Cycloid psychoses – from clinical concepts to
B. E. Jabs
1, B. Pfuhlmann
1, A. J. Bartsch
2, M. G. Cetkovich-Bakmas
and G. Stöber
2 Department of Neuroradiology, Julius-Maximilians-University, Würzburg,
3 Department of Mental Health, Buenos Aires, Argentina
Received January 21, 2002; accepted February 9, 2002
The modern concept of cycloid psychoses is primarily based upon
the clinical delineation of their phenotypes according to Leonhard. By settling
the dilemma of Kraepelinean “atypical psychoses”, their description may be
considered one of the major achievements of clinical psychiatry in the last
century. In particular, this had been facilitated by the work of Wernicke and
Kleist. Albeit not yet generally recognized, cycloid psychoses have already
stimulated great efforts of research yielding remarkable results. In this article,
we elucidate the concept of cycloid psychoses and present recent findings
pertaining to their putative biological foundations. Finally, future perspec-
tives for the field of biological psychiatry are proposed fostering the heuristics
of Leonhard’s nosology.
Leonhard, nosology, cycloid psychosis, genetics, family study, elec-
trophysiology, functional neuroimaging.
The development of the concept of cycloid psychoses goes back to theproblem of “atypical psychoses” which arose from Kraepelin’s dichotomyof endogenous psychoses (Kraepelin, 1923). It concerned the classificationof psychoses, which could be assigned neither to dementia praecox nor tomanic-depressive illness. One strategy for a solution of this problem wasto broaden the concept of schizophrenia as inaugurated by Bleuler (1911).
* Most respectfully dedicated to Prof. Peter Riederer on the occasion of his 60th
Psychoses of the schizophrenic spectrum in Leonhard’s nosology
Schizophrenia was then thought to include lots of clinical conditions withentirely different cross-sectional symptomatology, long-term course and out-come, thus considerably reducing the heuristic value of the diagnosis. Further-more, reliable prognoses became impossible according to Bleuler’s concepts.
Inevitably, the idea was generated that there might be a nosologically
independent group of endogenous psychoses in addition to schizophreniasand manic-depressive illness. Based upon the previous work of Wernicke andKleist (Bartsch et al., 2000a; Leonhard, 1961, 1999), Leonhard further estab-lished the concept of cycloid psychoses. Rejecting nosological hybridisation,the independence of these psychoses was emphasized. Representing one ofthe three main groups in his subdivision of psychoses with “schizophreniform”symptomatology (Table 1), Leonhard meticulously elaborated on preciseclinical diagnostic criteria for cycloid psychoses.
Cycloid psychoses are subdivided into three subforms: anxiety-happiness
psychosis, excited-inhibited confusional psychosis and hyperkinetic-akineticmotility psychosis. The clinical pictures are polymorphous but neverthelesstypical in that they allow establishing the diagnosis of a specific subform formost cases just relying on the cross-sectional presentation of the syndrome. Ifthe differential diagnosis between the subforms is complicated in the acutecondition, careful observation of the course further facilitates a reliable diag-nosis of the given subsyndromes.
A phasic course with favourable outcome is one of the main characteristics
of cycloid psychoses. Primary deficit or genuine residual syndromes neveroccur in cycloid psychoses. However, repeated phases of cycloid psychosesmay at times result in a purely reactive diminution of psychic functioning.
Since cycloid psychoses do remit always completely, even if a given phasemay last for a long period of time, one must not misinterpret issues related tocoping strategies of the patients as indicating residuum formation.
Another general characteristic is the bipolar and polymorphous structure
of symptomatology. Mixed states with intrasyndromal bipolarity are not un-common. Sometimes symptoms from another subform can modify the clinicalpicture of a specific subsyndrome as well. However, considering the clinical
The cycloid psychoses
mood alterations from anxious
pictures as a whole with regard to their essential features a precise diagnosisof one subform is nearly always possible (Table 2). Only the diagnosis of acharacteristic subsyndrome allows for a valid classification as cycloid psy-chosis, a fact repeatedly emphasized by Leonhard. Therefore, the assembly ofdiagnostical criteria for a singular “cycloid psychosis” as proposed by Perrisand Brockington (1981) may be a hazardous over-simplification.
