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Gloria Pitts, DO, and Patricia A. Wallace, PhD

Primary Psychiatry. 2003;10(4):84-88

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Donald S. Robinson, MD

Primary Psychiatry. 2003;10(4):51-52

 

Dr. Robinson is a consultant with Worldwide Drug Development, in Melbourne, Florida. He was formerly vice president of Central Nervous System Drug Development for Bristol-Myers Squibb.

Disclosure: Dr. Robinson is a consultant for Somerset Pharmaceuticals, Inc.

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Anita H. Clayton, MD

Primary Psychiatry. 2003;10(4):38-40

 

Dr. Clayton is professor of psychiatric medicine at the University of Virginia in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer.


  

Depression in Women

Depressive disorders occur twice as frequently in women as in men,1 yet, until the last 5 years, most of the published literature pertained to men. There are, however, significant differences between women and men, including biological differences, psychosocial and behavioral factors of gender, age-related differences, and racial/ethnic differences, which may contribute to the difference in mental disorder prevalence observed. The biological differences include reproductive system function, brain structure and function, and drug interactions/metabolism. Depressive illness is frequently associated with reproductive life-phase transitions, such as the onset of puberty, the reproductive period, the menopausal transition, and the postmenopausal years. Changes in reproductive system function may explain the increased incidence of depression in women during reproductive life events.

 

Sex Hormones

The infradian or near-monthly cycling of sex hormones including estrogen, progesterone, and testosterone, may influence symptoms in premenstrual dysphoric disorder (PMDD), first onset of a major depressive disorder (MDD) episode, and a premenstrual exacerbation of depressive symptoms. Exogenous hormones, such as hormonal contraceptives and hormone replacement therapy (HRT), may be associated with depressive illness in some women. Significant changes in sex steroids may affect mood in pregnant women, during the postpartum period, and during the menopausal transition. These changes may occur in a pulsatile fashion (over minutes to hours), with a circadian or diurnal pattern, on an infradian cycle, or circannually (seasonally). Estrogen enhances the efficiency of serotonergic neurotransmission,2 thereby affecting mood, sleep, appetite, and concentration/memory.

Sex hormones in women increase blood levels of most medications, except during pregnancy when metabolism and volume of distribution are also increased.3 Oral contraceptives may alter the blood levels of some drugs, and oral contraceptives may be rendered ineffective by other medications (eg, carbamazepine). Some women may have increased metabolism of medications in the late luteal phase, requiring a dosage increase premenstrually to maintain the therapeutic effect.

 

Reproductive Life Events

Mood disorders occur about twice as frequently in women as in men,1 with the exception of bipolar affective illness. This gender difference is linked to the reproductive years in women, with increased risk of depression in women beginning at puberty, and persisting through midlife.4 As such, the clinical presentation of depressive illness in women is often associated with reproductive life events, an increased risk of a seasonal pattern, atypical features, frequent comorbidity of psychiatric and medical illnesses, and a chronic or recurrent course of illness.

Reproductive life events associated with mood disorders include the late luteal phase in reproductive-age women, pregnancy and the postpartum period, the menopausal transition, and treatment with hormonal therapies (oral contraceptives and HRT). PMDD is defined as the cyclic occurrence of premenstrual symptoms that have resolved by the end of the menstrual period.1 As such, women with major depression or dysthymia who experience a premenstrual exacerbation of depressive symptoms are not diagnosed with PMDD, as symptoms do not resolve during the follicular phase of the menstrual cycle. Symptoms include depressed or labile mood, anxiety, irritability, and somatic symptoms such as headache, breast tenderness, joint aches, sleep disturbance, and food cravings. Severe mood symptoms are associated with impairment in occupational or social function in approximately 5% of women.5 The mean age of onset of PMDD is the mid-twenties, with worsening symptoms until menopause.

Prior history of MDD puts a woman at greater risk for development of PMDD, and the risk is bidirectional. PMDD has been linked to serotonin dysregulation, with mood symptoms triggered by normal fluctuations in sex steroids. Thus, current treatment of choice is with selective serotonin reuptake inhibitors (SSRIs), taken either continuously, just during the late luteal phase, or when symptomatic.6

 

Maternity and the Postpartum Period

Depressive feelings associated with maternity, or “baby blues,” occurs in up to 75% of women with mild mood symptoms occurring between postpartum days 3 and 14.7 Spontaneous resolution occurs by 2 weeks postpartum in most women, but about 8% to 15% of women experience worsening symptoms, such that they meet diagnostic criteria for MDD by week 4 postpartum.7 Even fewer women experience an associated puerperal psychosis (1:1,000), which usually represents MDD with psychotic features or bipolar illness with psychosis.7 For 60% of women, their index episode of depression occurs in the postpartum period,8 while 30% have a prior history of MDD. At least 50% of women who experience postpartum depression suffer a recurrence of MDD with a subsequent pregnancy.9

While symptoms may be subtle and interpreted as related to the changes associated with care of an infant, treatment of postpartum depression often requires full doses of an antidepressant plus an augmenting strategy (eg, psychotherapy, thyroid supplementation, or a second antidepressant). Breastfeeding infants are exposed to the antidepressant in the breast milk, but no significant negative effects are known. If the child is at least 3 months of age, the primary physiologic benefits of breastfeeding have been realized, so weaning will reduce infant exposure to the antidepressant. Antidepressant treatment should not be withheld if the woman chooses to continue breastfeeding with informed consent. Treatment for a full 12 months is recommended.

