NR ABWD
AU Brown,P.; Cathala,F.; Castaigne,P.; Gajdusek,D.C.
TI Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases.
QU Annals of Neurology 1986 Nov; 20(5): 597-602
PT journal article
AB In this consecutive series of 230 patients with neuropathologically verified Creutzfeldt-Jakob disease (CJD), the disease was found to affect men and women with approximately equal frequency in a peak plateau between the ages of 55 and 75 years (mean, 61.5 years). Familial cases accounted for 4 to 8% of the total series. Nonspecific prodromal symptoms occurred in one third of the patients, and the neurological presentation, although usually a gradually evolving mental deterioration, was of rapid onset in 20% of patients and in 36% of patients consisted exclusively of neurological symptoms. The great majority of these symptoms were of cerebellar or visual origin. Extrapyramidal muscular rigidity, myoclonus, and characteristic periodic electroencephalographic (EEG) complexes were observed comparatively late in the illness, and some type of involuntary movement or periodic EEG activity was seen in over 95% of the patients. The median duration of illness was 4 months (mean, 7.6 months); 90% of patients died within a year of onset.
VT
The series of consecutive cases that is the subject of this report consists of 230 patients with neuropathologically verified Creutzfeldt-Jakob disease (CJD), the largest collection of cases yet assembled in a single study of the disease. This concludes our clinical analysis of CJD that began in 1977 as a 10-year retrospective study [7] and that was continued through 1982 as a prospective study.
Materials and Methods
The population base for this study consisted of all resident citizens of continental France during the 15-year period between January 1, 1968, and December 31, 1982. A nationwide census taken in 1975 showed a population total of 52,365,960. Patient-finding methods described in our previous publication [7] yielded a total of 329 patients who died during the period of study, of whom 230 had neuropathologically verified CJD. We reviewed and abstracted the clinical and pathology records of each patient; in addition, we were able to review the electroencephalographic (EEG) tracings and neuropathology slides from all atypical or questionable cases, and to examine many of the living patients identified during the prospective phase of the study. The disease has been transmitted to primates using homogenates of frozen brain tissue from 29 of 30 patients.
Results
Numerical data for the total case series of 230 patients are presented in Tables 1 to 3 and Figures 1 and 2; here we supply additional clinical details, and, where appropriate, give interpretative emphasis.
Descriptive Summary
Fewer cases of CJD occurred in men than in women, but the male-to-female ratio of 0.83 was not significantly different from the general population ratio of 0.94 (p > 0.1, test of the normal approximation to the distribution of a proportion). Analysis of age-specific mortality rates according to sex did not reveal any significant differences between men and women (p >= 0.2, Pearson's chi-square test), although because of the female preponderance in older age groups of the general population, the mortality rate in females 65 years of age and over was actually lower than in males.
Definite familial cases accounted for 4% of the total series, and another 4% of the cases were possibly familial, but clinical or neuropathological information was insufficient to establish the diagnosis of CJD in other suspected family members.
Age at onset of illness ranged from 19 to 83 years (mean, 61.5 years); the mean duration of the illness was 7.6 months, and the median duration was 4 months.
Clinical Presentation
The prodromal symptoms that occurred in about one third of the patients consisted mainly of aesthenia and disturbances of sleeping and eating patterns, which usually began a few weeks before the onset of symptoms referable to the central nervous system. Most often, the prodrome merged gradually into a neurological syndrome, but 20% of patients experienced a rapid (or even sudden) appearance of neurological symptoms. Some form of mental deterioration occurred among the earliest symptoms in about two thirds of the patients, many of whom also described the coincidental onset of physical neurological symptoms. In about one third of the patients, the presenting symptoms were exclusively neurological, and mostly of cerebellar or visual origin: gait disturbance, clumsiness, diplopia, bizarre color perception, and generalized or hemianoptic loss of vision. Headache, vertigo, and sensory symptoms occurred less often, and other physical neurological complaints were rare; in particular, only 1 patient complained of involuntary movements at the onset of illness, and these were found to be choreoathetoid on examination.
