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Clinical detection with the NP-C Suspicion Index

 

Clinical assessment

 

Diagnosis of Niemann-Pick type C (NP-C) requires comprehensive medical history assessment, general physical examination, neurologic assessment and psychiatric/cognitive investigation.1

The medical history and general physical examination should focus on:1

·       Evidence of neonatal cholestasis, isolated splenomegaly or hepatosplenomegaly, seizures, cataplexy and impaired academic or work performance (specifically loss of skills);

·       Vital signs, body weight, height and head circumference;

·       Eye movement abnormalities.

Neurologic assessment should focus on:1

·       Vertical saccadic eye movement (SEM) impairment

·       Vertical supranuclear gaze palsy (VSGP) and vertical supranuclear saccade palsy (VSSP) may be missed if voluntary saccades are not assessed (see assessment 2. below):

1. To assess the smooth pursuit, patients should be tested for their ability to follow an object
2. To assess the vertical voluntary saccades the physicians will ask the patient to spontaneously move their gaze up and
    down without following an object (ask to look between two points fixed by the upper part of their head and at chest level)


  • With mild vertical SEM impairment, the patient is still able to look up but cannot look down
  • With advanced vertical SEM impairment, the patient can no longer look up or down

 

  • ·       Examination of cranial nerves, muscle bulk, tone, power and stretch reflexes, gait, cerebellar and extrapyramidal function and swallowing;

    ·       Development (particularly arrested or delayed speech development) in children under 4 years;

    ·       Gait (including tandem gait), using the 10m or timed walk test;

    ·       Presence of ataxia, using established scales;

    ·       Evidence of seizures, ideally with electroencephalogram (EEG) confirmation;

    ·       Evidence of cataplexy;

    ·       Evidence of impaired hearing.

    ·       Video-oculography allows the recording of all types of eye movements and can be used for quantitative analysis of ocular motor function (http://eyeseecam.com/).

    ·       For additional guidance on how to conduct eye movement assessments, please see Neurocular.com.

    Psychiatric assessment should focus on:1

    ·       Mood and psychotic symptoms using established rating scales;

    ·       Degree of behavioral disturbance, particularly in juvenile adolescent/adult-onset patients;

    ·       Differentiating the effects of drugs, for example, antipsychotics and antidepressants, from those due to the disease; treatment resistance of psychiatric symptoms is also an important sign to take into account.

    Cognitive assessment should:1

    ·       Monitor cognition, using validated clinical tools available for both adults and children.

    At-risk clinical patient niches:

    The clinical manifestations of NP-C may be nonspecific, for example, ataxia, dystonia, or cognitive decline. As such, patients with NP-C may be ‘hidden’ within larger clinical patient cohorts who also present with nonspecific signs and symptoms.2,3 Several patient cohorts that are at-risk of harboring hidden patients with NP-C have been identified including the following:2,3

    ·       Early-onset ataxia

    ·       Intellectual disability and developmental delay

    ·       Cognitive impairment and early-onset cognitive decline

    ·       Dystonia

    ·       Frontotemporal dementia

    ·       Organic psychosis, atypical schizophrenia, and early-onset psychosis

    ·       Cholestasis and hepatosplenomegaly in early-infantile patients

    ·       Familial aspects and ancestry

    ·       Parkinsonism

    ·       Progressive supranuclear gaze palsy

    ·       Amyotrophic lateral sclerosis

    ·       Chronic inflammatory central nervous system disease (e.g. multiple sclerosis)

    ·       Antenatal findings and fetal abnormalities

    NP-C should be considered as a differential diagnosis for patients in these at-risk groups. Such patients may only be detected through broad screening approaches, such as biomarker or gene panel screening.

Resources

Details of validated assessment and rating scales suitable for use in the diagnosis of NP-C can be found in Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update – 2012

For additional guidance on how to conduct eye movement assessments, please see Neurocular.com

For additional information on VSGP, please see the VSGP leaflet

The NEW NP-C Suspicion Index (SI) has been developed by international experts to help identify patients suspected of having NP-C, with a view to establishing better and earlier diagnosis. The NP-C SI is suitable for patients of all ages, with an NP-C SI0–4 years and an NP-C SI>4 years available for patients up to 4 years of age and older than 4 years of age, respectively. 

For more information regarding at-risk patient niches, please see Hendriksz et al. 2017.

 

 

References

  1. Patterson MC, Hendriksz CJ, Walterfang M, et al., on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update Mol Genet Metab 2012;106:330–344.
  2. Marquardt T, Clayton P, Gissen P, et al, on behalf of the NP-C Diagnostics Working Group. New consensus recommendations for the detection and diagnosis of Niemann-Pick disease type C. J Inherit Metab Dis 2016;39:35.
  3. Hendriksz CJ, Anheim M, Bauer P, et al. The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease. Curr Med Res Opin 2017;33:877-890.

