A Non-Motor Diagnostic Framework
For the past five years, Dr. Ciaran Considine and Dr. M. Agu Rossetti have served as co-chairs of the HSG’s neuropsychology working group (NPWG). Of late, the heart of their mission has been to advocate for adjusting the clinical diagnostic framework for HD to integrate non-motor symptoms — cognitive impairment and behavioral/psychiatric symptoms. To do this, they published practice guidance for neuropsychologists assessing patients with HD. This included a recommended approach for assigning a neurocognitive disorder diagnosis, with or without behavioral disturbance, attributed to HD pathology in known genetic carriers who do not meet current motor criteria for manifest HD diagnosis.
Ciaran Considine, PhD, ABPP-CN is an Assistant Professor of Neurology at Vanderbilt University School of Medicine and a board certified clinical neuropsychologist at Vanderbilt University Medical Center.
A separate practice guidance article provided a cognitive and behavioral dysfunction screening and triage protocol designed for neurologists and psychiatrists to use with their HD genetic carriers. This group is also in the process of creating an asynchronous education program on this guidance, via HSG’s CME4HD platform.
This is important for a multitude of reasons. In one sense, such guidance formalizes what clinicians are doing now — but within widely variable parameters — to make sure our patients get the best care we can offer, as early as we can offer it. Such an unsteered approach, however, is suboptimal for providers, and by definition has its share of misses, whether misdiagnoses or missed opportunities to diagnose and treat early.
By standardizing the way we define and measure non-motor symptoms, we are not only treating our patients and their families with greater confidence, but also setting the stage for impactful research on associations with age, CAG repeats and other variables that will guide future treatment.
An Uphill Battle
Recognition of early behavioral and psychiatric symptoms is most certainly on the forefront of HD. As recently as 2021, a publication in Neurology studied the European Huntington’s Disease Network registry, concluding that:
… because it is impossible to distinguish confidently between non-motor symptoms arising from HD and primary psychiatric disorders, particularly in younger premanifest patients, non-motor symptoms should not be used to make a clinical diagnosis of HD.
In Dr. Considine’s response, he argued that it is imperative to embrace a diagnostic model that accounts for diverse non-motor symptoms, especially neuropsychological and psychiatric manifestations. The longitudinal databases from the registry included only patients who convert to motor manifest disease, and poorly characterize the breadth of cognitive and psychiatric symptoms. Dr. Considine decided to work within the HSG NPWG to begin concerted efforts to create a more comprehensive model.
What We Know
Our work has a foundation based on substantial past research showing that:
1. Predominant cognitive and behavioral/psychiatric phenotypes are common in persons with HD, often beginning a decade or more before motor symptoms.
2. These symptoms frequently cause distress and functional impairment in HD genetic carriers with none-to-minimal motor symptoms.
3. These symptoms are frequently not assessed, are misattributed to non-HD causes, and undermanaged in clinical care.
Much of the data supporting these studies has been accrued through TRACK-HD, PREDICT-HD and PHAROS, large-scale registries that have measured and documented subtle cognitive impairment and associated functional decline years prior to clinical motor diagnosis.
The NPWG’s task has been to organize and formalize what we know, so that these early symptoms are defined and recognized within future clinical diagnostic criteria for known HD genetic carriers.
Why It Matters
Revisions to reflect non-motor manifestations of Huntington’s disease are crucial for both clinical practice and the patient community. These updates offer several key benefits, including improved access to social support systems through non-motor diagnosis, validation for patients and families regarding the consistency of non-motor symptoms with HD diagnosis, and optimized clinical follow-up targeting HD-specific symptoms.
Furthermore, these revisions allow for more comprehensive characterization of complex symptom presentations, accurately reflecting HD’s heterogeneous nature. They also underscore the need for developing non-motor therapies addressing cognitive and behavioral symptoms, while facilitating earlier access to disease-modifying therapies, particularly for clinical trials based on symptom onset.
