Day: 12/09/2012

A 10-year-old boy with ADHD symptoms.

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The patient presented to the psychiatric clinic for evaluation when he was in third grade due to behavioral and attention difficulties in school. He was unable to sit still, would not wait his turn, made inappropriate outbursts during class, and did not properly complete his work. He could not stay focused even in one-to-one conversation, and daydreamed frequently. Additionally, he often got into fights with his peers, leading to both school detentions and multiple suspensions. The mother reports that many of these symptoms had been present at a very early age.

Birth, medical, developmental and family history were unremarkable. There is no history of anxiety, depression, psychosis or suicide attempts, and no previous psychiatric hospitalizations.

The diagnosis of attention deficit/hyperactivity disorder (ADHD) was made and he was started on medication treatment. He failed trials of both amphetamines (Adderall XR, DuraMed) (up to 20 mg) and methylphenidate (Concerta, Janssen) (18 mg). On methylphenidate, he developed suicidal ideations and would get very irritable stating “kids were teasing [him] a lot.” He was started on dexmethylphenidate hydrochloride (Focalin XR, Novartis), which was well tolerated. The dose was titrated up to 20 mg over a period of 8 months and an afternoon dose of dexmethylphenidate hydrochloride 5 mg was added in response to residual afternoon symptoms of ADHD. Two months later, the afternoon bridging dose was increased to 10 mg due to recurrence of declining grades, hyperactivity, and inability to complete and turn-in homework.

When the patient was 11 years old and in sixth grade, 1 month after his last adjustment in ADHD medications, he had an abrupt onset of neurological symptoms including weakness in his lower extremities, gait instability, slurred speech and confusion. He was hospitalized and his physical examination at that time was notable for photophobia, brisk deep tendon reflexes (DTRs) especially in the left side, left hand dysmetria, clonus in the left ankle, positive bilateral Babinsky and unsteady gait.

His laboratory work-up yielded mildly elevated CSF protein (59 mg/dL) negative meningo- encephalitis panel (EBV, CMV, HSV ½, HHV6) and negative oligo-clonal bands. An MRI demonstrated symmetric posterior white matter changes with post-contrast enhancement, predominately involving the periventricular and mesial temporal white matter, corpus callosum, posterior internal capsule, and adjacent cortico-spinal tracts with associated mild mass effect but no midline shift. MRI of the spine was mildly technically limited but showed no abnormalities.

The patient was discharged home, but he returned to the hospital 1 month later with persistent headache, shortterm memory loss and ataxia. An EEG was obtained and demonstrated episodic slowing without epileptiform discharges. An adrenocorticotropic hormone (ACTH) stimulation test identified adrenal insufficiency and DC was discharged home on hydrocortisone 8 mg/m2/day.

Diagnosis:

Adrenoleucodystrophy.

The results of his very long chain fatty acid profile were elevated (C26:0) and elevated ratios of C24/22 and C26/22, consistent with a diagnosis of adrenoleucodystrophy (ALD). For confirmation of his diagnosis, the ABCD1 gene mutation test was sent, which confirmed a positive novel frameshift mutation of the ABCD1 gene.

Another month later, the patient had a seizure in school. The seizure semiology was unclear, but it lasted less than 1 minute and was preceded by headache, vision changes and emesis. The boy was prescribed levetiracetam (Keppra, UCB Pharma) 500 mg twice daily and has not had any recurrent seizures since then. He continues having daily frontal headaches associated with photo-phonophobia, decreased vision, and at times seeing red and green “polka dots” that move across the visual field. They improve with ibuprofen and sleep. His mother also notices diminished hearing and has to repeat herself loudly when speaking with him. He is forgetful and also at times hyperactive. The boy continues taking dexmethylphenidate hydrochloride 20 mg even after getting diagnosis of ALD, since it seems to be effective for managing inattention, hyperactivity and impulsivity, especially in the classroom setting.

The psychiatrist also continues providing emotional support and care for this child and his family as they face a chronic and progressive condition with poor prognosis.