Table 1. Descriptive Summary of 230 Consecutive Patients with Neuropathologically Veryfied Creutzfeldt-Jakob Disease
Number of patients: 230
Male-to-female ratio: 0.83
Familial cases (%): 4
Age at onset (years)
Range: 19-83
Mean (SD): 61.5 (9.7)
Prodromal symptoms (%): 36
Neurological debut (%)
Gradual (weeks, months): 80%
Rapid (sudden, days): 20%
Mental deterioration only: 41%
Neurological symptoms only: 36%
Mixed mental and neurological symptoms: 23%
Clinical evolution with triad of dementia, myoclonus, and 1-2 cycleslsecond EEG activity (%): 51%
Duration (months)
Mean (SD): 7.6 (12.4)
Median: 4.0
SD = standard deviation; EEG = electroencephalogram.
Clinical Course
Progressive mental and physical deterioration eventually terminated in the deaths of 90% of patients within a year of onset, and another 5% died within the next year. Most of the remaining 5% of patients with longer disease durations (up to 10 years) had clinical courses characterized by very gradually progressive mental deterioration, followed by a final stage of more rapidly evolving mental and physical disability typical of the subacute form of the disease. With advancing illness, the frequency of cerebellar and extrapyramidal signs (the latter most often manifesting as a lead-pipe type of rigidity) came to exceed that of pyramidal and visual signs; the typically late-appearing movement disorders (usually myoclonic) were observed in 91%, and periodic EEG activity (usually triphasic 1 cycle/second) was seen in 80% of all patients. Movement disorders ranged from tremors and ill-defined complex movements to classic chorea, athetosis, and hemiballismus.
Fig 1. Age at onset of illness in 230 consecutive patients with verified Creutzfeldt-Jakob disease. Solid bars represent patients during 1968 to 1977; cross-hatched bars represent patients during 1978 to 1982; open bars indicate total patients.
Characteristic periodic EEG complexes have been identified far more often in recent years than in the past, and together with a slight increase in the frequency of myoclonus, accounted for their combined occurrence in nearly three-quarters of patients in the prospective series, compared with only about one third in the retrospective series (and in half the total series). At least one of the features was seen in 93% of all patients.
Among the less frequent neurological abnormalities were a variety of oculomotor disorders, including 9 patients with supranuclear palsies (failure of convergence on upward gaze), isolated sixth nerve paresis, mydriasis, and ptosis. Sensory dysfunction consisted mostly of paresthesias, but a few patients experienced auditory, olfactory, or gustatory abnormalities of central origin. All types of seizures were observed -grand mal, petit mal, jacksonian, and even 1 case of epilepsia partialls continua. The category of vegetative dysfunction encompassed various unexplained hormonal and autonomic disorders of probably central origin, such as marked changes in appetite, thirst, libido, or menstruation, or recurrent episodes of hyperthermia, perspiration, or widely fluctuating vasotension.
Table 2. Symptoms and Signs on Clinical Presentation and During the Course of Illness in 230 Patients with Creutzfeldt-Jakob Disease
Symptoms/Signs Percentyge of Patients with Symptoms or Signs:
On Clinical Presentation During Clinical Course
Mental deterioration 64 100
Dementia 31 96
Behavioral abnormalities 29 49
Higher cortical function 15 47
Cerebellar 34 61
Visual 17 42
Oculomotor 6 16
Other 14 31
Vertigo 7 10
Headache 7 14
Sensory 5 11
Hypothalamic ("vegetative") 3 7
Pyramidal 2 43
Extrapyramidal 2 67
Muscular rigidity 0 51
Other 2 16
lower motor neuron 0.4 11
Seizures 0.4 8
Movement disorder 0.4 91
Myoclonus 0 88
Other 0.4 26
Periodic EEG activity 0 80
Triphasic 1 cycle/second 0 56
Slow-wave burst/suppression 0 32
Cranial nerve 0 0.4
Correlations
No particular "form" of illness could be correlated with the variables of age at onset, duration of illness, or familial versus sporadic forms of the disease. However, patients with exclusively physical neurological presentations tended to have rapid onsets and correspondingly short clinical courses; and the youngest patients tended to have the longest illnesses.