These multifaceted advantages highlight the importance of recognizing and incorporating non-motor aspects of HD in diagnostic and treatment approaches.
History of Recognizing Early Cognitive Symptoms
Back in the 1980s and early 1990s, studies on cognitive impairments in executive and visuospatial functions and memory produced mixed results, with some studies detecting no differences in cognition between high- and low-risk individuals. Then, in 2014, PREDICT-HD, through a large-scale international study, produced robust evidence of cognitive impairment as a clinical indicator of manifest HD. Duff and colleagues went that critical step further, demonstrating that nearly 40% of pre-diagnosed CAG expansion carriers in PREDICT-HD met formal criteria for mild cognitive impairment compared with at-risk gene-negative participants.
This was followed by Ross and colleagues outlining a specific diagnostic approach to incorporating cognitive impairment into HD diagnosis and clinical practice, though it still relied on the presence of at least mild motor symptoms and did not integrate behavioral/psychiatric symptoms.
At Last, Behavioral Symptoms Become Recognized
More recent studies emerged that showed behavioral disorders and psychiatric phenomena to be among the earliest and most functionally impairing signs of HD, and can include anxiety, apathy, depression, irritability, perseveration, obsessions, and psychosis.
However, the heterogeneity with which these symptoms are expressed in HD complicates their use as diagnostic criteria. These symptoms tend to fluctuate and are subject to environmental and treatment factors; it is hard to discern where these conditions start and what keeps them active or progressing. Do they arise because of the HD gene? Out of other genetic predilections? Fear and anxiety over their own or family members’ diagnoses or behaviors? Other social factors? Medications? After all, the most common psychiatric symptoms of HD (e.g., apathy, irritability, depressive suicidality, anxiety) are non-specific to HD CAG expansion carriers.
Despite this conundrum, potential associations with HD cannot be dismissed on the basis of “too many variables.” “A major part of our project at the NPWG, therefore, was to reach consensus on behavioral/psychiatric manifestations in relation to cognitive signs in HD, expanding on the guidance of Ross and colleagues,” Dr. Considine said.
They proposed that:
- the presence of behavioral and psychiatric symptoms in a confirmed HD CAG expansion carrier warrants close monitoring of cognitive and motor status.
- behavioral disorders are intrinsically and reciprocally linked to cognitive function.
- a “behavioral disturbance” modifier should incorporate documentation of behavioral/psychiatric manifestations of HD into a unitary neurocognitive disorder (NCD) diagnosis, unless its etiology in HD is unclear. In that case, a separate primary psychiatric disorder diagnosis should be independently assigned.
- Evidence of significant or modest cognitive impairment would need to be supported by the patient/informant to qualify as an NCD.
Recent updates to diagnostic criteria, reflected in the DSM-5-TR, do provide specific codes for the presence/absence of “behavioral disturbance” even in the mild NCD diagnosis. The ICD-10/11 also has provisions for associating behavioral/psychiatric disturbance to a comorbid neurocognitive diagnosis.
While this guidance opens an avenue for neuropsychologists to assign a neuropathological diagnosis as causal for cognitive and/or behavioral/psychiatric symptoms, neuropsychologists rely on neurologists and psychiatrists to initiate specialty referrals to see these patients. Thus, guidance for these physicians to assist in screening, monitoring, and triaging up to neuropsychology was needed. The NPWG published a second set of practice guidance designed to fulfill this need.
Cognitive Screening Recommendations
The resulting published clinical guidance again promoted shifting the overall approach to HD diagnosis to include genetic testing to confirm HD and CAG expansion, followed by assigning a symptomatology in those presenting with neurobehavioral symptoms (motor and/or non-motor) that are thought to be probably attributable to HD pathology. This would allow a diagnosis of symptomatic HD, in a confirmed genetic carrier, even in the absence of motor signs.
Following a positive screening, we recommend triage to appropriate specialists (e.g., behavioral neurologist, neuropsychiatrist, movement disorders specialist, neuropsychologist, occupational therapist, genetic counselor) to aid in evaluating for a non-motor manifest HD diagnosis.