Case Discussion

Deterioration in school performance can be a sign of multiple medical and psychiatric problems. The first case of ALD was described in 1910 by Haberfeld and Spieler; a previously healthy 6-year-old boy developed a deeply bronzed skin, impaired visual acuity and deterioration in his school performance. The initial manifestations of ALD in childhood include signs of neurodegeneration with neurodevelopmental regression, adrenal insufficiency or both. Very frequently, symptoms and signs that are commonly used to describe psychiatric disorders are the initial manifestation of ALD; and the potential for initial misdiagnosis is significant.

Psychiatric symptoms may be the most prominent manifestation of this disorder for years, as occurred in our case: a boy who presented with symptoms of ADHD with only partial response to stimulants for 3 years, before developing any neurologic and endocrine symptoms that led to the diagnosis of ALD. Close to 70% of children who have ADHD have a positive response to stimulants such as methylphenidate. An additional 20% responds to the alternative class of stimulant medications. Poor response to these medications could possibly suggest the presence of a comorbid disorder.

ALD is an inherited metabolic storage disease associated to a defect in an enzyme that results in defective peroxisomal B-oxidation and the accumulation of very long-chain fatty acids (VLCFA C24, C26) in tissues of the body, especially the brain and the adrenal glands. It results in demyelination associated with an intense inflammatory response in the white matter. ALD affects only boys. Female carriers can manifest with some degree of disability. Approximately 70% of boys with ALD have adrenal insufficiency.

If no focality is found on the neurological exam, a brain MRI might be appropriately deferred which would result in underdiagnosis of ALD. Elevated plasma VLCFA level is highly reliable in the diagnosis of ALD, which is confirmed by mutation analysis of the ABCD1 gene. Molecular studies are essential in determining a carrier state and especially in prenatal diagnosis, which can be performed in all peroxisomal disorders. MRI findings in ALD correlates with neuropathological features of bilaterally symmetric demyelination in the parieto-occipital region with involvement of the splenium of the corpus callosum. Although there is no definitive treatment, evidence suggests that early interventions before CNS involvement clinically and in MRI may offer a better prognosis to these patients.

Although a rare condition (the incidence of ALD has been estimated to be 1:17.000 newborns), ALD is very likely to present with symptoms and signs usually first brought to the attention of a child or general psychiatrist. Clinical psychiatrists must be mindful of the possibility of organic disease masking as a psychiatric disorder. It is very important to obtain a detailed medical and family history along with a thorough physical and neurological exam. When a patient is referred for developmental evaluation if school deterioration is a subject of concern, a test for adrenal reserves may be indicated.

References:
  • Bakos JT. J Clin Endocrinol Metab. 1995;80:2869-2872.
  • Ievers CE. J Dev Behav Pediatr. 1999;20:31-35.
  • Kaufman DM. Clinical Neurology for Psychiatrists. 6th edn. Philadelphia: Elsevier Health Sciences; 2007.
  • Kitchin W. Biol Psychiatry. 1987;22:1375-1387.
  • Kopala LC. Schizophr Res. 2000;45:263-265.
  • Listernick R. Pediatr Ann. 2009;38:72-75.
  • MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1073-1086.
  • Ramos-Rios R. CNS Spectr. 2009;14:711-712
  • Riva D. Neurology. 2000;54:1651-1655.
  • Christine Marie Clark, BA, is a 4th year medical student, RUSH University.
  • Lauren Shin, MD, is Assistant Professor of Child and Adolescent Psychiatry and director of the ADHD and Disruptive Behaviors Disorders Clinic, RUSH University Medical Center.
For more information:
  • Rosario M. Cosme Cruz, MD, is a 2nd year Child and Adolescent Psychiatry Fellow, RUSH University Medical Center. Cruz can be reached at Rush University Medical Center, Rush West Campus, 2150 W. Harrison Street, Chicago, IL 60612; email: Rosario_m_cosme@rush.edu.

 

 

 

Diabetes increased long-term CV events in older PCI-treated patients .

