Prader–Willi syndrome

Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a genetic disorder due to loss of function of specific genes.

In newborns, symptoms include weak muscles, poor feeding, and slow development.

Beginning in childhood, the person becomes constantly hungry, which often leads to obesity and type 2 diabetes.

Also, mild to moderate intellectual impairment and behavioral problems are typical.

Often, the forehead is narrow, hands and feet are small, height is short, skin is light in color, and most of the affected are unable to have children.

About 74% of cases occur when part of the father’s chromosome 15 is deleted.

In another 25% of cases, the person has two copies of chromosome 15 from their mother and none from their father.

As parts of the chromosome from the mother are turned off, they end up with no working copies of certain genes.

PWS is not generally inherited, but instead the genetic changes happen during the formation of the egg, sperm, or in early development.


Franco et al., presented case series from the Hospital das Clínicas. Four patients with genetically confirmed Prader-Willi syndrome (PWS) presenting with severe obesity were included.

Deep brain stimulation electrodes were bilaterally implanted in the lateral hypothalamic area. After DBS implantation, the treatment included the following phases: titration (1-2 months), stimulation off (2 months), low-frequency DBS (40 Hz; 1 month), washout (15 days), high-frequency DBS (130 Hz; 1 month), and long-term follow-up (6 months).

Primary outcome measures were adverse eventrecorded during stimulation and long-term DBS treatment. Secondary outcomes consisted of changes in anthropometric measures (weightbody mass index [calculated as weight in kilograms divided by height in meters squared], and abdominal and neck circumference), bioimpedanciometry, and calorimetry after 6 months of treatment compared with baseline. The following evaluations and measurements were conducted before and after DBS: clinical, neurological, psychiatric, neuropsychological, anthropometry, calorimetry, blood workup, hormonal levels, and sleep studies. Adverse effects were monitored during all follow-up visits.

Four patients with PWS were included (2 male and 2 female; ages 18-28 years). Baseline mean (SD) body mass index was 39.6 (11.1). Two patients had previous bariatric surgery, and all presented with psychiatric comorbidity, which was well controlled with the use of medications. At 6 months after long-term DBS, patients had a mean 9.6% increase in weight, 5.8% increase in body mass index, 8.4% increase in abdominal circumference, 4.2% increase in neck circumference, 5.3% increase in the percentage of body fat, and 0% change in calorimetry compared with baseline. Also unchanged were hormonal levels and results of blood workup, sleep studies, and neuropsychological evaluations. Two patients developed stimulation-induced manic symptoms. Discontinuation of DBS controlled this symptom in 1 patient. The other required adjustments in medication dosage. Two infections were documented, 1 associated with skin picking.

Safety of lateral hypothalamic area stimulation was in the range of that demonstrated in patients with similar psychiatric conditions receiving DBS. In the small cohort of patients with PWS treated in the study, DBS was largely ineffective 1).


Lateral hypothalamic area (LHA) local field potentials (LFPs) were recorded in a Prader-Willi patient undergoing deep brain stimulation (DBS) for obesity. During hunger, exposure to food-related cues induced an increase in beta/low-gamma activity. In contrast, recordings during satiety were marked by prominent alpha rhythms. Based on these findings, Talakoub et al., delivered alpha-frequency DBS prior to and during food intake. Despite reporting an early sensation of fullness, the patient continued to crave food. This suggests that the pattern of activity in LHA may indicate hunger/satiety states in humans but attest to the complexity of conducting neuromodulation studies in obesity 2).

References

1)

Franco RR, Fonoff ET, Alvarenga PG, Alho EJL, Lopes AC, Hoexter MQ, Batistuzzo MC, Paiva RR, Taub A, Shavitt RG, Miguel EC, Teixeira MJ, Damiani D, Hamani C. Assessment of Safety and Outcome of Lateral Hypothalamic Deep Brain Stimulation for Obesity in a Small Series of Patients With Prader-Willi Syndrome. JAMA Netw Open. 2018 Nov 2;1(7):e185275. doi: 10.1001/jamanetworkopen.2018.5275. PubMed PMID: 30646396.
2)

Talakoub O, Paiva RR, Milosevic M, Hoexter MQ, Franco R, Alho E, Navarro J, Pereira JF Jr, Popovic MR, Savage C, Lopes AC, Alvarenga P, Damiani D, Teixeira MJ, Miguel EC, Fonoff ET, Batistuzzo MC, Hamani C. Lateral hypothalamic activity indicates hunger and satiety states in humans. Ann Clin Transl Neurol. 2017 Oct 20;4(12):897-901. doi: 10.1002/acn3.466. eCollection 2017 Dec. PubMed PMID: 29296618; PubMed Central PMCID: PMC5740250.

