Journal Article Annotations
2021, 1st Quarter

Neuropsychiatry

Annotations by Brandon Francis, MD, MPH, Kontos, Nicholas
March, 2021

Psychiatric comorbidities in patients with psychogenic nonepileptic seizures
Clinical predictors of discordance between screening tests and psychiatric assessment for depressive and anxiety disorders among patients being evaluated for seizure disorders
Clinical differences between patients with psychogenic nonepileptic seizures and functional motor disorder
Role of the Nucleus Basalis as a Key Network Node in Temporal Lobe Epilepsy

PUBLICATION #1 — Neuropsychiatry

Psychiatric comorbidities in patients with psychogenic nonepileptic seizures

Ahmed Rady, Amr Elfatatry, Tarek Molokhia, Aya Radwan

Abstract: Epilepsy Behav. 2021 Mar 15;118:107918. doi: 10.1016/j.yebeh.2021.107918. Online ahead of print.

Background:
Psychogenic nonepileptic seizures (PNES) are major challenges for diagnosis and management. The heterogeneity of psychogenic seizures is attributed to diverse psychopathological comorbidities, and the causal relationship between PNES and underlying psychopathologies is still enigmatic.

Objective:
Our objective was to study psychiatric comorbidities and personality constructs in patients with PNES and compare them to a control group of patients with epilepsy.

Method:
We randomly recruited 33 patients with PNES and 33 patients with epilepsy. All patients completed the Mini-International Neuropsychiatric Interview (MINI) to screen for psychiatric comorbidities, the Structured Clinical Interview for psychiatric disorders in Axis II (SCID II) to screen for personality disorders, and Goldberg’s International Personality Item Pool (IPIP) Big Five personality questionnaire to study the psychological constructs of extroversion-introversion, agreeableness, conscientiousness, emotional stability-neuroticism, and intellect.

Result:
Mood and anxiety disorders were highly prevalent in patients with PNES (72.7% and 54.5%, respectively); however, the prevalence of only cluster B personality disorder was higher in patients with PNES (69.7%) compared to 33.3% among patients with epilepsy (p < 0.05). Screening for personality disorders using SCID II showed that the prevalence of borderline and depressive personality disorders was significantly higher in patients with PNES (p < 0.001). Patients with psychogenic seizures were more likely to be receiving polydrug therapy (75.8%) compared to patients with epileptic seizures (45.5%); this difference was statistically significant (p < 0.05).

Conclusion:
Psychiatric comorbidities are highly prevalent among patients with PNES.

Annotation

The finding:
Their primary goal was to identify and determine the frequency of psychiatric and personality disorders among patients with PNES compared to patients with epilepsy. The authors utilized video electroencephalopagraphy (vEEG) to identify patients with PNES. The Mini International Neuropsychiatric Interview (MINI) was used to identify psychopathology along with the Structured Clinical Interview for Axis II Disorders (SCID-II). The Goldberg’s International Personality Item Pool (IPIP) Big Five was used to assess personality pathology. All of psychometric tools were translated into Arabic, the primary language spoken by the participants in the study. The authors found that mood (73%) and anxiety (55%) disorders along with cluster B personality (69.7%) were more common in patients with PNES compared to those with epilepsy (p < 0.05).

Strength and weaknesses:
The authors cohorted the study group so that they were randomly recruited in an effort to minimize selection bias. This is a small sample size which risks identifying potentially spurious findings. The evaluation of personality disorders can take significant time and can requires significant collateral data which this study did not report utilizing. The study takes place in Egypt in a predominantly Arabic speaking population which can limit the generalizability of their results.

Relevance:
This cross sectional prospective study highlights the diagnostic challenges in trying to differentiate psychogenic non-epileptic seizures (PNES) from epilepsy. Patients with PNES have substantial psychiatric comorbidity that complicates diagnosis and management. Caring for patients with PNES comorbidities demands coordinated treatment by a multidisciplinary team.