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Diabetes, particularly when treated with insulin, was independently and strongly associated with increased long-term adverse events in older patients who had undergone drug-eluting and bare-metal stent implantation.

Researchers of the study, published in the Journal of the American College of Cardiology, characterized long-term outcomes of PCI in patients with diabetes aged older than 65 years in routine practice by examining data from 405,679 patients aged older than 65 years who underwent PCI from 2004 to 2008 at 946 US hospitals. Data were linked to Medicare inpatient claims data. Overall, 33% of the patients had diabetes, of whom 9.8% were treated with insulin and 23.3% were not treated with insulin.

During a median of 18.4 months of follow-up, there was a significantly increased risk for death among insulin- (HR=1.91; 95% CI, 1.86-1.96) and noninsulin-treated (HR=1.32; 95% CI, 1.29-1.35) patients with diabetes compared with nondiabetic patients.

There was also more MI for insulin- (HR=1.87; 95% CI, 1.79-1.95) and noninsulin-treated (HR=1.29; 95% CI, 1.25-1.34) patients with diabetes compared with nondiabetic patients. The adjusted hazards were also significantly increased for those undergoing additional revascularization procedures (HR for insulin-treated patients=1.14; 95% CI, 1.10-1.18; HR for noninsulin-treated patients=1.08; 95% CI, 1.05-1.10) and subsequent hospitalization for bleeding (HR for insulin-treated patients=1.40; 95% CI, 1.31-1.50; HR for noninsulin-treated patients=1.18; 95% CI, 1.13-1.24).

“The mechanisms for this incremental risk of adverse CV events in older diabetic patients compared with nondiabetic patients, particularly for death and MI after PCI with both DES and BMS, is likely multifactorial,” researchers wrote. “Hypotheses include a greater underlying burden of atherosclerosis, microvascular disease, a prothrombotic state, more neointimal hyperplasia, greater vascular inflammation and/or further accumulation of diabetes-related end-organ damage and comorbidities during the 30- to 50-month follow-up period.”

  • Source: Endocrine Today.

 

 

 

 

Liraglutide may reduce liver enzyme levels in patients with type 2 diabetes.

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Patients with elevated liver enzymes were safely treated with liraglutide, although the treatment’s effect was reduced by its impact on weight and glycemic control, according to recent results.

Researchers performed a meta-analysis of data on 4,442 patients enrolled in six 26-week, phase 3 randomized controlled trials evaluating the impact of liraglutide on liver enzymes in patients with type 2 diabetes. Liraglutide was assigned to 2,734 patients in the cohort, while 524 received placebo and 1,184 received other diabetes treatments.

In all studies, patients initially received 0.6 mg intravenous liraglutide once a day, titrated to 1.2 mg daily after 7 days, with some studies increasing dosage to 1.8 mg after 7 additional days. One study (LEAD-2) randomly assigned patients to receive 0.6 mg, 1.2 mg or 1.8 mg once a day, along with metformin and 4 mg glimepiride or placebo per day. LEAD-2 also included a sub-study assessing the drug’s impact on hepatic steatosis.

Abnormal baseline ALT levels were present in 50.8% of patients. A 1.8 mg dose of liraglutide resulted in a significantly larger ALT reduction than that observed among patients receiving placebo (–8.20 IU/L vs. –5.01 IU/L; P=.003 for difference); no significant differences were observed between placebo and smaller doses of liraglutide. Investigators noted that adjusting for HbA1c (P=.63) and liraglutide’s weight reduction (P=.21) eliminated the statistical significance of the drug’s impact. Rates of adverse events were similar among patients with or without elevated ALT at baseline when treated with 1.2 mg or 1.8 mg liraglutide.

In the LEAD-2 sub-study, the 1.8 mg liraglutide dose trended toward improving steatosis relative to placebo, with a 0.10 improvement to liver-to-spleen attenuation ratio among treated patients compared with 0.0 among those receiving placebo (P=.07). Adjusting for changes to weight (P=.25) and HbA1c (P=.93) reduced this trend.