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Table 3. Percentage Frequencies of Various Combinations of Abnormal Movements and Periodic Electroencephalographic Activity During the Clinical Course of Disease in 230 Patients with Creutzfeldt-Jakob Disease
Combinations Myoclonus Myoclonus + Other Other Type No Type of
Only Type of Abnormal of Abnormal Abnormal
Movement Movement Only Movement Totals
"typical" 1-2 cps 32 12 1 3 48
EEG periodicity only
1-2 cps + other type 5 2 0 1 8
of EEG periodicity
Other type of EEG 15 6 1 2 24
periodicity only
No periodicity 13 3 1 3 20
Totals 65 23 3 9 100
cps = cycles per second; EEG = electroencephalogram.
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Discussion
In a previous paper [7], we compared our retrospective case series to the three principal nonoverlapping series published before 1979 [21, 28, 34]. One of these series (from Great Britain) has since been further enlarged [37], and additional sizable series have appeared from Chile [16] and Japan [29, 35]. There are no ready explanations for differences among the several studies in regard to sex ratio, familial incidence, and age at onset of disease; differences in the frequencies of other clinical features can often be attributed to varying analytical formats or symptom classifications. For example, the British researchers assigned all cases of muscular rigidity to a pyramidal category; the Chilean investigators grouped together a number of visual disturbances with origins in other parts of the nervous system; the Japanese group separated ataxia from cerebellar signs. Various concepts of staging the illness have led to differences in the figures given for the average duration of illness in some studies, but the comparative longevity of Japanese patients exceeds anything seen in the Western world: only 15% of patients died in less than 5 months, and the mean duration of illness was 17.5 months. Also, a large proportion of Japanese patients had panencephalopathic disease, with significant involvement of white as well as gray matter [22, 29, 38], a feature that has rarely been described in nonjapanese patients [24, 36]. The unusual transmission characteristics of many such cases [32] suggest that differences in virus strains may be responsible for these distinctive clinicopathological features.
On the whole, similarities far outweigh differences among the various series, and an appreciation of the spectral richness of CJD symptomatology has largely replaced the concept of various distinct "forms" of disease, including the transmissible subset of the Gerstmann-Sträussler syndrome, with mild to severe spongiform change associated with large numbers of cerebellar plaques [26, 33], and an even smaller transmissible subset of CJD patients with early amyotrophic signs [31].
Several clinical features of the disease merit emphasis. We have already pointed out that up to one third of patients may present with exclusively physical complaints, and up to 20% of patients may have a rapid, or even sudden, clinical onset [7]. Additional reports of sudden onset in patients with CJD have since been cited [14]. The importance of cerebellar or visual disorders in the early clinical picture has also been noted [4, 7, 10, 13, 17-20] and, as Bernoulli and colleagues correctly observed [3], may provide the initial clue to the differentiation of CJD from other dementias, notably Alzheimer's disease.
Although the presence of all three elements of the "diagnostic triad"-dementia, myoclonus, and periodic EEG activity-may be lacking in as many as 25% of patients, the combined absence of involuntary movements and periodic EEG activity is extremely unusual and virtually excludes the diagnosis from serious consideration.
Increased awareness of the nearly pathognomonic character of the repetitive, approximately 1 cycle / second, biphasic or triphasic EEG complexes, sometimes unilateral but eventually diffuse [1, 2, 12, 20, 30], has resulted in a correspondingly improved rate of detection. Recognition of these complexes nearly doubled between the retrospective and prospective phases of our own study (from 40 to 75%), and with serial tracings the typical pattern may be seen in over 90% of patients, as was found in a study of Chilean patients [12]. Visual, somatosensory, and brainstem auditory evoked responses [11, 20], radiological brain scans [15, 23, 37], and cerebrospinal fluids [34,35, 37] have not shown any characteristic changes during CJD, but when abnormal, can be extremely important in suggesting alternative diagnoses.
In 1979, Masters and associates [27] presented a classification of CJD that has been used in several sub-sequent studies to assess patients according to the degree of diagnostic certainty. The diagnosis is confirmed in patients whose brains transmit disease to experimental animals (transmitted CJD) or in patients whose brains show unequivocal spongiform change (neuropathologically verified CJD). From a consideration of our own results and the accumulated case material published within the past few years, we now propose a simplified schema for the clinical diagnosis of CJD (Table 4).