This holds true for the ICD-10 classification (WHO, 1991), too. In ICD-10,
cycloid psychoses are assigned to a broad spectrum of disorders, such as the“acute polymorphous psychotic disorders”, the schizoaffective or the schizo-phrenic psychoses. All of them are characterized by rather arbitrary criteria ofduration, no precise differentiation of symptom clusters and a lack of clearprognostic judgement (Harrow et al., 2000; Marneros et al., 2000; Peraltaand Cuesta, 1999). For these reasons, it still seems advantageous to useLeonhard’s original descriptions of these subforms as a diagnostic guideline ifone is considering the scientific evaluation of the cycloid psychoses.
The diagnosis of a cycloid psychosis may be of high significance with respectto therapeutical consequences. Clinical experience has demonstrated that thespecific subform may play quite a considerable role for the pharmacothera-peutic approach. The acute therapy of anxiety psychoses usually requires
neuroleptic medication, but additional use of anxiolytic substances consider-ably improves the symptoms including the paranoid ideas basing on seriousanxiety. The hyperkinetic expressive and reactive motions of the motilitypsychosis can be rapidly controlled by neuroleptics in most cases. The therapyof akinetic states is more difficult. Here, neuroleptics can possibly facilitatethe development of severe akinetic complications (often mistaken for a malig-nant neuroleptic syndrome) and may not prove beneficial. Thus, the man-agement of akinetic motility psychosis predominantly requires careful clinicalobservation and additional use of anxiolytic substances (Ungvari et al., 1994).
But it should always be kept in mind that the phases also remit spontaneously.
In the case of dangerous akinetic complications, electroconvulsive therapy(ECT) may become the therapy of first choice. Interestingly, Franzek et al.
(1994) noticed that 7 out of 9 patients subject to the development of a malig-nant neuroleptic syndrome suffered from a cycloid psychosis. In the pre-neuroleptic era, Neele (1944) had already stated that the majority of casescorresponding to Stauder’s lethal catatonias occur among patients sufferingfrom cycloid psychoses with severe and exhausting hyperkinetic and akineticfeatures – all of them with full recovery following convulsive therapy.
It must be stressed that these phasic and completely remitting diseases
do not require neuroleptic long-term medication although long-term medi-cation is frequently prescribed to these patients, unfortunately, due to“schizophreniform” symptomatology according to (Neo-) Schneiderian crite-ria. However, patients who are well in intervals between phases should notreceive such treatment because of the considerable risks for side effects ofsuch medications. Last but not least, an otherwise healthy patient may stillbe regarded as ill due to some of these side effects (Beckmann et al., 1992).
Although studies of sound methodological control are still lacking, clinicalexperience indicates that for the phasic repetitions prophylactic treat-ment with lithium or anticonvulsive agents may be superior to neurolepticmaintenance therapy. In his initial studies, Perris (1978) found neurolepticsfar less effective than lithium for prophylactic treatment of cycloid psychoses.
On the other hand there are indications that after an abrupt discontinuationof long-term neuroleptic treatment of cycloid psychoses the rate of relapsemay even increase (Albert, 1986). Though there is no sufficient experiencewith regards to potential benefits of atypical neuroleptics yet, there is someempirical evidence that they might offer distinct advantages compared totypical neuroleptics in terms of the side effects, especially in the acute phasetreatment.
Clinical significance and prognosis
Additionally to Leonhard’s own catamnestic studies (von Trostorff andLeonhard, 1990), Beckmann et al. (1990) have demonstrated excellent stabil-ity and prognostic validity of cycloid psychoses. In a prospective study theywere able to follow up 26 out of 31 patients originally diagnosed by Leonhardas suffering from a cycloid psychosis. In personal examinations as well as using
the Strauss-Carpenter-Scale they found no residual states after a period of4 years. All but two of the patients, who were actually in an acute phase oftheir cycloid psychosis, showed complete remission. The diagnosis of cycloidpsychoses proved to be stable and there were little shifts between thesubforms.