“[Twenty-six] weeks’ treatment with liraglutide 1.8 mg has an acceptable safety profile and significantly improves liver enzymes vs. placebo in patients with type 2 diabetes and asymptomatic liver injury,” the researchers wrote. “These effects appear to be mediated by the effect of liraglutide on weight loss and glycemic control. Our data support the rationale to prospectively investigate GLP-1 analogues in liver injury associated with type 2 diabetes and the metabolic syndrome.”

  • Source: Endocrine Today.

 

Obesity increases surgery time, cost in patients with lung cancer.

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In a recent study published in The Annals of Thoracic Surgery, researchers determined that for every 10-unit increase in BMI, operating room time increased by 7.2 minutes for lung cancer patients undergoing lobectomy. While this increase may not seem substantial, researchers suggest the cost burden is more worrisome.

“The fact that we are putting more and more costly resources into caring for obese patients needs to be considered as hospitals and policy makers think of ways to control future health care costs. More public health emphasis on healthy lifestyle choices and weight loss is needed,” researcher Jamii B. St. Julien, MD, MPH, from Vanderbilt University Medical Center in Nashville, said in a press release.

St. Julien and colleagues included lung cancer patients in The Society of Thoracic Surgeons General Thoracic Surgery database (STS GTSD) who also underwent lobectomy as a primary procedure between 2006-2010 (n=19,337) for the multi-institutional, retrospective study.

Mean BMI measurements were 27.3 kg/m2 for 13,222 patients (68.4%) with a BMI <30 kg/m2; 4,898 patients (25.3%) had a BMI of 30 kg/m2 or more; and 625 patients were morbidly obese. There was no BMI data for 1,217 patients (6.3%), researchers wrote.

Prior to multivariate regression analysis, the average total operating room time was 240.1 minutes; preprocedure time was 48.4 minutes, procedure time was 174.1 minutes and postprocedure time was 17.4 minutes. The researchers said that length of stay tended to be 6.9 days, with an average 1.8% overall 30-day mortality rate.

Upon further analysis, the researchers wrote that for every 10-unit increase in BMI, there was a 7.2-minute increase in operating room time (P<.0001).

“For example, a lobectomy in a patient with a BMI of 45 kg/m2 takes approximately 15 minutes longer than for a patient with a BMI of 25 kg/m2,” researchers wrote.

This increase in operating room time led to cost estimates within the study. Every 10-unit increase in BMI has the potential to cost an additional $446, the researchers wrote. However, it remains difficult to estimate the true cost, they added.

“As any clinician will attest, an additional 7 minutes of total operating room time for an obese patient hardly seems clinically significant. However, I do not believe the authors consider this clinically relevant either,” David R. Jones, MD, from the department of surgery in the division of thoracic and cardiovascular surgery at the University of Virginia, wrote in an invited commentary accompanying the study. “Instead, I think the intent of this publication is to begin the process of deducing the true cost of performing thoracic procedures in the ever-increasing obese population.”

Jones wrote that he agrees more obese patients will require thoracic surgical procedures, and that a better understanding of both the obesity and lung cancer epidemic is valuable.

Disclosure: Grogan is a recipient of the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service career Development Award. St. Julien is a recipient of the Vanderbilt University Surgical Oncology T32 Training Grant. All other researchers report no relevant financial disclosures.

Perspective

 

George A. Bray

  • Obesity is a common problem and carries with it the risk for many kinds of other ailments. It can also be a handicap when it comes to surgical and other medical procedures. This is clearly illustrated in this paper on surgical treatment. Obesity can also pose challenges for anesthesia during surgery, for post-operative recovery and for wound healing in the post-operative state.
    • George A. Bray, MD
    • Endocrine Today Editorial Board member

 

  • Source: Endocrine Today.

 

Injectable steroid for back pain led to BMD loss in postmenopausal women .

