Clinical detection with the NP-C Suspicion Index
Diagnosis of Niemann-Pick type C disease (NP-C) requires comprehensive medical history assessment, general physical examination, neurological 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.
Neurological assessment should focus on:1
- Vertical saccadic eye movement (SEM) impairment
Vertical supranuclear gaze palsy (VSGP) may be missed if voluntary saccades are not assessed (see assessment 2. below):
- 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 10-m 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.
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.
NP-C Suspicion Index
The Niemann-Pick type C disease (NP-C) Guidelines Working Group revised the Recommendations for the diagnosis and management of Niemann-Pick type C disease in 2012, to provide the most up-to-date information about NP-C. A new tool – the NP-C Suspicion Index – has also been developed for healthcare professionals to help identify patients for whom further investigation is required. This will hopefully help to achieve earlier and improved diagnosis of NP-C in patients suspected of having the disease.2
How to use the Suspicion Index
The Suspicion Index tool can be used to determine suspicion of NP-C in patients. It was developed and validated by a team of international experts in NP-C, comprising pediatricians, neurologists, psychiatrists and biostatisticians, using retrospective analysis of patient data.
The results showed that a number of different symptoms indicate the presence of NP-C, but can be found in diseases other than NP-C. This therefore makes accurate diagnosis of NP-C particularly challenging.
Figure 1: The NP-C Suspicion Index tool. Symptoms are scored according to their relative association with accurate NP-C diagnosis (Wijburg et al, 2012).2 Physicians should work through each of the three category symptoms in the tool, marking which signs and symptoms are or have been present in their patients.
The Suspicion Index tool assigns weighted scores according to the different symptoms identified and family history of NP-C. Adding together these weighted scores provides an overall risk prediction score and guides clinicians in making the decision whether further investigation for the possibility of NP-C is warranted.
|Risk prediction Score|
|<40||indicates a low probability of having NP-C and alternative causes should be considered before further investigation for NP-C|
|40-69||indicates that further follow-up observation and discussion with an NP-C center is required|
|≥70||should prompt immediate referral to an NP-C center for testing for NP-C|
Due to a lower sensitivity in patients below 4 years old, a prediction score below 70 is not conclusive in this group of patients.
- 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(3):330-344.
- Wijburg FA, Sedel F, Pineda M, et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology 2012;78(20):1560-7.