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Table 4. Criteria for the Clinical Diagnosis of Creutzfeldt-Jakob Disease in Patients with a Normal Metabolic Status and Spinal Fluid a
Degree of Multiple Neurological Abnormalities that Include
Diagnostic Any Type of
Certainty Mental Myoclonus 1-2 cycle/sec Movement Disorder Duration
Deterio- Periodic EEG or Periodic of Illness
ration Complexes EEG Activity (months)
Definite x and X and X <12
Probable X and X or X <18
Possible X and X <24
a If the clinical course includes the early appearance of cerebellar or visual symptoms and the eventual appearance of muscular rigidity, or if another family memher has died of histologically verified Creutzfeldt-Jaltob disease, the degree of certainty may be upgraded to the next higher category.
EEG a = electroencephalogram; X = condition present.
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Among the hundreds of demented patients brought to our attention over the past 15 years, no patient with a disease other than CJD has completely satisfied our criteria for "definite" CJD. In the category of "probable CJD, Alzheimer's disease is the major alternative diagnosis, and despite increasingly sophisticated laboratory evaluation (including brain scans), individual cases of progressive multifocal leukoencephalopathy, bilateral Ammon's horn atrophy, neuroaxonal dystrophy, reticulosarcoma, astrocytoma, and glioblastoma have also been mistaken for CJD. Patients with longer clinical durations have posed a difficult or impossible problem in differential diagnosis [9]: we have found fairly good imitations of long-duration CJD in several patients who on autopsy were found to have Alzheimer's disease (sometimes in association with Parkinson's disease or amyotrophic lateral sclerosis), and in individual cases of bilateral internal capsule hematomas, striatonigral atrophy, and diffuse cortical gliosis. A diagnosis of CJD can be confirmed in such patients by the identification of a specific protein in brain biopsy tissue [5, 6, 8, 25], but absence of the protein does not resolve the choice among other diseases; in this situation, the correct diagnosis cannot presently be established without neuropathological examination or experimental transmission of the disease to subhuman primates.
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Fig 2. Duration of illness in 230 consecutive patients with Creutzfeldt-Jakob disease. Solid bars represent patients during 1968 to 1977; cross-hatched bars represent patients during 1978 to 1982; open bars indicate total patients.
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We are most grateful to all members of the French neurological Community whose continued support was essential to this study, to Dr Richard Raubertas for statistical analyses, and to Dr Pamela Rodgers-Johnson for critical review of the manuscript.
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Received Dec 2, 1985, and in revised form Jan 30 and Mar 10, 1986. Accepted for puhlication Mar 11, 1986.
Address reprint requests to Dr Brown.
IN
Zwischen dem 1.1.1968 und dem 31.12.1982 wurden in Frankreich 230 Creutzfeldt-Jakob-Fälle neuropathologisch verifiziert. Bezogen auf ihre Anteile an der Bevölkerung und der verschiedenen Altersgruppen erkrankten Männer und Frauen gleich häufig an der Creutzfeldt-Jakob-Krankheit. 4% der Fälle waren sicher, weitere 4% wahrscheinlich familiär. Die klinischen Symptome begannen mit 19-83 Jahren, im Durchschnitt mit 61,5 Jahren. Die Krankheit dauerte im arithmetischen Mittel 7,6 Monate, der Median lag bei 4 Monaten. Der Unterschied kommt dadurch zustande, dass die meisten Patienten nach wenigen Monaten, einige aber erst nach vielen Monaten sterben.
Etwa ein Drittel der Patienten hatte bereits einige Wochen vor dem Ausbruch der Krankheit unspezifische Symptome wie Empfindungs-, Eß- und Schlafstörungen. Bei 80% der Patienten entwickelten sich die neurologischen Störungen langsam über Wochen oder Monate, aber bei 20% der Patienten entwickelte sich binnen Tagen neurologisches Syndrom. Bei 41% der Fälle wurden zunächst nur mentale Ausfälle, bei 36% nur neurologische Störungen und bei 23% von Anfang an beides beobachtet. Zu den anfänglichen neurologischen Störungen zählten Gehstörungen, Schwerfälligkeit, Doppeltsehen, bizarre Farbwahrnehmung, völlige oder Halbseitenblindheit. Kopfschmerzen, Schwindel und gestörte Tastempfindungen kamen seltener vor.