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Previous studies have established that one of the major adverse effects of steroid use is glucocorticoid-induced osteoporosis. In a recent study published in Spine, researchers have suggested that postmenopausal women who were administered a single epidural steroid injection as treatment for back pain adversely experienced significant BMD loss of the hip.

“The findings of our study suggest that epidural steroid injections (ESI) for back pain relief should be approached cautiously in patients at risk for bone fragility,” co-author of the study and orthopedic physician at Henry Ford Health System, Shlomo Mandel, MD, said in a press release. “Physicians who do prescribe them should consider measures that optimize bone health such as calcium and vitamin D supplements and exercise as part of their patient’s treatment plan.”

In the prospective, observational study, Mandel and colleagues examined white women (n=28) who were at least 10 years postmenopausal with nerve root compression at the L4-L5 level.

Kenalog-80 (80 mg/mL of triamcinolone acetonide injectable suspension; Bristol-Myers Squibb) was administered at the L4-L5 level. Patients underwent baseline BMD of the total hip, femoral neck and spine using dual-energy X-ray absorptiometry (DEXA); and a measurement of 2 serum biochemical markers of bone turnover (C-terminal telopeptide of type 1 collagen; CTX). They also underwent bone-specific alkaline phosphatase (BSAP) for bone formation measurement.

According to data, the mean BMD of the hip before ESI was 0.979g/cm2. Six months after the injection, the mean BMD of the hip measured 0.961g/cm2, the researchers wrote. Moreover, the decline of 0.018g/cm2 in the total hip BMD from baseline to 6 months following injection was significant (P=.002).

“Therefore, our finding of a 0.018g/cm2 during a 6-month period after ESI suggests a 6-fold increase in the average yearly rate of bone loss in the hip,” the researchers wrote.

They suggest careful approaches to lumbar radiculopathy in patients at risk for bone loss and further studies with a longer follow-up period.

Source: Endocrine Today.

 

 

Researchers evaluate public health relevance of Graves’ orbitopathy.

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In an observational study conducted by researchers in Germany, data suggest productivity loss and a prolonged therapy for patients with Graves’ orbitopathy result in considerable indirect and direct costs.

The most common extrathyroidal manifestation of autoimmune Graves’ disease — Graves’ orbitopathy (GO) — is marked by physical illness and an impaired working ability and quality of life.

“We hypothesized that direct costs would be higher in patients with severe forms of the disease, e.g. in cases of optic neuropathy and/or constant diplopia,” researchers wrote.

Katharina A. Ponto, MD, from the department of ophthalmology at Johannes Gutenberg University Medical Centre in Mainz, Germany, and colleagues examined 680 patients (310 GO patients; 370 healthy patients).

According to data, of 215 employed patients, 47 (21.9%) were on temporary disability and 12 (5.6%) were on permanent work disability. Moreover, five patients (2.3%) lost their jobs and nine (4.2%) retired. Sick leaves were measured at 22.3 days per year. Compared with average Germans who took 11.6 sick days per year, 32 (15%) patients took longer sick leaves, they wrote.

“If approximately 40% of patients with Graves’ disease have clinically overt GO and if the prevalence of Graves’ disease is at least 0.5%, there will be 410,000 GO patients in Germany. Direct costs of GO would then be a total of 159,080,000€ ($200,122,640) per year, whereas the indirect costs would average between 1,360,380,000€ ($1,711,358,040) and 2,762,580,000€ ($3,475,325,640) per year,” the researchers wrote.

Finally, researchers said disease severity increased indirect and direct costs. Although these data are estimates, the researchers conclude that economic consequences and public health relevance were demonstrated in this study.

Source: Endocrine Today.

 

 

LAGB, RYGB equally improved insulin sensitivity, beta-cell function

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According to data from a study published in the Journal of Clinical Investigation, researchers at the University of Washington School of Medicine in St. Louis have found that both laparoscopic adjustable gastric banding or Roux-en-Y gastric bypass surgeries improved insulin sensitivity and beta-cell function.