Cognitive screening should be done with the caveat that it is not diagnostic or equivalent to neuropsychological evaluation. For the testing component, we recommend the Montreal Cognitive Assessment (MoCA) with the Chelune formula be used in diagnosis (and then continued longitudinally). We found that the most used Mini Mental Status Exam (MMSE) has merit, but less sensitivity to cognitive dysfunction in HD.
For the clinical assessment, the report of a a collateral informant is important given the frequency of both denial and anosognosia in people with HD.
For functional screening, we suggest clinical assessment and the WHO Disability Assessment Schedule 2.0, which covers basic activities of daily living (ADLs) as well as higher-complexity domains, which are obviously important adjuncts to cognitive and behavioral diagnoses. Acceptable substitutes include the UHDRS sub-scales that are related to function.
Behavioral/Psychiatric Screening Recommendations
As we have alluded to, greater clinical judgment is needed to assess behavioral and psychiatric manifestations of HD, and particularly in premanifest cases, where the gray zone is the largest.
Clinicians need to compare reports to observations and collateral reports, as well as monitor for atypical behavioral manifestations in clinic, documenting the presence and severity of these symptoms.
Short-form questionnaires with empirically-based cutoffs for clinically significant symptoms should be considered for depression, anxiety, apathy, and sleep–wake disturbance. We recommend screening for safety-related behavioral symptoms (i.e., suicidality, aggression/violence toward others), using questionnaires and interviews, and drawing on forensic sources, as needed.
Triage, then Monitor
In cognitive, functional and behavioral assessments, a triage approach is recommended, assigning patients into High, Moderate, Low or Lowest risk of non-motor manifest HD. These should be monitored over time. For those in the Lowest and Low risk categories, clinical judgment, established cut-scores, and cognitive screening can be used to document the stability or degree of progression, of the symptoms.
This may help answer important questions that impact diagnosis and, thereby, treatment, safety and quality of life, such as:
- Is there evidence of marked cognitive and behavioral decline from baseline/prior assessment in a patient without an NCD or with Mild NCD due to HD?
- Are cognitive and behavioral symptoms linked to functional decline or functional safety considerations (e.g., access to firearms/weapons, heavy machinery, driving, independent management of medications, financial capacity, decision-making capacity)?
- Is there a comorbid condition exacerbating HD dysfunction?
- Is the patient applying for, or are they candidates for disability, vocational rehabilitation services, or in-home care?
Next Steps
As the NPWG has outlined, appropriate screening and triage by non-neuropsychologist clinicians can aid in detecting non-motor HD manifestation and effectively monitoring the complete clinical course of HD. Monitoring and managing potential non-HD causes for these symptoms, as well as escalating to neuropsychological evaluation offers a means to more confidently associate these symptoms with HD pathology.
A manuscript under review advances an opinion that for adults with known genetic HD expansion, with non-or-equivocal motor symptoms, the longitudinal screening approach is sufficient to offer possible and probable symptomatic HD diagnosis.
Future revisions to the diagnostic criteria for Huntington’s disease will hopefully address several key areas. As the field progresses, advancements in neuroimaging, neurophysiological, and molecular biomarkers may be integrated into the diagnostic process, contingent upon their validation and widespread accessibility in clinical settings. Additionally, the development of separate clinical diagnostic criteria for juvenile HD that integrates cognitive and behavioral/psychiatric symptoms is recognized as a critical need, given the distinct differences in symptom presentation and disease progression observed in this subset of patients.
These ongoing refinements underscore the dynamic nature of HD diagnostics and the commitment to improving accuracy and comprehensiveness in clinical assessments.As always, patient and family engagement in these discussions is critical for the field to advance in a direction that improves diagnosis, access to care and clinical trials, and the lived experience of those served by the clinical researchers working toward a disease- modifying or preventative treatment for HD.