What is etiology of a disease

Interactive Models

To treat BPD, we need to know what causes it. But this complex disorder has no single cause, but a range of interacting risk factors. BPD has a complex etiology that is both multifactorial and biopsychosocial. Claims for the discovery of single risk factors that account for the disorder, from neurotransmitters to trauma, have all fallen short. Some risks have a statistical relationship to outcome, but none, by themselves, necessarily lead to BPD.

In this way, BPD resembles most psychiatric diagnoses, which do not resemble acute medical disorders with one major cause, but chronic disorders (such as arteriosclerosis or hypertension) with many causes. The search for a single etiological agent in medicine is based in part on past successes in infectious disease. It has also been influenced by a hoped-for future success in mapping the genome. But in mental disorders, such as schizophrenia, that have been carefully studied with genome-wide association studies (Schizophrenia Working Group of the Psychiatric Genetics Consortium, 2014), genetic effects reflected small contributions from over a hundred gene variants.

Even if we knew the location of genetic risk for any diagnosis, mental disorders usually arise from interactions between genes and environment. Simple Mendelian inheritance rarely applies to psychiatry. One can have a genetic risk, yet never develop a disorder, if the environment is favorable (Rutter, 2006).

Similar problems arise from claims that BPD arises from adverse environmental events in childhood. Yet even after a severe trauma, only a minority goes on to develop lasting symptoms time (McNally, 2003). Since the 1990s, widely publicized claims appeared in the literature stating that child abuse is the main cause of BPD (e.g., van der Kolk, 2014). This is a classic example of confusing correlation with causation. First, although many BPD patients are more likely to have experienced severe child sexual and/or physical abuse, more have not (Paris, Zweig-Frank, & Guzder, 1994a,b). Second, most people who have been abused during childhood do not develop BPD or any other major mental disorder (Fergusson & Mullen, 1999). The explanation lies in gene–environment interactions. Child abuse is a risk factor for BPD, but not the main cause. The combination of a vulnerable temperament and an adverse environment is most likely to lead to the development of this disorder.

As Ciccheti and Rogosch (2002) have emphasized, the pathways to mental disorder in adulthood reflect both equifinality and multifinality. In other words, different risk factors can produce the same result, and one risk factor can lead to many different outcomes. Thus, there is no linear pathway from any factor to any disorder, only an increase of risk. Moreover, even temperamental factors that increase risk in an adverse environment may be associated with superior functioning in a positive environment, a phenomenon termed differential susceptibility to the environment (Belsky & Pluess, 2009).

Another reason why there is no definite correspondence between risk and outcome is the ubiquity of resilience. The factors shaping resilience to adversity, which reflect both temperament and environment, often determine whether adverse circumstances lead to a positive or negative outcome (Rutter, 2006).

In summary, etiological factors in mental disorders are not single and determinative, but multiple and interactive. BPD is one of the best examples of this model.

Sporadic Adult-Onset Ataxia of Unknown Etiology

SAOA is a sporadic adult-onset ataxia disorder. It is clinically distinguished from MSA by the lasting absence of parkinsonism and severe autonomic failure. Epidemiological studies and clinical case series suggest that SAOA occurs with twice the frequency of MSA. An epidemiological survey in Wales found a prevalence of 8.4 in 100 000.

The etiology and pathogenesis of SAOA are unknown, and there is only limited knowledge of the neuropathology of this disorder. The few available autopsy studies suggest that the degeneration mainly affects the cerebellar cortex with or without involvement of the inferior olives. This degeneration pattern was previously designated as late cerebellar cortical atrophy. GCIs are not found in SAOA brains.

SAOA begins around the age of 50 years and affects men more frequently than women. Clinical presentation is characterized by progressive cerebellar ataxia accompanied by signs of peripheral neuropathy and pyramidal tract dysfunction in half of the patients. At first presentation, the differentiation between MSA-C and SAOA is often impossible. However, the more benign course and the absence of severe autonomic failure and parkinsonism allow differentiation of SAOA from MSA. The majority of SAOA patients are still ambulant 10 years after onset of ataxia. Median survival ranges from 20 to 25 years, resulting in an almost normal life expectancy. On MRI, SAOA patients usually have isolated cerebellar atrophy with little or no involvement of the brain stem. Currently, there are no treatment options for SAOA.

Certain Etiologies Have an Increased cEEG Seizure Risk

Etiology helps to determine the risk for seizure on cEEG, with a few etiologies dramatically overrepresented. Multiple studies of consecutive series of cEEG patients have reported increased seizures in patients with ischemic stroke, intracranial hemorrhage, central nervous system (CNS) tumors, traumatic brain injury (TBI), CNS infections/inflammation, and anoxic brain injury. This is certainly not all the etiologies that present with cEEG seizures, but this list represents the highest incidence etiologies. It is also important to combine the etiology with the other primary risk factor of a change in mental status (as described in the previous section). For example, in a patient with a right MCA stroke presenting in a comatose state, the nondominant hemisphere stroke itself is not enough to explain the complete loss of consciousness and this needs to be investigated on cEEG with a high-risk etiology (stroke) and high-risk mental status (coma).