In a recent study (Jabs et al., in preparation), 33 patients with cycloid
psychoses reported significantly higher satisfaction with their global qualityof life (measured by the German version of the Lancaster quality of lifeprofile) than 44 patients suffering from schizophrenic psychoses according toLeonhard. In both groups the mean duration of illness was about 13 years.
Concerning outcome and social functioning, patients suffering from cycloidpsychosis also reached significantly higher scores in the Strauss-CarpenterOutcome-Scale and Global Assessment of Functioning (GAF-) Scale thanschizophrenic patients.
With regard to the aetiology of cycloid psychoses Leonhard (1976, 1999)already postulated a prominent role of somatic factors in these psychoses,which show only low familial loading. He reported a higher number of cycloidpsychoses among twins than expected by chance. Frequently, he could findlow birth-weight and other birth complications in the ill twin. Among thecycloid psychoses, high concordance rates (82%) were found only amongmonozygotic pairs with motility psychoses, but dizygotic index-twins withmotility psychoses all had a healthy partner.
Franzek and Beckmann (1998, 1999) replicated similar findings in a
systematic twin study including 47 same-sex twin pairs. In pairs with cycloidpsychoses, they found nearly the same concordance rate for monozygoticpairs (39%) as for dizygotic pairs (31%), reflected by a low heritability indexof 0.21. Remarkably, among the concordant monozygotic twins sufferingfrom any psychosis, motility psychosis was the only occurring type of cyloidpsychosis (2 out of 14 pairs), whereas the other subforms, anxiety-happiness-psychosis and confusional psychosis, represented the predominant diagnosis(8 out of 8 pairs) in discordant monozygotic pairs. In the latter, the ill twinsshowed significantly more frequent and more severe birth complications thantheir healthy co-twins. In concordant pairs with cycloid psychoses, the moreseriously ill twin showed more such complications. There findings stronglysuggest that hereditary influences – even when taking in account some geneticliability in motility psychosis – play a subordinate role in the aetiology ofcycloid psychoses, whereas somatic influences seem to be of remarkableimportance.
Low heredity in patients with cycloid psychoses – originally described in
Leonhard’s series (1999) – was further substantiated by a recent family studywhich has been performed satisfying recent methodological standards bypersonal interviews of the relatives by an experienced psychiatrist blind to thediagnosis of the index cases (Pfuhlmann et al., in preparation). The morbidityrisk of first degree relatives was evaluated in 45 index cases with cycloid
psychoses, 32 with manic-depressive illness, and 27 healthy controls. Out oftotal of 431 first-degree relatives 353 could be traced and evaluated (82%).
Whereas 24.4% of the 45 index cases with cycloid psychoses had at leastone first-degree relative with an endogenous psychosis, the percentage was62.5% in the 32 manic-depressive probands and 14.8% in the control group.
The corresponding cumulative risk for first-degree relatives to suffer from anendogenous psychosis was 10.8% in cycloid probands vs. 35.2% in manic-depressive probands (p Ͻ 0.001) and 5.7% in the control group. The latterrate was insignificantly different from cycloid psychoses. These data contra-dict the thesis of a bipolar affective spectrum and corroborate the nosologicindependence of the cycloid psychoses. This corresponds to earlier observa-tions of a morbidity risk of 5.1% for parents, and 4.1% for siblings (Leonhard,1999).