The NP-C Suspicion Index1,2

The NP‑C Suspicion Index (SI) is a simple and reliable screening tool, developed by a team of international expert diagnosticians. The aim of the NP-C SI is to assist clinicians with identifying patients who should undergo further testing for NP-C, and to raise awareness of the key signs and symptoms of NP-C.1,2

The NEW NP-C Suspicion Index has been fully updated to provide the following features:

·       Two age-specific indices for patients aged <4 years and those aged >4 years

·       Improved performance in patients aged >4 years as a result of the inclusion of symptom combinations (NP-C SI>4 years)

·       Identification of 7 key discriminatory signs and symptoms highly suggestive of NP-C

·       Improved performance in subjects aged <4 years as a result of new analyses of a newly recruited cohort of early-onset patients (NP-C SI0–4 years)

NP-C SI>4years

Development of the NP-C SI>4years was based on retrospective chart review performed on a cohort comprising:1

·       71 NP-C cases

·       64 NP-C non-cases

·       81 controls

Statistical analyses were conducted to determine the strength of association between individual and combinations of signs and symptoms and a diagnosis of NP-C.1

Further analyses identified a list of 7 key discriminatory signs and symptoms of NP-C, whereby NP-C should be strongly suspected when any 2 of the 7 symptoms are present.1 These are highlighted ( ) in Figure 1.

For further information regarding the development and validation of the NP-C SI>4 years, see Hendriksz CJ, et al. (2015).1

How to use the NP-C SI>4years

To use the NP-C SI>4years, 5 simple steps should be followed:

1.     Carefully assess the signs and symptoms, selecting those that are present in your patient

2.     Pay close attention to the 7 key discriminatory signs and symptoms ( )

3.     Calculate the total risk prediction score for your patient

4.     Save and/or print your patient's results

5.     Refer your patient as appropriate

Figure 1: The NP-C Suspicion Index symptoms are scored according to their relative association with an accurate NP-C diagnosis.1 Physicians should work through each of the four symptom categories in the tool, marking which signs and symptoms are, or have been, present in their patients.

Understanding the new NP-C SI>4 years

The NP-C SI>4 years provides results as a percentile and total risk prediction score:

·       Total risk prediction score – The sum of the risk prediction scores of all of the individual symptoms selected.

·       Percentile score – Indicative of how a patient’s total risk prediction score compares with those of each patient with NP-C from the database; e.g. a percentile of 30% indicates that a patient’s risk prediction score is greater than 30% of all patients in the database.

Cutoff scores

Cutoff scores for low, moderate, and high likelihood of NP-C are:

NP-C SI0–4years

Development of the NP-C SI0−4years was based on a retrospective chart review performed on an international cohort of 200 patients aged up to 4 years, and comprised:2

·       106 NP-C cases

·       31 NP-C non-cases

·       63 controls

Statistical analyses were conducted to determine discriminatory signs and symptoms of NP-C. Risk prediction scores were assigned to each sign or symptom based on the strength of association with an NP-C diagnosis versus symptoms observed in controls.2

For further information regarding the development and validation of the NP-C SI0–4 years, see Pineda M, et al. (2016).2

How to use the NP-C SI0−4years

1.     Carefully assess the signs and symptoms, selecting those that are present in your patient

2.     Pay close attention to the co-occurrence of ataxia and/or mental regression with central nervous system or spleen symptoms

3.     Calculate the total risk prediction score for your patient

4.     Save and/or print your patients’ results

5.     Refer your patient as appropriate

Figure 2: The NP-C Suspicion Index symptoms are scored according to their relative association with accurate NP-C diagnosis.2 Physicians should work through each of the symptom categories in the tool, marking which signs and symptoms are or have been present in their patients.

The Suspicion Index includes only those symptoms found to be highly predictive of NP-C in this population. It should be noted that symptoms which were not found to be discriminatory in the 0-4 years age group e.g. developmental delay, hypertonia, but may raise initial suspicion of NP-C, were not included in the NP-C SI0–4years. Therefore, the NP-C SI0–4years does not constitute a full clinical description of NP-C in the 0–4 years age group.

Understanding the new NP-C SI0–4 years

The NP-C SI0–4 years is based on a novel cohort of 200 patients aged 0–4 years and provides a total risk prediction score for each patient.

Cut-off scores

Cut-off scores for low, moderate and high likelihood of NP-C are:

 

For further information regarding the development and validation of the NP-C SI0–4 years, see Pineda M, et al. (2016)2.

Resources

  • The NP-C Suspicion Index Tool is available online at www.npc-si.com, providing clinicians who are unfamiliar with NP-C with a simple-to-use and interactive screening tool. NP-C Suspicion Index applications (apps) are available for both Apple (iOS 7.0 and above) and Android (Android 4.1 and above) devices. The apps are downloadable from the Apple App Store and Google Play Store and allow healthcare professionals to use the NP-C Suspicion Index without internet connection.

    For more information about these tools, please visit www.npc-si.com.

     

 

References

  1. Hendriksz C, Pineda M, Fahey M, et al. The Niemann-Pick disease Type C Suspicion Index: development of a new tool to aid diagnosis. J Rare Dis Diagn Ther 2015;1:11.
  2. Pineda M, Mengel E, Jahnova H, et al. A Suspicion Index to aid screening of early-onset Niemann-Pick disease Type C (NP-C). BMC Pediatr 2016;16:107.