Type of study:
Cohort study

PUBLICATION #2 — Neuropsychiatry

Clinical predictors of discordance between screening tests and psychiatric assessment for depressive and anxiety disorders among patients being evaluated for seizure disorders

Sarah Holper, Emma Foster, Michael Lloyd, Genevieve Rayner, Maria Rychkova, Rashida Ali , Toby T Winton-Brown, Dennis Velakoulis, Terence J O’Brien, Patrick Kwan, Charles B Malpas,

Abstract: Epilepsia. 2021 Mar 18. doi: 10.1111/epi.16871. Online ahead of print.

Objective:
This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder scale (GAD-7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study; rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment.

Methods:
Adult patients admitted for inpatient video-electroencephalographic monitoring completed eight psychometric instruments, including the NDDI-E and GAD-7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists’ diagnoses. Screening was “discordant” if the outcome differed from the psychiatrist’s diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance.

Results:
A total of 411 patients met inclusion criteria; mean age was 39.6 years, and 55.5% (n = 228) were female. Depression screening was discordant in 33% of cases (n = 136/411), driven by false positives (n = 76/136, 56%) rather than false negatives (n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases (n = 121/411, 29%) due to false positives (n = 60/121, 50%) and false negatives (n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient-reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group (n = 29, 47%) compared to the epilepsy group (n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65).

Significance:
Patients with seizure disorders who self-report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.

Annotation

The finding:
This study was not a validation study but rather was designed to detect discordance between screening tools [Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder (GAD-7) scale] and a clinical diagnosis by a psychiatrist in patients evaluated for psychogenic non-epileptic seizures (PNES). In the 411 patients evaluated, they found that about 1/3 of depression and anxiety screening was discordant compared to a clinical diagnosis. Those with PNES had a higher rate of discordance. Interestingly, most of the discordance was due to false positive screening results.

Strength and weaknesses:
These patients were all recruited from an epilepsy monitoring unit where they were admitted for video electroencephalography (vEEG). These patients often had polypharmacy complicating evaluation and management. This setting may limit generalizability; however, many psychiatric providers who encounter patients with PNES and/or epilepsy may work in similar settings. The robust sample of 411 patients strengthens the statistical analyses, although only 56% of patients were female. (Most studies that evaluate patients with PNES have a slightly higher female to male ratio.) The NDDI-E is not validated in patients with PNES which can impact the utility of the data. Additionally, the authors did not exclude patients with known cognitive limitations that can impact participants’ ability to accurately respond to questions that require at least a 4th grade reading level.

Relevance:
This study encourages clinicians to remain vigilant when evaluating patients with PNES and epilepsy for psychiatric comorbidities regardless of any screening test result. This patient population is complex and heterogenous. It is important to note that patients with more self-reported symptoms were more likely to be inaccurately represented by one of the screening tools used in the study.

Type of study (EBM guide):
Cohort study

PUBLICATION #3 — Neuropsychiatry

Clinical differences between patients with psychogenic nonepileptic seizures and functional motor disorder

Daniela Huepe-Artigas, Olivia L Carter, Shimaa K Morsy, Richard A A Kanaan

Abstract: Epilepsy Behav. 2021 Jan;114(Pt A):107577. doi: 10.1016/j.yebeh.2020.107577. Epub 2020 Dec 1.

Objectives:
Why a patient might present with psychogenic nonepileptic seizures (PNES) as opposed to another functional neurological symptom is unknown. A recent review suggested that patients with PNES and functional motor disorders (FMD) differ on demographic and clinical factors of potential aetiological and mechanistic significance, arguing they might represent different disorders, though direct comparisons are limited. We sought to determine whether these factors differed in patients presenting with FMD and PNES at our clinic, as well as whether preceding medical complaints would differ between the two, particularly those affecting the limbs or head.

Methods:
A retrospective chart review of all presentations with FMD or PNES patients to a functional neurology clinic, collecting demographic and clinical data, including medical and surgical history.

Results:
Fifty-six patients with FMD and 52 with PNES were included. Significantly more patients with FMD had functional somatic syndromes (46% vs 27%, p = 0.036) and preceding medical events that affected their limbs than patients with PNES (34% vs 14%, p = 0.013); significantly more patients with PNES had dissociative symptoms (31% vs 4%, p < 0.001) and lifetime suicidal ideation (56% vs 32%, p = 0.013).

Significance:
These results highlight the substantial comorbidities affecting FMD and PNES, but find clinical differences between the two groups that may be of aetiological or mechanistic significance.