The aetiological importance of exogenous factors, such as exposure to
gestational infections and other obstetric complications was the focus ofseveral earlier investigations (Maj et al., 1990; Beckmann and Franzek, 1992;Stöber et al., 1997; for review: Franzek and Beckmann, 2000). Seasonalityof birth in cycloid psychoses succeeding exposure to annual peaks of acuterespiratory infectious diseases in the general population was followed bystudies on individual exposure to maternal gestational infections in probandswith cycloid psychosis. Mothers of patients with cycloid psychoses had suf-fered from infectious diseases, particularly influenza and common cold withfever, predominantly in the first trimester of gestation. This contrasted to asignificantly increased exposure to mid-gestational infectious diseases inpatients with systematic schizophrenias, which show no essential heredity intheir aetiology as well. In cycloid psychoses other obstetric complications onlyshowed an insignificant increase compared to controls and seemed to be ofno influence on the age at the onset. This was opposite to subtypes with highgenetic loading, like manic-depressive illness or unsystematic schizophrenias,which show no association with any exposure to gestational infections contra-dicting the double-strike hypothesis of genetic loading and perinatal adverseevents in the aetiology of familial endogenous psychoses (Stöber et al., 1993).
An interesting hint towards the triggering of cycloid psychoses was dis-
covered by a catamnestic study on 39 postpartum psychoses (Pfuhlmannet al., 1998). Here, 54% of the postpartum psychoses turned out to be cycloidpsychoses (57% of the latter being motility psychoses), clearly predominatingunipolar depressive psychoses (8%), manic-depressive illness (13%), and un-systematic schizophrenias (10%) after a mean follow-up of 12.6 years.
An other activating factor for cycloid psychoses may be deduced from a
study by Althaus et al. (2000), who determined the menstruational phase in155 women at the time of admission to the clinic due to an acute non-organicpsychiatric disease. Generally, there was no significant difference betweennon-psychotic diseases and endogenous psychoses, but women sufferingfrom cycloid psychoses were significantly more frequently admitted to hospi-tal during the luteal-/menstrual phase than patients with schizophrenia.
This may point to an endocrinological factor in the exacerbation of cycloidpsychoses.
Studies of event-related potentials revealed distinct characteristics in cycloidpsychoses (Strik et al., 1996). Significantly higher amplitudes for the P300were reported among patients with cycloid psychoses than for age- and sex-matched controls. Both, cycloid psychoses and controls showed a dislocationof the mean P300 peak away from the midline towards the left hemispherewhereas in schizophrenic patients P300 peaks were located within the righthemisphere. Moreover, in schizophrenics amplitudes were significantly lowerthan in cycloid psychoses and slightly lower than in controls. During perfor-mance of a simple cognitive task (standard oddball paradigm) patients withcycloid psychoses did not exhibit signs of abnormal functional asymmetry ofcerebral function as did schizophrenic patients. The right-lateralised peaks inschizophrenics correspond to reduced left hemispheric amplitudes and arepossibly related to structural and functional abnormalities of the left temporallobe.
Franzek et al. (1996) found significantly more cycloid psychoses among pa-tients with non-specific abnormalities in their cranial computertomographies(cCT), which resulted most plausibly from pre- or perinatal brain damageaccording to the judgement of an independent neuroradiologist, than amonga matched control group of psychotic patients without cCT – abnormalities.
These findings corresponded well with preliminary cCT- and magnetic reso-nance imaging studies (Becker et al., 1995; Falkai et al., 1997) and the resultsof studies mentioned above, which indicated disturbances in early phases ofthe development of the central nervous system.
Although the described structural abnormalities cannot be viewed as spe-
cific for cycloid psychoses, it can be hypothesized that somatic influences suchas gestational infections during the vulnerable first trimester may disturb thedevelopment of structures within the central nervous system.
Recently, Jabs et al. (2001) employed neuro(ultra)-sonography as a tool
for imaging brain parenchyma to test for differences in the susceptibility toneuroleptic induced parkinsonism related to the echogenicity of the substan-tia nigra in 79 patients classified according to Leonhard. Here, cycloid psycho-ses displayed a significantly larger echogenic area of the substantia nigra thanpatients with systematic schizophrenia and healthy controls. Echogenicity ofthe substantia nigra was not correlated to the lifetime intake of neurolepticagents as estimated by the duration of illness. Generally, a significant correla-tion between echogenicity of the substantia nigra and severity of neurolepticinduced parkinsonism could be demonstrated indicating a link to the suscep-tibility for severe neuroleptic-induced side effects or severe akinetic states inthe cycloid psychoses (Franzek et al., 1994).
