Systematic review of psychiatric signs in Niemann-Pick disease type C.

Objectives: We conducted the first systematic literature review and analysis of psychiatric manifestations in Niemann-Pick disease type C (NPC) to describe: (1) time of occurrence of psychiatric manifestations relative to other disease manifestations; and (2) frequent combinations of psychiatric, neurological and visceral disease manifestations. Methods: A systematic EMBase literature search was conducted to identify, collate and analyze published data from patients with NPC associated with psychiatric symptoms, published between January 1967 and November 2015. Results: Of 152 identified publications 40 were included after screening that contained useable data from 58 NPC patients (mean [SD] age at diagnosis of NPC 27.8 [15.1] years). Among patients with available data, cognitive, memory and instrumental impairments were most frequent (90% of patients), followed by psychosis (62%), altered behavior (52%) and mood disorders (38%). Psychiatric manifestations were reported before or at neurological disease onset in 41 (76%) patients; organic signs (e.g., hepatosplenomegaly, hearing problems) were reported before psychiatric manifestations in 12 (22%). Substantial delays to diagnosis were observed (5-6 years between psychiatric presentation and NPC diagnosis). Conclusions: NPC should be considered as a possible cause of psychiatric manifestations in patients with an atypical disease course, acute-onset psychosis, treatment failure, and/or certain combinations of psychiatric/neurological/visceral symptoms.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. METHODS: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. FINDINGS: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. CONCLUSIONS: Several clinical niches have been identified that harbor patients at increased risk of NP-C.

Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update.

PURPOSE OF REVIEW: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. RECENT FINDINGS: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified. SUMMARY: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review.

OBJECTIVE: It is important for psychiatrists to be aware of certain inborn errors of metabolism (IEMs) as these rare disorders can present as psychosis, and because definitive treatments may be available for treating the underlying metabolic cause. A systematic review was conducted to examine IEMs that often present with schizophrenia-like symptoms. DATA SOURCES: Published literature on MEDLINE was assessed regarding diseases of homocysteine metabolism (DHM; cystathionine beta-synthase deficiency [CbS-D] and homocysteinemia due to methyltetrahydrofolate reductase deficiency [MTHFR-D]), urea cycle disorders (UCD), acute porphyria (POR), Wilson disease (WD), cerebrotendinous-xanthomatosis (CTX) and Niemann-Pick disease type C (NP-C). STUDY SELECTION: Case reports, case series or reviews with original data regarding psychiatric manifestations and cognitive impairment published between January 1967 and June 2012 were included based on a standardized four-step selection process. DATA EXTRACTION: All selected articles were evaluated for descriptions of psychiatric signs (type, severity, natural history and treatment) in addition to key disease features. RESULTS: A total of 611 records were identified. Information from CbS-D (n = 2), MTHFR-D (n = 3), UCD (n = 8), POR (n = 12), WD (n = 11), CTX (n = 14) and NP-C publications (n = 9) were evaluated. Six non-systematic literature review publications were also included. In general, published reports did not provide explicit descriptions of psychiatric symptoms. The literature search findings are presented with a didactic perspective, showing key features for each disease and psychiatric signs that should trigger psychiatrists to suspect that psychotic symptoms may be secondary to an IEM. CONCLUSION: IEMs with a psychiatric presentation and a lack of, or sub-clinical, neurological signs are rare, but should be considered in patients with atypical psychiatric symptoms.

A large ApoE ε4/ε4 homozygous cohort reveals no association with Parkinson's disease.