Annotation

The finding:
This retrospective study of 56 patients with functional mood disorder (FMD) and 52 patients with psychogenic non-epileptic seizures (PNES) found that those with FMD were more likely to have somatic syndromes (46% vs 27%, p = 0.036) and medical events that included their limbs (34% vs 14%, p = 0.013). Patients with PNES were more likely to have suicidal ideation (56% vs 32%, p = 0.013) and dissociative symptoms (31% vs 4%, p < 0.001).

Strength and weaknesses:
The study design was retrospective in nature limiting the conclusions drawn from the data. This study was particularly susceptible to recall bias given symptoms were more likely to be recorded if both the physician and patient thought they were relevant at the time. It is also possible that patients engaged with the clinic through different pathways, such as from an epilepsy monitoring unit or from a primary care referral which can lead to selection bias. The study included approximately 50 patients in each functional group, which are challenging to construct given the stigma and diagnostic uncertainty in these disorders.

Relevance:
This study provides additional data that functional disorders are complicated, heterogenous, and require thoughtful evaluation. This study was essentially a follow up on a previous study by the same group (Kanaan R.A.A., Duncan R., Goldstein L.H., Jankovic J., Cavanna A.E.: Are psychogenic non-epileptic seizures just another symptom of conversion disorder?. J Neurol Neurosurg Psychiatry 2017; 88: pp. 425-429) and even the predictions from their previous study, in the same population, was not as accurate as the authors anticipated.

Type of study:
Retrospective cohort study

PUBLICATION #4 — Neuropsychiatry

Role of the Nucleus Basalis as a Key Network Node in Temporal Lobe Epilepsy

Hernán F J González, Saramati Narasimhan, Graham W Johnson, Kristin E Wills, Kevin F Haas, Peter E Konrad, Catie Chang, Victoria L Morgan, Mikail Rubinov, Dario J Englot

Abstract: Neurology. 2021 Mar 2;96(9):e1334-e1346. doi: 10.1212/WNL.0000000000011523. Epub 2021 Jan 13.

Objective:
To determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses.

Methods:
We acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing.

Results:
We observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures (r = -0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%).

Conclusions:
These results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder.

Annotation

The finding:
Functional connectivity was reduced between the nucleus basalis of Meynert (NBM) and broad neocortical regions in temporal lobe epilepsy (TLE) patients, including both ipsilateral as well as contralateral cortical regions (with respect to laterality of seizure onset) Decreases in connectivity were found between the ipsilateral NMB and frontoparietal cortex in TLE patients, and this decrease was greater in patients with a higher frequency of consciousness-impairing seizures but not in patients with a higher frequency of consciousness-sparing seizures. Further investigations using network modelling found that ipsilateral NBM connectivity abnormalities correctly differentiated patients from healthy controls.

Strength and weaknesses:
This was a fairly large study by functional neuroimaging standards, comparing 40 patients with TLE to 40 healthy controls. The diagnosis of TLE itself may challenging and this study also benefits from a confirmed diagnosis of TLE by a multidisciplinary group employing robust diagnostic data points. The authors note limitations primarily involving the heterogeneity of the patient population, which could not control for medication type or dosage, and included patients with differing epilepsy histories in terms of duration of epilepsy, the presence of generalized tonic-clonic seizure, and the presence of hippocampal sclerosis on MRI. This heterogeneity may limit generalizability to all TLE patients.

Relevance:
TLE is one of the classic disorders of C-L psychiatry, being a condition with a wide range of neuropsychiatric symptoms including acute disruptions of consciousness, psychosis, and interictal/chronic changes in mood, personality and cognition. However, the precise mechanisms by which TLE produces this array of symptoms has long been the subject of debate. The NBM may be viewed as a component of both the brainstem arousal network (ascending reticular activating system) as well as the limbic system, and pathology of the cholinergic neurons of the NBM is implicated in development of major neurocognitive disorders. The identification of the NBM as a significant node of abnormal connectivity in patients with TLE may have broad implications for further understanding the mechanism behind clinical symptoms observed in this population, particularly the subacute and chronic changes that often generate neuropsychiatric referrals and C-L psychiatry consultations.

Type of study:
Case control study