Researchers examined 20 consecutive, eligible patients who were scheduled to undergo Roux-en-Y (RYGB; n=10) or laparoscopic adjustable gastric banding (LAGB; n=10) at Barnes-Jewish Hospital in St. Louis, Missouri. The patients completed body composition analyses, hyperinsulinemic-euglycemic clamp procedure and a mixed-meal metabolic study prior to gastric surgery and following a 20% surgery-induced weight loss, the researchers wrote.

Patients in the LAGB group lost 19.3% of their body weight by 22 weeks, and patients in the RYGB group lost 20.1% of their body weight by 16 weeks after surgery.

“All study subjects were insulin resistant, based on a HOMA-IR value greater than 2.5, but none had type 2 diabetes. Studying subjects without type 2 diabetes allowed us to avoid the confounding effects of differences in baseline glycemic control, glucose toxicity, and changes in diabetes medications on our metabolic outcomes measures,” the researchers wrote.

These similar results were reportedly beneficial. However, researchers said that data do not support clinically meaningful weight loss-independent effects of RYGB surgery on beta-cell function and insulin sensitivity in obese patients without diabetes.

They suggest further research to determine if the findings apply to those with type 2 diabetes who are also obese.

Source: Endocrine Today.

 

Response to Some Hypertension Treatments May Vary by BMI .

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Hypertension treatment with the calcium-channel blocker amlodipine is effective in people of all BMI subgroups, whereas thiazide-based treatment is not as effective in normal-weight people, according to an industry-funded Lancet study.

In the ACCOMPLISH trial, some 11,000 patients with hypertension received benazepril and were randomized to add either hydrochlorothiazide or amlodipine.

After roughly 3 years’ treatment, all BMI subgroups in the amlodipine group had roughly the same rate (5%) of the primary outcome — a composite of cardiovascular death, stroke, and MI. In contrast, in the hydrochlorothiazide group, obese patients had a lower rate of the primary outcome than did overweight or normal-weight patients (5%, 7%, and 9%, respectively).

The authors conclude: “Diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment … An alternative therapeutic regimen that includes a calcium-channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”

Source: Lancet

 

Benzodiazepines Associated with Increased Pneumonia Risks .

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Benzodiazepines as a class are associated with heightened risks for community-acquired pneumonia and pneumonia-related death, according to a case-control study in Thorax.

Researchers used a U.K. database to assemble a cohort of some 5000 cases of community-acquired pneumonia and 30,000 matched controls. Benzodiazepine exposure was associated with a higher risk for pneumonia (odds ratio, 1.54) as compared with no exposure. After a pneumonia diagnosis, benzodiazepine use — whether current, recent, or past — was also associated with higher mortality.

The authors speculate that the effect observed may be due to activation of GABA receptors on immune cells. That speculation was strengthened by finding an increased pneumonia risk with another — nonbenzodiazepine — drug that also targets GABA receptors. The authors consider their findings “hypothesis-generating,” but consistent with “movement away from benzodiazepine sedation” during intensive care.

Source: Thorax

Extended Duration of Tamoxifen Therapy Enhances Breast Cancer Survival .

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Ten years of adjuvant tamoxifen therapy in women with estrogen receptor–positive breast cancer is associated with lower rates of recurrence and breast cancer mortality than 5 years of treatment, according to a Lancet article.

Researchers followed outcomes in some 6800 women with receptor-positive disease who’d completed 5 years of tamoxifen therapy, half of whom were allocated to 5 additional years of treatment.

Recurrences and breast cancer mortality were both significantly lower among those on continued therapy, with reductions being even more pronounced after 9 years. During years 5–14, mortality was 12.2% for those allocated to continue treatment versus 15.0% for controls (absolute mortality reduction, 2.8%). The incidence of pulmonary embolism (but not of death from it) was higher in the continued-treatment group, and the risk of endometrial cancer was also higher with longer treatment, including an absolute increase in mortality risk of 0.2%.

A commentator writes that confirmation of these results by meta-analysis with other tamoxifen trials “should herald a change of practice.”

Source: Lancet