Clinical presentation

SAOA patients typically present with ataxia of gait and stance. Most patients have ataxia of their upper extremities with decomposition of movement, dysmetria, dysdiadochokinesis, and action tremor. However, prominent tremor is rather unusual. An abnormal heel–shin test with hypermetria and ataxic performance is an almost universal finding in SAOA patients. In addition, SAOA patients usually have an ataxic speech disorder and oculomotor abnormalities (Harding, 1981; Klockgether et al., 1990; Bürk et al., 2005). Oculomotor abnormalities consist of broken-up smooth pursuit, reduced optokinetic nystagmus, gaze-evoked nystagmus, saccadic dysmetria, and reduced suppression of vestibulo-ocular reflex (Fetter et al., 1994).

In a considerable fraction of SAOA patients, clinical examination reveals additional extracerebellar involvement. Harding (1981) observed pyramidal weakness in 31%, extensor plantar responses in 50%, absent ankle reflexes in 36%, and sensory loss in 25%. In the study of Bürk et al. (2005), pyramidal tract signs were present in 36%, reduced tendon reflexes in 18%, sensory loss in 18%, and decreased vibration sense in 64%. Abele et al. (2002) found pyramidal tract signs in 34%, decreased or absent ankle reflexes in 34%, and decreased vibration sense in 62%. Other neurological symptoms, including chorea, dystonia, and myoclonus, have been reported only rarely. Increased bladder frequency was reported by 33% of a group of 27 SAOA patients. Formal autonomic testing revealed mild autonomic abnormalities, mainly reduced heart rate variability, in 58% (Abele et al., 2007).

Harding (1981) found 28% of her patients demented. This comparably high rate was not confirmed in subsequent studies. In a detailed study of cognitive function of 67 SAOA patients, only mild and unspecific cognitive disturbances were found (Berent et al., 2002). In a group of 27 SAOA patients, Abele et al. (2007) reported Mini Mental State Examination scores ranging from 25 to 30 with a median of 29.

In summary, these studies consistently show that SAOA is a predominantly cerebellar disorder. Nevertheless, there is additional extracerebellar involvement in a considerable portion of SAOA patients. About one-third of SAOA patients have either polyneuropathy or pyramidal tract involvement. Cognitive impairment is not the rule, and, if present, only mild.

Etiology

The etiology of SE is either known (symptomatic) or unknown (cryptogenic).8 Symptomatic causes can be further defined as acute, remote, or progressive, according to the temporal relationship to the occurrence of SE. Common etiologies include cerebrovascular diseases, central nervous system (CNS) infections, neurodegenerative diseases, intracranial tumors, cortical dysplasias, head injury, alcohol-related, drug intoxication, antiseizure drug (ASD) withdrawal, cerebral hypoxia or anoxia, metabolic disturbances, autoimmune disorders, mitochondrial diseases, chromosomal aberrations and genetic anomalies, neurocutaneous syndromes, metabolic disorders, and other miscellaneous causes. Mortality is often higher with acute etiologies.

3.5 Chronic kidney disease of unknown etiology (CKDu)

CKDu occurs in epidemic in Sri Lanka [110]. It was first reported about a decade ago (year 2002) [111]. It commonly affects male agricultural workers and is said to lead to mortality in about 5000 individuals annually. They are usually asymptomatic at the outset but later develop progressive CKD and ESRD. Histology usually reveals tubular atrophy, and interstitial fibrosis.

These patients also are neither hypertensive nor diabetic. The cause is still unknown although Wimalawansa [112] has suggested that it may actually be CKD of multifactorial etiology. Several researchers have attempted to define the etiology; they have proposed hypothesis of water contamination with heavy metals, agrochemicals, ionicity, climate change, and so on. The levels of the heavy metals or pollutants have not been found to be different from that in normal individuals. However, other nephrotoxins prevalent in the region, including medications, infections, local or traditional herbs, hydrocarbons via use of petrochemicals, illicit alcohol and locally grown tobacco, and petrochemicals have not been extensively studied.

It has also been suggested that prevention seems to be the only plausible solution until the etiology(ies) is/are clearly defined. Some suggested solutions include (1) preventing environmental pollution, (2) avoiding use of toxic agrochemicals, (3) taking proper precautions when using agrochemicals and safe disposal of their containers, (4) encouraging behavioral modification in farmers to engender environmental preservation, (5) provision of clean potable water to all affected regions, and (6) use of environmentally friendly agrochemicals.

