Time and relative dimensions in syndromology: Towards endophenotypes in neurology,psychiatry and in-between

It is time to sing in the seat of the wise,

Of what at Urd’s Well I saw in silence,

saw and thought on.

Hávamál (Ancient Norse Sayings of Odin) – Translated by W. H. Auden & P. B. Taylor

One of the unique aspects of the finiteness of human existence is the role of religion, myth, history and narrative in our sense of personal identity. Accordingly, the effect of mental illness on the personal narrative is germane to the practice of psychiatry. Key to such consideration is the role of diagnosis and temporal progression of illness. Thus, like the Norse god Odin (who sacrificed an eye and much more for wisdom under the world-tree Yggdrasil), we should be informed in conceptualisation of mental illness by Hugin (thought) – diagnostic thinking – and Munin (memory) – understanding of the time course of diagnostic entities that represent illness.

The cognate medical fields of neurology, psychiatry and the liminal territory in-between have long been reliant upon syndromal diagnosis. Diagnosis on this basis may be considered as an iterative pattern-matching process with the ultimate aim of guiding further assessment and management. In some of neurological disorders, such as Huntington’s disease (HD), the aetiological foundation of the syndrome has been established, although the relationship between gene, structure, physiology and dysfunction needs further development. Such iterative investigations between levels of disease pathophysiology can be considered as efforts towards crafting endophenotypes, subsets of features cleaving more closely to underlying pathophysiology and, preferably, aetiology (Gottesman and Gould, 2003). In the hinterlands of neurology and psychiatry, idiopathic Parkinson’s disease (PD) remains essentially a syndromal clinical diagnosis relying upon history (including longitudinal course) and physical examination, albeit supplemented occasionally by further investigations in search of endophenotypes. The true shape of Loki (the protean Norse god) signifying disease will only reveal itself post-mortem, when we can determine the pathophysiological process, though as the renowned neuropathologist Kurt Jellinger once observed, ‘Most of you see the movie [of life] – I see only the final credits’ (Personal recollection JCLL). In psychiatric diagnoses, such as psychosis, the identification of symptom clusters is central, although there may in fact be subtypes that may lend themselves to endophenotypic characterisation and thus have associated clinical investigation findings as well as a more specific symptomatic-temporal progression. We seek to identify approaches to clinical syndromes from neurology, psychiatry and in-between that encompass phenomenology, clinical investigations and longitudinal course leading towards refining diagnoses.

Aetiology, pathophysiology and endophenotypes in neuropsychiatric disorders

The definitive diagnosis of HD necessarily involves genetic testing and assessment of aetiology. However, clinical diagnosis before this stage involves a comprehensive history and physical examination, supplemented by specific cognitive and neuropsychiatric assessments as well as neuroimaging. Even in a clearly genetic disorder, great effort has been made into defining a clinical phenotype encompassing the prodromal period through to the development of neurological and psychiatric features. For example, there has been evidence that compensatory motoric electrophysiologic processes in HD are correlated with the structural integrity of neurocircuits serving these functions (Turner et al., 2016). The development of such multi-level pathophysiologic measures may lead to the better characterisation of endophenotypes, such as corticostriatal circuit dysfunction leading to cognitive, motoric and emotional manifestations. However, the example of HD shows that such endophenotypes, in a condition with known aetiology and phenotype, defy substantive mapping.

Spatio-temporal course in neuropsychiatric disorders

In idiopathic PD, the clinical evolution of manifest movement disorder, autonomic dysfunction and neuropsychiatric features has long been used to stage disease progression. However, it has been recognised that the development of more comprehensive measures of disease progression that encompass more than the focus on manifest motor features to date is necessary for prognostication in this multisystem disorder (Poewe, 2009). The example of PD shows that endophenotypes are spatio-temporally moving targets and as such involve understanding of the progression of disease, in relation to the neural circuitry affected, the compensatory mechanisms at play, as well as the order in which this may commonly occur.

Applications in psychiatric disorders

The diagnosis of psychosis, and particularly the clinical subtype of schizophrenia, perhaps has begun to incorporate temporal course and perhaps to a lesser degree, clinical investigations in clinical practice. One of the pivotal problems for psychiatric diagnoses is in definition of a clinical phenotype, and in this schizophrenia is no different, with a diagnostic focus on clinical phenomenology such as hallucinations, delusions and thought disorder of a sufficient duration and persistence (American Psychiatric Association, 2013). The refining of a clinical phenotype is foundational to the development of and application of clinical investigations, and it is here there has been difficulty in discerning a signal in genetic, biochemical and neuroimaging investigations, although there have been advances in identifying neurocognitive and some neuroimaging endophenotypes. Currently, the role of the temporal course in diagnosis seems limited to the at-risk group or potential prodrome, the index qualifying episode and the number of subsequent relapses (American Psychiatric Association, 2013). The search for endophenotypes for what are regarded as cognate functional psychiatric disorders (anxiety, mood and bipolar disorders) will face similar problems as in neuropsychiatric conditions, that is, a pathophysiological validity and mapping spatio-temporally moving targets into endophenotypes.

Treatment and relationship with spatio-temporal course in neuropsychiatric diagnosis

The disorders grouped as frontotemporal lobar dementias (FTD) present with neuropsychiatric features that arise from spatio-temporal patterns of neurodegeneration, resulting in cognitive, emotional and motor dysfunctions that correspond to the presumed underlying neuro-pathophysiology (Mocellin et al., 2015). For example, patients suffering from the language variant FTDs have been found to have prominent atrophy of primarily left temporal lobar regions on magnetic resonance imaging (MRI) and display, on neuropsychological testing, fluent or non-fluent language problems, before manifesting frontal system dysfunction. Although the development of effective disease-modifying treatments remains a challenge, the accurate mapping of clinical manifestations along with temporal progression helps inform the staging of illness, and application of stage-specific symptomatic treatments, for example, SSRIs for frontal system mediated impulsivity, irritability, disinhibition and repetitive behaviours (Mocellin et al., 2015). Also, the spatio-temporal development in FTD can be partly predicted by the molecular protein pathology, that is, a phenotype, and thus may exemplify when the pattern of spatio-temporal development may constitute a valid endophenotype in itself.

Conclusion

Although it may seem as lofty as the upper reaches of Yggdrasil, the Norse world-tree, the effort to better characterise the phenotypes of neurological and psychiatric disorders is crucial task, no less so than to descry the progression of clinical course towards prognostication. The path we choose should be informed by careful four-dimensional mapping: definition of clinical characteristics, quantification of measurable manifestations using scales and clinical investigative technology, and tracking progression through temporal and spatial (neuroanatomic) course. Characterisation of valid endophenotypes will need all these four dimensions. Temporal progression may very well be one of the more informative aspects, especially in differential diagnosis. This will require sustained investment in terms of intellectual effort and research funding that can draw from and contribute to both neurology and psychiatry. Thus, through time and relative dimensions in syndromology, we can improve our understanding and treatment of neurologic, psychiatric disorders and disorders in-between, in order to better care for those suffering from mental illness.