Topic 14.1. Literature review of prevalence of mental health issues in Friedreich ataxia

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

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The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

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These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
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14.1 Literature review of prevalence of mental health issues in Friedreich ataxia

Caroline Spencer, Alexandra Durr, George Wilmot, Susan Perlman and Louise Corben

Jennifer Farmer is acknowledged for much of the content of the literature review and overview of depression, taken from the previous version of the guidelines (2014).

While psychiatric symptoms are not part of the presenting or diagnostic clinical features of Friedreich ataxia (FRDA), published literature and clinical experience indicate that many individuals with FRDA experience depression, anxiety and associated mental health issues. Literature from the early 1900s suggests the presence of dementia and psychosis in individuals with FRDA. However, these reports were prior to clear diagnostic criteria and, in later publications thought to be complicated by misdiagnosis and selection bias (individuals reported were institutionalized and not a representative sample of individuals with the disease) (1, 2).

In a later study, Flood and colleagues (1) reported their clinical experience and a retrospective medical record review of 38 individuals who met the clinical diagnostic criteria for FRDA and attended the Ataxia Clinic at University of California Los Angeles. They found that whilst dementia and severe cognitive disturbances were rare, most (92%) individuals with FRDA had mood disturbances, ranging from a mild, grief-related, reactive depression to severe depression. They concluded that the depression was a consequence of living with a chronic, progressively disabling, neurological disease rather than being intrinsic to FRDA. This report elegantly reminds the clinician of the likely psychological impact of living with a disease that causes continual loss of abilities, loss of livelihood and loss of future. The authors further suggest that what are initially normal responses of grief and depression can become prolonged and clinicians need to consider that individuals with FRDA may be at an increased risk for major depression and suicide (1). Giordani and colleagues (2) also examined the psychological status of individuals with FRDA and reported significantly higher levels of anxiety, depression and social isolation than in controls. Both studies identified that FRDA not only affects the individual diagnosed with FRDA, but has a far-reaching effect on the entire family, particularly the burden and loss that they face over the prolonged course of the disease.

Others have also reported the frequency of affective disorders in small cohorts of individuals with FRDA (3-5). White and colleagues (4) reported neuropsychological and neuropsychiatric characteristics of 15 adults with FRDA (mean age 36.1 years). While finding some differences in performance on cognitive tests, there was no difference in mood disorders when screened with the Symptom Checklist-90 (SCL-90) and Hamilton depression scale compared to age-matched controls. A few of the subjects with FRDA did have a history of adjustment disorder with depressed mood. The authors specifically mentioned that one third of the individuals with FRDA demonstrated inappropriate jocularity during testing (4). Ciancarelli and colleagues (5) found that 29% of individuals with FRDA (24 adults) had mood disorders, mostly depression, when assessed for cognitive disorders with a neuropsychiatric battery.

Mantovan and colleagues (3) administered the Minnesota Multiphasic Personality Inventory (MMPI) to eight adults with FRDA and half of the individuals showed a profile outside the normal range. None of the control participants demonstrated similar profiles. The personality pattern of the individuals with FRDA was characterized by increased irritability, poor impulse control, or blunting of affect. In addition, those with FRDA had low scores on the MMPI K scale and negative dissimulation index suggesting reduced defensiveness and a poor self-presentation. The authors point out that the significant physical disability associated with FRDA and having an onset in childhood and adolescence may play a significant role in the development of personality or lead to maladaptive behavior observed in this profile (3). Despite being a small cohort, the results of this investigation provide a fascinating insight into the little investigated area of personality characteristics related to FRDA. Findings from a more recent study support the existence of specific personality characteristics in FRDA (6). The authors hypothesize that diagnosis of FRDA during the crucial period of adolescence could partly explain this specific personality development (6).

Studies examining cognitive function in FRDA screened participants with and without FRDA for depression using the Beck Depression Inventory (BDI). The first two studies (7, 8) demonstrated significantly greater scores on the BDI in 15 and 13 individuals with FRDA, respectively, compared to a similar number of individuals without FRDA. Two later studies (9, 10) did not show a significant difference in BDI scores between participants with FRDA and those without FRDA (n = 13 and n = 10, respectively).

An exploratory study of transitional life events in individuals with FRDA highlighted that the usual transitional events in a person’s life are exacerbated by the presence of FRDA. Moreover, such transitional events are accompanied by significant grief and loss associated with challenges to identify and self-esteem (11). As such it is not unusual to find a greater incidence of reactive depression in a cohort of individuals with FRDA compared to a control group. Indeed, one study has examined depression in individuals with FRDA in the context of neuroimaging (12). Twenty-two individuals with FRDA were screened for depression using the BDI followed by cerebral 3T MRI scans to examine volumetric differences between individuals with depression and those without. A little more than a third (36.3%) of individuals with FRDA fulfilled the DSM-IV criteria for major depression. Whilst this is higher than in the general population, it is similar to reports in other neurodegenerative diseases (12). There was no correlation between age, disease severity or disease duration and the BDI score. The MRI studies showed grey matter atrophy in the frontal lobe of depressed individuals with FRDA. In addition, the severity of depression correlated with atrophy in the right superior frontal gyrus. As discussed by the authors, whether the observed atrophy is due to long-term major depression or the neurodegenerative process of the disease cannot be ascertained (12).