Etiology

The etiology of CP is extensive, ranging from prenatal and perinatal events to postnatal insults (Table 17-1).7,24–27 Hypoxic-ischemic encephalopathy represents only a small category within the neonatal encephalopathies and an even smaller contributor to the causes of CP. Nonhypoxia/asphyxia causes of CP are numerous and include cerebral dysgenesis, intrauterine infection,28 intrauterine growth restriction,29 preterm birth,30 coagulation disorders, antepartum hemorrhage,31 multiple pregnancies, abnormal presentations, neurometabolic diseases,32 chromosomal anomalies,33 selected polymorphisms,34,35 congenital abnormalities, and many others affecting either the mother or child.7 Despite the extensive list of potential etiologies, it is not unusual to fail to identify a clear etiology.

Criteria supporting an acute intrapartum hypoxic event sufficient to cause a CP event are presented in Boxes 17-1 and 17-2.36,37

Prevention and Treatment Strategies

Etiologies of IHD are varied in pathophysiology (atherosclerotic and nonatherosclerotic) and anatomy (obstructive, nonobstructive, and coronary microvascular dysfunction). While landmark clinical trials have guided development of many therapies for obstructive CAD with improvements in mortality, women and especially minority women have been underrepresented in major cardiovascular trials (Ouyang et al., 2016). There is limited knowledge on the optimal management for etiologies of IHD including MINOCA, INOCA, and CMD (Bairey Merz et al., 2017). Current therapeutic strategies are extrapolated from knowledge from primary and secondary prevention clinical trials including antiplatelet therapies, statins, angiotensin receptor blockers, ACE inhibitors, as well as therapies targeted at specific conditions such as coronary vasospasm including nitrates and calcium channel blockers in CMD (Bairey Merz et al., 2017). Further research into roles that sex hormones and sex-specific risk factors contribute to the pathogenesis of IHD in women can potentially lead to successful therapeutic choices.

Purpose of etiologic assessment

Etiology is the underlying cause of the epilepsy, and it should not be confused with epilepsy syndrome, which is an electroclinical entity. Etiology must be addressed from the moment the patient presents to the physician's care, as not only can it help achieve a more precise classification, but it can also fundamentally affect choice and response to treatment as well as overall prognosis. With advances in imaging and genetics seen in the past two decades, our understanding of the etiology and pathophysiology of the epilepsies has changed dramatically making the once used terms “cryptogenic,” “idiopathic,” and “symptomatic” obsolete. The ILAE has recognized six groups of etiologies of the epilepsies: structural, genetic, infectious, metabolic, immune, and unknown when an underlying cause could not be demonstrated (Scheffer et al., 2017). These categories are not hierarchic or mutually exclusive. The classic example is that of a patient with tuberous sclerosis whose epilepsy has both a genetic and structural etiology, the former being more important when giving genetic counseling or considering novel genetic therapies and the latter being key when discussing epilepsy surgery (Scheffer et al., 2017). The relative prevalence of each of these categories differs between resource-rich and resource-poor countries. In the latter, “preventable” causes of epilepsy such as traumatic, perinatal, and infectious disorders are more prevalent. Conversely, in resource-rich countries, most of the cases of epilepsy are currently not preventable (Camfield and Camfield, 2007).

Two population cohort studies in Nordic countries using the latest ILAE definitions (Aaberg et al., 2017; Sokka et al., 2017) have shown that the majority of children with epilepsy still have an unknown cause (43% in the Norwegian cohort, 65% in the Finish cohort). When etiology was known, the most frequent category was presumed genetic; metabolic and infectious causes were rare and none had immunologic causes. Genetic epilepsies are thus of particular interest to the pediatric neurologist. This group comprises epilepsies with known abnormalities (chromosomes, single genes, or multiple genes) but also those in which a genetic defect is inferred based on the family history (e.g., benign familial neonatal epilepsy, autosomal dominant nocturnal frontal lobe epilepsy) or suggested by population or twin and familial aggregation studies (Scheffer et al., 2017). Genetic and inherited are not synonymous as de novo genetic defects are frequent. It is also important to highlight that a genetic cause does not exclude an environmental contribution. The best-known example of an “epilepsy gene” is the SCN1A gene that codes for the alpha subunit of a neuronal voltage-gated sodium channel. Mutations in this gene are found in over 80% of patients with Dravet syndrome but are also associated with much milder phenotypes (e.g., genetic epilepsy with febrile seizures plus, GEFS +). This is a perfect example of the complexity of the genetics of epilepsy, as defects in this same gene, depending on their location, type, and whether they affect all cells of the body or just a part (Myers et al., 2018; Xu et al., 2015) (mosaicism), reflect on phenotype, response to treatment, overall prognosis, and risk of heritage.