To investigate the correlation between cognitive impairment, Parkinson's disease (PD) symptoms and ApoE ε4/ε4 homozygosity an ApoE ε4/ε4 homozygous cohort was compared with an ApoE ε3/ε3 homozygous comparison group. A total of 696 outpatients with memory complaints had undergone comprehensive neuropsychiatric assessment including interview and examination by clinical psychiatrists and neurologists as well as laboratory blood testing (including ApoE genotyping). Patients also underwent the Consortium to Establish a Registry on Alzheimer's Disease (CERAD) test battery and the Clock-Drawing Test (Shulman scoring). Of the 623 selected individuals 258 were homozygous for ApoE ε3 and 133 were homozygous for ApoE ε4, while 232 were heterozygous for ApoE ε3/ε4. Thirty patients in the entire sample were diagnosed with PD (4.8 %). In the ApoE ε4/ε4 group seven persons had PD (5.3 %), while in the ApoE ε3/ε3 comparison group nine persons were diagnosed with PD (3.5 %). In the ApoE ε3/ε4 heterozygous group we found 14 (6.03 %) subjects meeting criteria for PD, P = 0.406. This is to our knowledge the largest retrospective cohort study to date of ApoE ε4 homozygous carriers. In comparison with the ApoE ε3 homozygous carriers in our study, subjects who were homozygous for ApoE ε4 demonstrated a slightly but statistically insignificant higher prevalence of PD, while in the ApoE ε3/ε4 heterozygous group we detected the highest rate of probands diagnosed with PD. We conclude that there is no correlation between allele combinations of ApoE ε3 and ApoE ε4 in their heterozygote and homozygote composition and prevalence of PD.

Niemann-Pick disease type C symptomatology: an expert-based clinical description.

Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months-6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca(®)), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.

Implementation of a cost-effective HPLC/UV approach for routine medical quantification of memantine in human serum.

BACKGROUND: In the near future, there will be no innovative drug principle for the treatment of dementia. Therefore, optimizing the efficacy of a drug is at present the most promising way to exploit its full pharmacological potential. METHOD: A high performance liquid chromatography with ultraviolet assay for memantine in serum from demented patients has been developed and validated. The analytical procedure involves offline solid phase extraction cartridges. Because memantine molecules lack chromophoric π-electrons, a derivatization with dansyl chloride was required for detection by ultraviolet (UV) photometry. Analyses were performed on a Dionex high-performance liquid chromatography system with a Phenomenex Luna Phenyl-Hexyl analytical column and 0.02 mol/L potassium dihydrogen phosphate buffer/acetonitrile (40/60 V/V) as mobile phase at a flow rate of 0.4 mL/min. Dansylated memantine was detected at 218 nm; 2 more ultraviolet wavelengths at 254 nm and 336 nm were used as an overlay-control check. RESULTS: The retention time for dansylated memantine was 17.1 ± 0.2 minutes. The calibration curve was linear over a concentration range from 5 to 160 ng/mL (n = 8/r² > 0.999). The method had an accuracy of >90%. Intra-assay and inter-assay coefficients of variation were <5% and <13%, respectively, at 3 different concentrations. The limit of quantification and the limit of detection were 2.9 ng/mL and 0.8 ng/mL, respectively. Among 100 substances prescribed as comedications in the treatment of dementia only fluvoxamine and zuclopenthixole showed retention times close to dansylated memantine (17.8 minutes and 18.1 minutes, respectively). However, these 2 drugs were removed from patients' specimens during solid-phase extraction sample preparation. CONCLUSIONS: The method is applicable under conditions of daily routine as has been demonstrated by application of the method to patient serum samples. The quantification of 29 samples showed that memantine concentrations suggested as "therapeutic" in the literature may only be reached by high doses of memantine.

Treatable metabolic psychoses that go undetected: what Niemann-Pick type C can teach us.

OBJECTIVE: The objective of this review is to raise awareness of the prevalence of inborn errors of metabolism, in particular NP-C, in psychiatric populations. METHODS: This review summarises research presented at a satellite symposium held on 28 August 2010 at the 23rd European College of Neuropsychopharmacology (ECNP) meeting. RESULTS AND CONCLUSION: Organic causes of psychoses may have an unrecognised yet notable prevalence, particularly in adolescent or adult patients. Several inherited metabolic disorders can present with psychiatric signs. In some disorders, such as Niemann-Pick type C (NP-C), the disease may remain unrecognised for many years due to a heterogeneous and subtle clinical presentation. In patients presenting with psychoses, subtle signs such as vertical supranuclear gaze palsy, ataxia and splenomegaly should raise the suspicion of NP-C. Miglustat is so far the only approved treatment for NP-C. Miglustat can stabilise neurological disease, particularly in adolescent or adult-onset patients who are detected as early as possible, before irreversible neurological damage occurs.