Dravet Syndrome

Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is a type of epilepsy with seizures that are often triggered by hot temperatures or fever.

Dravet and Bureau in 1981 described “benign myoclonic epilepsy in infancy” in 7 normal children with onset of myoclonic seizures in the first 3 years of life 1). The syndrome was defined as including myoclonic seizures only, except rare simple febrile seizures, with good prognosis regarding response to therapy and cognitive functions.

Dravet Syndrome (DS) is a severe epileptic encephalopathy of childhood involving intractable seizures, recurrent status epilepticus and cognitive decline. Because DS is a rare disease, available data is limited and evidence-based treatment guidelines are lacking.

Both VNS and corpus callosotomy (CC) can be effective at reducing seizure frequency. Patients with DS may benefit from earlier and more aggressive surgical intervention. Studies using larger patient cohorts will help clarify the role that surgery may play in the multidisciplinary approach to controlling seizures in DS. Further studies will help determine the appropriate timing of and type of surgical intervention 2).

Loss of function in the Scn1a gene leads to Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures.

Ritter-Makinson et al., showed enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. The study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. They propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment 3).


Vagus nerve stimulation (VNS) is an established neurostimulation treatment for intractable epilepsy, however little evidence is published on its efficacy in patients with DS.

Dibué-Adjei et al., performed a meta-analysis of all peer-reviewed English language studies reporting seizure outcomes of patients with DS treated with adjunctive vagus nerve stimulation. The primary and secondary outcome measures were ≥50% reduction of seizures or of the most-debilitating seizure type and seizure reduction per patient.

13 studies comprising 68 patients met the inclusion criteria of which 11 were single-center retrospective case series, one was a multi-center retrospective analysis and one was a case report. 52.9% of patients experienced a ≥50% reduction of seizures and the average seizure reduction, which could only be assessed in n=28 patients was 50.8%. 7 out of 13 studies reported additional benefits of VNS, however this could not be assessed systematically.

Vagus nerve stimulation appears to reduce seizure frequency in patients with DS. Based on this preliminary analysis, controlled trials of VNS in this rare condition using patient-centric outcome measures are indicated 4).

1)

Dravet C, Bureau M. [The benign myoclonic epilepsy of infancy (author’s transl)]. Rev Electroencephalogr Neurophysiol Clin. 1981 Dec;11(3-4):438-44. French. PubMed PMID: 6808601.
2)

Dlouhy BJ, Miller B, Jeong A, Bertrand ME, Limbrick DD Jr, Smyth MD. Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature. Childs Nerv Syst. 2016 Sep;32(9):1703-8. doi: 10.1007/s00381-016-3201-4. Epub 2016 Jul 27. Review. PubMed PMID: 27465677.
3)

Ritter-Makinson S, Clemente-Perez A, Higashikubo B, Cho FS, Holden SS, Bennett E, Chkaidze A, Eelkman Rooda OHJ, Cornet MC, Hoebeek FE, Yamakawa K, Cilio MR, Delord B, Paz JT. Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome. Cell Rep. 2019 Jan 2;26(1):54-64.e6. doi: 10.1016/j.celrep.2018.12.018. PubMed PMID: 30605686.
4)

Dibué-Adjei M, Fischer I, Steiger HJ, Kamp MA. Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: A meta-analysis of 68 patients. Seizure. 2017 Aug;50:147-152. doi: 10.1016/j.seizure.2017.06.007. Epub 2017 Jun 17. Review. PubMed PMID: 28666193.

Cyclic Cushing’s syndrome

Cyclic Cushing’s syndrome is a rare variant of Cushing’s syndrome, which demonstrates periodic cortisol excess.

Cyclical Cushing’s syndrome may render the diagnosis and management of Cushing’s disease difficult.

It has been suspected that inhibition of a glucocorticoid positive feedback loop is associated with remission of hypercortisolism in ACTH-dependent cyclic Cushing’s syndrome. However, the underlying mechanism to trigger the development of its hypercortisolism is still unknown.

Seki et al., from the Tokyo Women’s Medical University, experienced a case of ACTH-dependent cyclic Cushing’s syndrome developed by exogenous glucocorticoids possibly through a glucocorticoid positive-feedback loop.

