o other seizure types were noted.
Patient 4 (Patient 15 of Crocker and Farber [9])
Among the first symptoms, starting in his “early years,” in
this boy with Niemann-Pick disease type D (Nova Scotia)
was the propensity to “faint whenever he was made to
laugh”; later, in response to something humorous, he
would “break into an internal giggle and then collapse in
convulsions.” In infancy he had a hand tremor, and sometime prior to school age he developed increasing incoordination and unsteadiness. Intellectual and motor deterioration was progressive, and splenomegaly was present.
Paralysis of vertical gaze was noted at age 71/2 years. He
died, undiagnosed, at 19 years 7 months of age. At autopsy
he had Niemann-Pick cells in his liver and spleen.
Patient 5 (Patient 2 of Wiedemann et al [25])
This girl, as well as Patients 6 and 7, is a member of a family
with the “Wiedemann” variant of Niemann-Pick disease.
At 4 years of age she had splenomegaly and retarded
speech. A bone marrow specimen showed foam cells.
Motor and intellectual deterioration was progressive, and
she died at 8 years of age. Frequent cataplectic attacks were
confirmed by personal communication with Professor
Wiedemann. She did not have paralysis of vertical gaze.
Spleen sphingomyelin content was elevated fivefold, and
liver sphingomyelinase activity was 59% of control values.
The EEG was diffusely abnormal. Seizures of a generalized
286 Annals of Neurology Vol 12 No 3 September 1982
This girl with the ”Wiedemann” variant of Niemann-Pick
disease is the sister of Patients 5 and 6. She had the onset of
motor and intellectual deterioration at age 2 years; she also
has hepatosplenomegaly and bone marrow foam cells.
Professor Wiedemann (personal communication) did not
state the time of onset of her cataplectic attacks but noted
that they were frequent and resulted in numerous
hematomas of her forehead. Seizures were not noted at any
time. Vertical eye movements were normal. Sphingomyelinase activity and tissue sphingomyelin were not assayed.
Discussion
Relationship between Cataplexy and
Niemann-Pick Disease
I n addition t o our t w o patients, five o t h e r s with varia n t f o r m s of Niemann-Pick disease and c o n c u r r e n t
cataplexy have been described. Cataplexy is believed
t o be a dissociated manifestation of REM s l e e p [ 131.
N o r m a l l y , REM sleep is regulated b y t h e p o n t i n e reticular formation. I n t h e cat, abolition of muscle t o n e
d u r i n g REM sleep is triggered b y t h e caudal third of
t h e locus ceruleus [ 1 4 ] . The importance of p o n t i n e
structures in modulation of muscle t o n e in h u m a n s
during REM sleep has b e e n s u p p o r t e d by the findings
i n a b o y with a p o n t i n e g l i o m a whose REM s l e e p was
characterized by lack of muscular atonia [ 3 ] . Additionally, a patient with a microglioma of t h e u p p e r
brainstem and t h e walls a n d floor of t h e third ventricle developed horizontal and vertical gaze abnormalities, narcolepsy, and cataplexy [ 11.
F u r t h e r clinical evidence for brainstem involvem e n t i n Niemann-Pick disease is provided by o u r
two patients, b o t h of w h o m have supranuclear vertical gaze paresis. Although vertical gaze pathways
have n o t b e e n clearly defined [lo], t h e relatively
normal pursuit and t h e intact vestibuloocular reflexes
i n our patients suggest intact medial longitudinal fasciculus pathways. Intact medial longitudinal fasciculus pathways i n the p r e s e n c e of vertical saccadic
paralysis with intact horizontal saccades implies dysfunction i n structures lying in t h e area of t h e
mesencephalic-diencephalic junction [2, 221. Al-
though involvement of the brain is quite general in
most of the lipidoses, the occurrence of relatively
localizable dysfunctions such as cataplexy or vertical
gaze paresis suggests that there are some areas of
predilection.
T h e seven cases summarized here represent the
first report of an association between cataplexy and
variant forms of Niemann-Pick disease. In the patients for whom data are available, the onset of
cataplexy ranged from before the onset of other
overt neurological involvement due to the storage
disorder (Patient 4 ) to a maximum of six years following the onset of neurological involvement (Patient 6).
T h e entity most likely to be confused with cataplexy in patients with degenerative diseases is the
akineticlatonic form of epilepsy [2 11. In our patients
(Nos. 1 and 2), epilepsy was excluded: their interictal
EEGs did not show spikes or spike waves; there was
no interruption of consciousness; the attacks were
overwhelmingly precipitated by strong emotion, and
they were cured with protriptyline rather than with
anticonvulsants. In Patient 1 (Figs 1, 2) the cataplectic nature of the attack was confirmed by EEG
telemetry. Other than their storage disorder, none of
these seven patients has had a process involving the
brainstem that could cause cataplexy. The possibility
of ictal laughter must also be raised with Patient 3
because he is said to have had laughter followed by a
brief loss of consciousness. In the absence of
telemetry, it is hard to evaluate this report of loss of
consciousness because of the patient’s associated dementia. As in our Patient 1, a severe deficit of
short-term memory and the blank expression (or inability to move) associated with loss of tone can simulate both amnesia and unconsciousness. In addition, the EEG of Patient 3 is not reported to have
shown the spike-wave abnormality or hypsarrhythmia one would expect if his episodes represented
ictal laughter preceding an epileptic flexion spasm
r 111.