Association of apolipoprotein E ε4 (ApoE ε4) homozygosity with psychiatric behavioral symptoms.

To examine the relationship between apolipoprotein E ε4 (ApoE ε4) and psychiatric symptoms, we compared ε4/ε4, ε3/ε3, and ε3/ε4 subjects. 659 outpatients with memory complaints underwent comprehensive neuropsychiatric assessment interview and neurological examination and ApoE genotyping: 98 were ε4/ε4. 18.4% (n = 18) ε4/ε4, 19.3% (n = 45) ε3/ε4, and 5.4% (n = 14) ε3/ε3 presented with symptoms of anxiety (p = 0.00001). ε4/ε4 patients with mild cognitive impairment (MCI; p < 0.0001) and those with Alzheimer's disease with late onset (p = 0.0175) were the most frequently affected. For anxiety, there were no gender dependent differences in the two homozygous groups, however, in the ε3/ε4 group, anxiety symptoms were evident in 7.3% (n = 8) of the male versus 30.1% (n = 37) of the female ε3/ε4 heterozygotes (p < 0.0001). Depression was found in 20.4% (n = 20) ε4/ε4 and 21.0% (n = 49) ε3/ε4 compared to 17.1% (n = 44) ε3/ε3 (p = 0.5181). Visual hallucinations were reported in 5.1% (n = 5) ε4/ε4 as opposed to 3.8% (n = 9) ε3/ε4 and 2.3% (n = 6) ε3/ε3 (p = 0.5278). We have seen a higher association of anxiety with the ApoE ε4 allele across all stages of disease and what may be a dosing effect in the early stage (MCI) for this ostensible risk, since we see a significantly higher frequency in the ApoE ε4 homozygotes when compared to the heterozygotes.

Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.

The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.

100th anniversary of Perusini's second case: patient RM and his kindred.

The first 4 cases of Alzheimer's disease published by Alois Alzheimer's laboratory were authored by the young Italian physician Gaetano Perusini. In his discourse, ''Uber klinisch und histologisch eigenartige Erkrankungen des späteren Lebensalters'' Perusini describes 4 cases of histological and clinical findings of peculiar psychiatric diseases of older age. With regard to case number II, Perusini remarks ''since 1899 RM has psychically changed.'' As RM is said to be 45 years of age on admission, this would imply the obvious onset of disease at the early age of 37. A detailed analysis of archival material revealed that RM was actually 10 years older. Perusini's hint that ''one of the patient's brothers does not seem to be normal'' initiated our search for this individual to rule out an autosomal dominant inheritance in this kindred. We initiated genealogical studies over 8 generations to get more detailed information about this early case of psychiatric history.

ApoE genotype and family history in patients with dementia and cognitively intact spousal controls.

OBJECTIVE: To test that a positive family history and ApoE e4 genotype are prevalent among dementia patients with onset before 70 years of age compared with healthy spousal controls. METHODS: A total of 210 patients with dementia and 82 spousal control participants. Neuropsychiatric examination, Consortium to establish a registry on Alzheimer's disease test battery, Clock-drawing Test, and ApoE genotyping were performed in patients and controls. RESULTS: Of the 131 patients with Alzheimer dementia, 25 were homozygous for Apo e4. Among dementia patients with a positive family history (n = 83), homozygosity for the Apo e4 genotype was found in 19 (22.9%). A positive family history was highest among Apo e4 homozygous Alzheimer dementia patients (72.0%) and lowest among the cognitively normal spousal controls (9.3%). CONCLUSIONS: In our sample of patients with Alzheimer dementia, approximately 3 of 4 (72.0%) were homozygous for the genotype Apo e4 when they had a positive family history.