A 75-year-old woman had experienced cyclic ACTH and cortisol elevations 6 times in the previous 4 years. Her diagnosis was cyclic Cushing’s syndrome. During the hypercortisolemic phase, neither low-dose nor high-dose dexamethasone suppressed her plasma ACTH and cortisol levels. Daily metyraponetherapy decreased her plasma cortisol and ACTH levels during every hypercortisolemic phase. After the sixth remission of a hypercortisolemic phase, she took 25 mg hydrocortisone for 4 weeks and developed ACTH-dependent hypercortisolemia. Treatment with 1 mg dexamethasone gradually increased both plasma ACTH and cortisol levels over 2 weeks resulting in the eighth hypercortisolemic phase. Treatment using a combination of dexamethasone with metyrapone did not increase plasma ACTH or cortisol levels and successfully prevented development of ACTH-dependent hypercortisolism.

It is an interesting case of cyclic Cushing’s syndrome in which ACTH-dependent hypercortisolemic phases relapsed during exogenous glucocorticoid treatment. A glucocorticoid positive-feedback loop and endogenous glucocorticoid synthesis may play key roles in the periodicity of hypercortisolism in cyclic Cushing’s syndrome 1).


Alexandraki et al., analysed the case records of 201 patients with Cushing’s disease in a retrospective case-note study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability.

Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. ‘Cycling’ patients were older but no difference in sex or paediatric distribution was revealed between ‘cycling’ and ‘non-cycling’ patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in ‘cycling’ compared with ‘non-cycling’ patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease.

This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushing’s disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers 2).


A 56-year-old male patient with cyclic Cushing’s disease remained in a state of remission for more than one year with a relatively low dose of bromocriptine (2.5-3.75 mg/day). It has been reported that bromocriptine treatment for cyclic Cushing’s disease induces only a transient remission; in the most effective cases, a relatively high dose (40 mg/day) was necessary. In the hypercortisolemic state, plasma adrenocorticotropic hormone (ACTH) and serum cortisol were not suppressed by dexamethasone and did not respond to corticotropin-releasing factor (CRF). An antehypophysectomy was not effective, even though the resected tissue contained ACTH-positive microadenomas. The present observations thus indicate the effectiveness of bromocriptine for some patients with this rare disorder 3).


A cyclic excess of cortisol secretion was detected in a patient with diabetes insipidus and diabetes mellitus. The cycles of hypercortisolism were of 7 days’ duration, but during the nadir of these cycles urinary excretion of corticosteroids and 17-ketosteroids was within the normal range. The radiological appearance of the sella turcica was normal; however, computerized axial tomography of the head revealed a small tumor immediately superior to the sella turcica. At operation a small chromophobe adenoma superior to the diaphragma sellae and involving the hypophysial stalk was partially resected. Postoperatively, the patient continued to have 7-day cycles of increased corticosteroid excretion, but the amounts excreted were less than they had been preoperatively. Other patients have been described in whom Cushing’s disease has been due to cyclic hypercortisolism. These cycles have been remarkably regular in individual patients, but of variable duration in different patients. Furthermore, cyclic hormonogenesis probably occurs in a variety of endocrinopathies 4).

References

1)

Seki Y, Morimoto S, Saito F, Takano N, Kimura S, Yamashita K, Yoshida N, Bokuda K, Sasaki N, Yatabe M, Watanabe D, Yatabe J, Ando T, Amano K, Kawamata T, Ichihara A. ACTH-dependent Cyclic Cushing’s Syndrome Triggered by Glucocorticoid Excess Through a Positive-Feedback Mechanism. J Clin Endocrinol Metab. 2018 Dec 17. doi: 10.1210/jc.2018-02268. [Epub ahead of print] PubMed PMID: 30561712.
2)

Alexandraki KI, Kaltsas GA, Isidori AM, Akker SA, Drake WM, Chew SL, Monson JP, Besser GM, Grossman AB. The prevalence and characteristic features of cyclicity and variability in Cushing’s disease. Eur J Endocrinol. 2009 Jun;160(6):1011-8. doi: 10.1530/EJE-09-0046. Epub 2009 Mar 16. PubMed PMID: 19289537.
3)

Adachi M, Takayanagi R, Yanase T, Sakai Y, Ikuyama S, Nakagaki H, Osamura Y, Sanno N, Nawata H. Cyclic Cushing’s disease in long-term remission with a daily low dose of bromocriptine. Intern Med. 1996 Mar;35(3):207-11. PubMed PMID: 8785455.
4)

Oates TW, McCourt JP, Friedman WA, Agee OF, Rhoton AL, Thomas WC Jr. Cushing’s disease with cyclic hormonogenesis and diabetes insipidus. Neurosurgery. 1979 Nov;5(5):598-603. PubMed PMID: 534067.
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