It is easier to differentiate cataplexy from epilepsy
when the other components of the narcolepsycataplexy tetrad are present. However, cataplexy can
occur alone, and perhaps some of these patients have
the rare disorder of isolated cataplexy [17]. Patient 1
has an equivocal history of excessive daytime sleepiness (sleep attacks) but does not appear to have had
hypnagogic hallucinations or sleep paralysis. Polysomnography showing sleep-onset REM periods,
however, has confirmed his diagnosis of narcolepsy
[ 2 0 ] , and the occurrence of rhythmical nocturnal
myoclonus has strengthened his diagnosis of a sleep
disorder [ 7 , 201. It is interesting that several other
patients with Niemann-Pick variants have had disordered sleep [ l S , 2 4 ) although only the ones dis-
cussed in this report appear to have had cataplexy as
well.
The gradually dementing nature of the NiemannPick variant makes it difficult to exclude the other
components of the narcolepsy-cataplexy tetrad in the
remaining patients described here. In narcolepsy,
cataplexy generally has its onset concomitantly with
excessive daytime sleepiness o r later, but it has been
known to precede the sleep attacks of narcolepsy by
as long as twenty years [16]. Akinetic episodes,
ptosis, slurred speech, flexion of the trunk, sudden
falls with upward deviation of the eyes refractory to
anticonvulsants, and episodic fatigue may be manifestations of cataplexy [16, 201. All these types of
episodes have been reported in patients with variant
forms of Niemann-Pick disease [9, 15, 241 and have
been referred to as seizures.
Differentiation of cataplexy from seizures is clearly
important in these patients because effective treatment for cataplexy currently exists. Imipramine has
been widely used in the past for treatment of cataplexy, but because of possible sedation and rapid development of tolerance to its anticataplectic effect, it
is now being supplanted by other agents such as
clomipramine [ 191 and, more recently, protriptyline
[ 181. y-Hydroxybutyrate appears to be a promising
agent for the treatment of narcolepsy-cataplexy but
must be given two to three times per night [GI. Development of a slow-release preparation may make
y-hydroxybutyrate a more practical therapeutic alternative.
Relationship betweeti These Cases atid the Types of
N ieniann-Pick Disease
Crocker [ 8 ] subdivided Niemann-Pick disease into
four forms (types A-D). Type E has recently been
added, and current reports emphasize the existence
of disease forms that d o not readily fit into the prese n t classification system. For Niemann-Pick disease
types A and B, the basic defect is a genetically determined deficiency of a lysosomal sphingomyelinase.
Niemann-Pick disease type C and the Wenger variant
show accumulation of sphingomyelin in the spleen
but not always in other tissues, and sphingomyelinase
activity is only moderately reduced. The greatest degree of uncertainty exists regarding the relationship
between Niemann-Pick disease type D and sphingomyelin metabolism. In this disorder, sphingomyelinase activity is normal or even increased. It is
mainly because of the increased amount of spleen
sphingomyelin and of certain other lipids that a relationship between this disorder and sphingomyelin
metabolism has been postulated at all.
The seven cases of cataplexy referred to in this report were observed in patients who were classified as
having Niemann-Pick disease types C or D , or the
Kandt e t al: Cataplexy in Niemann-Pick Disease
287
Neville o r Wiedemann variant forms. Additionally,
although our Patient 1 is of different ancestry, his
disease appears to resemble the Wenger variant most
closely, and we have classified it as such.
In all seven patients, cataplexy was associated with
progressive neurological disease and splenomegaly
and, with the important exception of Patients 5 , 6,
and 7 , with vertical supranuclear ophthalmoplegia. A
relationship to an abnormality of sphingomyelin
metabolism is indicated by the diminished tissue
sphingomyelinase activities of Patients 1, 2 , and 5
and by the greatly increased spleen sphingomyelin
level in Patient 5. Spleen sphingomyelin was not
measured in Patient 3 but was increased in other patients in the same series [ 151. Patient 4 is one of the
original Niemann-Pick type D cases. Histopathological findings in this patient were entirely typical, but
no lipid analyses or enzyme assays were performed
[9]. The clinical features of these patients are similar,
and in those patients for whom appropriate studies
are available, a disturbance in sphingomyelin metabolism is suggested by the reduced spingomyelinase activity or by the increased sphingomyelin content of the spleen.
The nosology of Niemann-Pick disease types C
and D and of the cases reported by Wenger [241,
Neville [ 151, and Wiedemann [ 2 5 ] remains unclear.
Wenger [ 2 4 ] has pointed out that the first four of
these groups of cases are similar; our report that
cataplexy occurs at least occasionally in all five groups
further strengthens this resemblance.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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