There have yet been few but two neuroimaging studies explicitly investigatingfunctional correlates of cycloid psychoses, i.e. global and regional cerebral
perfusion at rest (Warkentin et al., 1992; Bartsch et al., 2001; Köck et al.,2001). Warkentin et al. (1992) measured mean hemispheric blood flow and itsregional distribution in acute phases of cycloid psychoses as well as after oneweek of treatment and finally at discharge by 133Xe-inhalation cerebrography.
Their results suggested a global “hyperactivity” during the phasic occurrenceof cycloid psychoses favouring occipital on cost of frontal perfusion, particu-larly on the right side of the brain. On average, initial hyper-perfusion of bothhemispheres at admission was found to decrease within a week by more than10% and in seven out of eight patients under neuroleptic treatment. There-after, cerebral perfusion did not differ significantly from discharge (n ϭ 4) andcontrol subjects (n ϭ 39).
However, an ongoing study at the University of Würzburg (Bartsch et al.,
2001; Köck et al., 2001) using 99mTc-HMPAO-SPECT did not yet yield anyevidence for acute elevations of the global perfusion estimator in neithercycloid psychoses (n ϭ 8) nor hebephrenias (n ϭ 7). Differential diagnoses ofnon-systematic schizophrenias according to Leonhard as well as the medica-tion history may be crucial in these regards. In contrast to chronic schizophre-nias, some cases of cycloid psychoses may present an “acute hyperfrontality”which is redistributed to occipito-temporo-parietal areas upon their treatmentand remission. Notably, statistical parametric mapping revealed correspond-ing extrastriate clusters of significantly decreased cortical perfusion in acuteas compared to (partially) remitted stages of the cycloid illness. Significantlyincreased perfusion was observed in the right dorsolateral prefrontal cortex,the mesocortical cingulum and along the induseum griseum as well as withinsubcortical regions extending from the ventral and dorsal pallidum to theanterior thalamus. This warrants to reconsider traditional notions about func-tional brainstem alterations attributed by cycloid psychoses by Kleist (1928/1974).
In comparison to hebephrenias at admission as well as at their discharge,
acute cycloid psychoses presented a significantly pronounced perfusion of theleft dorsolateral prefrontal cortex and within the anterior cingulum. Interest-ingly, the latter survived a small volume correction centred on the Talairachspace coordinates given by Liddle et al. (1992) for maximum positive correla-tion with “schizophrenic disorganisation”. Moreover, cycloid psychosesexhibited a significantly steeper decrease of perfusion than hebephreniasaccording to Leonhard in the dorsolateral prefrontal cortex bilaterally, alongthe corpus callosum and in the right anterior cingulum from admission todischarge. Again, the latter survived a small volume correction centred onthe Talairach space coordinates given by Liddle et al. (1992) for increasing“schizophrenic disorganisation”. Therefore, this “hypercingularity” is eithernon-specific or even pseudo-schizophrenic in nature.
Differential treatment and prophylaxis
Since controlled studies on acute pharmacological treatment and long-termprophylaxis of cycloid psychoses have not yet been conducted, there is an
urgent need to perform such prospective and appropriately designed studiesbased on Leonhard’s criteria with further differentiation into the subtypesmotility psychosis, confusional psychosis, and anxiety-happiness-psychosis.
The efficacy of atypical neuroleptic agents, benzodiazepines and electrocon-vulsive therapy should be tested. Considering the observations of potentiallydisadvantageous effects of neuroleptics in the prophylaxis of cycloid psy-choses (Albert, 1986), the application of these drugs and especially of atypicalneuroleptics should be compared with lithium and anticonvulsive agents inlong-term studies. At the same time, it would be very interesting to detectfurther somatic (e.g. endocrinological or biorhythmic) factors, which mighttrigger the psychosis, similar to the mentioned effect of delivery.