Nieto and colleagues (13) surveyed 57 individuals with FRDA with the BDI and revealed significantly more depressive symptoms, as compared to a normative sample. Within the FRDA group, over half (59%) scored in the “minimal” range, while 19%, 18% and 4% scored in the “mild”, “moderate”, and “severe” ranges, respectively. Recently Perez-Flores and colleagues (14) surveyed 62 individuals with FRDA on health-related quality of life using the SF-36 Health Survey. Participants with FRDA scored significantly lower than the general population used for comparison on all domains of quality of life. The largest group differences were observed in the physical health and general health domains, with individuals with FRDA reporting significantly lower scores than the comparison group. Social and emotional dimensions were also significantly lower in individuals with FRDA, although differences from the comparison group were smaller. These findings remained significant even when taking age and gender into account, leading the authors to conclude that FRDA is associated with significant negative effects on quality of life, including physical, social, and emotional impacts.

Louise Corben, PhD
Principal Research Fellow, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

Alexandra Durr, MD, PhD
Professor of Neurogenetics, Sorbonne Université, Paris, France

Susan Perlman, MD
Clinical Professor of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Caroline Spencer, PhD
Postdoctoral Fellow, Boston University, Boston, Massachusetts, USA

George Wilmot, MD, PhD
Associate Professor, Department of Neurology, Emory University, Atlanta, Georgia, USA

1. Flood MK, Perlman SL. The mental status of patients with Friedreich’s ataxia. J Neurosci Nurs. 1987;19(5):251-5.

2. Giordani B, Boivan M, Berent S, Gilman S, Junck L, Lehtinen S, et al. Cognitive and emotional function in Friedreich’s ataxia (Abstract). J Clin Exp Neuropsychol. 1989;11(1):53-4.

3. Mantovan MC, Martinuzzi A, Squarzanti F, Bolla A, Silvestri I, Liessi G, et al. Exploring mental status in Friedreich’s ataxia: a combined neuropsychological, behavioural and neuroimaging study. Eur J Neurol. 2006;13:827-35.

4. White M, Lalonde R, Botez-Marquard T. Neuropsychologic and neuropsychiatric characteristics of patients with Friedreich’s ataxia. Acta Neurol Scand. 2000;102(4):222-6.

5. Ciancarelli I, Cofini V, Carolei A. Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapy. Funct Neurol. 2010;25(2):81-5.

6. Sayah S, Rotge JY, Francisque H, Gargiulo M, Czernecki V, Justo D, et al. Personality and neuropsychological profiles in Friedreich ataxia. Cerebellum. 2018;17(2):204-12.

7. Corben LA, Delatycki MB, Bradshaw JL, Horne MK, Fahey MC, Churchyard AC, et al. Impairment in motor reprogramming in Friedreich ataxia reflecting possible cerebellar dysfunction. J Neurol. 2010;257(5):782-91.

8. Corben LA, Delatycki MB, Bradshaw JL, Churchyard AJ, Georgiou-Karistianis N. Utilisation of advance motor information is impaired in Friedreich ataxia. Cerebellum. 2011;10(4):793-803.

9. Corben LA, Akhlaghi H, Georgiou-Karistianis N, Bradshaw JL, Egan GF, Storey E, et al. Impaired inhibition of prepotent motor tendencies in Friedreich ataxia demonstrated by the Simon interference task. Brain Cogn. 2011;76(1):140-5.

10. Corben LA, Georgiou-Karistianis N, Bradshaw JL, Hocking DR, Churchyard AJ, Delatycki MB. The Fitts task reveals impairments in planning and online control of movement in Friedreich ataxia: reduced cerebellar-cortico connectivity? Neuroscience 2011;192(382-390).

11. White BV, Leib JR, Farmer JM, Biesecker BB. Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. Behav Brain Funct. 2010;6(65).

12. da Silva CB, Yasuda CL, D’Abreu A, Cendes F, Lopes-Cendes I, Franca MC, Jr. Neuroanatomical correlates of depression in Friedreich’s ataxia: a voxel-based morphometry study. Cerebellum. 2013;12(3):429-36.

13. Nieto A, Hernandez-Torres A, Perez-Flores J, Monton F. Depressive symptoms in Friedreich ataxia. Int J Clin Health Psychol. 2018;18(1):18-26.

14. Perez-Flores J, Hernandez-Torres A, Monton F, Nieto A. Health-related quality of life and depressive symptoms in Friedreich ataxia. Qual Life Res. 2020;29(2):413-20.

15. Reetz K, Dogan I, Hohenfeld C, Didszun C, Giunti P, Mariotti C, et al. Nonataxia symptoms in Friedreich Ataxia: Report from the Registry of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS). Neurology. 2018;91(10):e917-e30.

16. Chan YC. Aripiprazole treatment for psychosis associated with Friedreich’s ataxia. Gen Hosp Psychiatry. 2005;27(5):372.

17. Ganos C, Schottle D, Zuhlke C, Munchau A. Psychosis complicating Friedreich ataxia. Mov Disord Clin Pract. 2015;2(1):84-5.

18. Salbenblatt MJ, Buzan RD, Dubovsky SL. Risperidone treatment for psychosis in end-stage Friedreich’s ataxia. Am J Psychiatry. 2000;157(2):303.

19. Oruç S, Gulseren G, Kusbeci OY, Yaman M, Geçici O. Quetiapine treatment for psychosis in Friedreich’s ataxia. Klinik Psikofarmakoloji Bulteni – Bulletin of Clinical Psychopharmacology. 2012;22:357-8.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.