Der mentale und physische Verfall endeten bei 90% der Patienten binnen eines Jahres, bei weiteren 5% während des zweiten Jahres, bei den letzten 5% jedoch erst nach bis zu 10 Jahren. Bei den meisten sehr lange kranken Patienten nahmen die geistigen Fähigkeiten über lange Zeit nur sehr langsam, am Ende jedoch schneller ab.
In den späten Krankheitsphase überwogen Kleinhirn- und extrapyramidal-bedingte Ausfälle, die pyramidalen und im visuellen Cortex bedingten Probleme. Meistens entwicklte sich eine bleirohrartige Steifheit. Meist spät auftretende Bewegungsstörungen (in der Regel Myoklonien, aber auch Muskelzittern, ungenau definierte komplexe Bewegungen, unwillkürliche und häufig asymmetrische Bewegungen wie bei Chorea Huntington, langsame und bizarr geschraubte Bewegungen, sowie plötzlich und mit großer Kraft einsetzende Schleuderbewegungen mit Armen und Beinen) wurden bei 91%, periodische EEG-Aktivitäten (meist triphasisch mit 1 Zyklus pro Sekunde) wurden bei 80% der Patienten beobachtet.
Unter den weniger häufigen neurologischen Störungen waren Störungen der Augenbewegungen, Pupillenerweiterung und hängende obere Augenlieder. Fehlfunktionen der Sensorik zeigten sich meist als Paresthesia, aber einige wenige Patienten erlebten auch abnorme Hör- Riech- oder Geschmackseindrücke. Auch alle Arten von Anfällen (grand mal, petit mal, Jackson-Syndrom) und verschiedenste vegetative Fehlfunktionen (starke Änderungen bei Appetit, Durst, Libido, oder Menstruation, oder wiederholte Episoden von Fieber, Schwitzen, oder starke Blutdruckschwankungen) wurden beobachtet.
Keine bestimmte Form der Creutzfeldt-Jakob-Krankheit ließ sich abgrenzen anhand der Variablen Alter bei der Erkrankung, Dauer der Krankheit, oder sporadisch versus erblich. Allerdings tendierten Fälle ohne mentale Ausfälle zu plötzlichem Auftreten und kurzem Verlauf, während junge Patienten zu längeren Krankheitsphasen neigen. Die Autoren betonen, das man die Creutzfeldt-Jakob-Krankheit und zumindest die übertragbaren Formen des Gerstmann-Sträussler-Scheinker-Syndroms nicht in Klassen einteilen, sondern als ein breites Spektrum verschiedenster Varianten verstehen sollte.
Zwar wird die diagnostische Triade Demens, Myoklonien (kurze ruckartige Muskelzuckungen mit geringem Bewegungseffekt) und periodische EEG-Aktivitäten bei immerhin 25% der CJD-Patienten nicht beobachtet, aber man findet praktisch immer entweder unwillkürliche Bewegungen oder periodische EEG-Aktivitäten. Zumindest hat die zunehmende Aufmerksamkeit gegenüber den CJD-typischen, etwa sekündlich auftretenden bi- oder triphasichen EEG-Komplexen die CJD-Erkennungsrate erhöht.
MH Adult; Aged; Aged, 80 and over; Brain/*physiopathology; Creutzfeldt-Jakob Syndrome/genetics/*physiopathology; Electroencephalography; Female; France; Human; Male; Middle Age; Movement Disorders/physiopathology; Vision Disorders/physiopathology
AD Paul Brown (pwb@codon.nih.gov) und Gajdusek,D.C., Laboratory of Central Nervous System Studies, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; Cathala,F. und Castaigne,P., Departement de Neurologie, Hopital de la Salpêtrière, Paris, France
SP englisch
PO USA
OR Prion-Krankheiten 2