The finding of an elevated echogenicity of the substantia nigra in cycloidpsychoses (Jabs et al., 2001) should be replicated with a larger sample and,then, could be the basis to examine patients with severe akinetic episodesby transcranial ultrasonography to establish a potential screening method forthese severe complications.
Since altered echogenicity in brain parenchyma seems to be caused by an
accumulation of minerals, esp. iron (Berg et al., 1999), this question could beanswered by other in-vivo imaging techniques. Unfortunately, T2*-weightedmagnetic resonance imaging and spectroscopy are difficult to perform accu-rately in these regions of the brain due to the proximity of the bony as wellas air-containing skull base as well as to pulsation of the cerebrospinal fluid.
Analogies to an impaired iron homeostasis in Parkinson’s disease (Double etal., 2000) and psychotic disorders have already been pointed out and discussedin terms of a glutamatergic-dopaminergic imbalance in the brain (Riederer etal., 1992).
This trace could also be followed in terms of functional abnormalities in
the glutamatergic, dopaminergic, serotonergic, and GABA-ergic neurotrans-mission, aiming to reveal possible dissimilarities between bipolar affectivepsychoses, schizophrenias, and cycloid psychoses.
So far, computerized neuroimaging has not yet employed voxel-,deformation- or tensor-based morphometry to address the issue of structuralcerebral deviations in cycloid psychoses. These may complement and extendprevious morphometric findings in areas of interest.
In terms of functional neuroimaging, future investigations will have to
segregate medication effects and incorporate psychometric such as Liddle’ssyndromatic dimensions (e.g. Liddle, 1995) in order to differentiate effectsrelated to the nosological categorization from other phenomena. Anatomi-cally guided a priori hypotheses may be derived electrophysiologically, e.g.
from altered NoGo-anteriorisations and the variance of functional imagingparameters may be reduced by accounting for genetic modulation effects(Bartsch et al., 2000b; Fallgatter et al., 1999). Cycloid psychoses await further
functional differentiation not only from non-cycloid forms but also from eachother. In addition, the various poles of cycloid psychoses are likely to repre-sent different conditions of functional segregation and integration.
Emerging evidence has pointed towards a phasic hyperfrontocingularity
of cycloid psychoses. This emphasises their differentiation from schizophre-nias that have been characterized by a variable degree of hypofrontocin-gularity (Blackwood et al., 1999; Blakemore and Frith, 2000). Any diagnosticoverlap between schizophrenias and cycloid psychoses should be avoidedas much as the construction of conceptual hybrids such as “schizoaffectivepsychoses”. Artifactual and inconsistent nosological stipulations are likely togenerate contradictory functional assumptions.
The cycloid psychoses appear as complex human diseases which involve mul-tiple genetic and environmental determinants. Thus, major gene effects (as inperiodic catatonia) will be unlikely to be established. To successfully searchfor susceptibility genes in families with increased incidence of the phasiccycloid psychoses, large sets of small to medium sized, multiply affectedfamilies or affected sib-pairs would have to be recruited in subgroups withincreased familial incidence. On the other hand, the hypothesis of neuro-development disturbances in cycloid psychosis may be a focus of DNAmicroarray analyses to assay gene expression levels in postmortem braintissue of patients who had suffered from cycloid psychoses. Recent studies inchronic schizophrenia pointed to dysregulations of myelination-related genesin schizophrenia. Additionally, genes involved in GABA signalling, signaltransduction, transport function as well as numerous large brain proteinsshowed aberrant expression patterns (Hakak et al., 2001; Mirnics et al., 2000).
Thus, case-control and family-based association analyses of candidate geneswith functional polymorphisms may be suitable to detect genes with relativelysmall albeit significant contribution to the disorder.
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V O L U M E 2 7 ⅐ N U M B E R 2 6 ⅐ S E P T E M B E R 1 0 2 0 0 9Phase III Randomized Study of Bendamustine ComparedWith Chlorambucil in Previously Untreated Patients WithUniversity Hospital, Jena; DSH Statistical Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin
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