 

Menopausal Transition

Some women are at risk for depression during the menopausal transition. The menopausal transition begins approximately 5 years before menopause, with the onset of menstrual changes/irregular menses, and increasing levels of follicle-stimulating hormone (FSH), and ends 1 year after cessation of menses. The period of risk for depression corresponds with the menopausal transition, but continues for up to 5 years following menopause. Women at risk include those with a prior history of depression,3 abrupt menopause via surgical or chemical means,10 a family history of depression, an early or prolonged menopausal transition10 (eg, before 45 years of age or for >5 years), and the presence of higher FSH levels.11 Cultural, social, and family factors also affect a woman’s response to the changes she experiences with perimenopause.11 In addition, a great deal of overlap exists between symptoms of the climacteric and criteria for depression, making the diagnosis difficult (Figure). Also, atypical features of mood reactivity, hypersomnia, hyperphagia or weight gain, rejection sensitivity, and leaden paralysis (sensation of heavy limbs and head) may complicate the picture. Treatment with an antidepressant is indicated if the criteria for MDD are met. Estrogen has been found to be useful treatment for depression in the menopausal transition,12 and in combination with an antidepressant after menopause,13 but recent concerns about risks associated with HRT have limited its use.

 

Comorbid Disorders in Women

Other factors to consider include comorbid psychiatric and medical conditions, and seasonal presentation of depression, where 80% are women and atypical features are common. Psychiatric conditions that are frequently comorbid with depression include anxiety disorders, somatoform disorders, eating disorders, borderline personality disorder, and sexual disorders. Medical conditions associated with depression include thyroid disorders, migraine, pain disorders such as fibromyalgia, irritable bowel syndrome, and obesity. The presence of a comorbid disorder makes the diagnosis more complex and finding the appropriate treatment more difficult.

 

Treatment

General treatment considerations in MDD in women comprise a healthy lifestyle (eg, exercise, vitamin supplements B, E, and calcium, reduction of caffeine and alcohol), pharmacotherapy, light therapy, psychotherapy, electroconvulsive therapy, and combination treatment. Newer antidepressants, such as SSRIs, are better tolerated and appear to provide greater therapeutic efficacy than tricyclic antidepressants in reproductive-age women.14 Medications with significant noradrenergic effects may have greater efficacy in women with atypical features than antidepressant medications with effects specific for the serotonin system. Lower doses should be used in women than are indicated for men, except during pregnancy, where higher doses may be needed when psychotropics are used in order to compensate for the increased metabolism and volume of distribution. Metabolism may also be increased in the late luteal phase in some women, requiring increased medication doses.

Counseling of reproductive-age women about potential medication effects on the fetus with an unintended pregnancy is important. Coexisting disorders, either psychiatric or medical, may decrease acute tolerability to any medication, particularly if anxiety is comorbid. Long-term side effects of sexual dysfunction and weight gain can be significant problems in women who are more likely to experience recurrent or chronic depression requiring long-term treatment. Augmentation strategies may include the addition of hormonal treatments, such as estrogen or thyroid supplements, a second antidepressant, psychotherapy, a mood stabilizer, psychostimulants, atypical antipsychotics, and pindolol (Table),14,15 and should be utilized to realize full remission of depressive symptoms. Thus, recognition of the physiological substrate of sex differences, factors complicating diagnosis and treatment, and issues in the management of depression in women, can aid in the achievement of full remission while maintaining quality of life. PP


References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.

2. Young EA, Korszun A, Altemus M. Sex differences in neuroendocrine and neurotransmitter systems. In: Kornstein SG, Clayton AH, eds. Women’s Mental Health: a Comprehensive Textbook. New York, NY: The Guilford Press; 2002:3-30.

3. Hamilton JA, Yonkers KA. Sex differences in pharmacokinetics of psychotropic medications, part I: physiological basis for effects. In: Jensvold MF, Halbreich U, Hamilton HA, eds. Psychopharmacology and Women: Sex, Gender, and Hormones. Washington, DC: American Psychiatric Press; 1996:11-42.

4. Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey, I: lifetime prevalence, chronicity, and recurrence. J Affect Disord. 1993;29:77-84.

5. Reid RL. Premenstrual syndrome. N Engl J Med. 1991;324:1208-1210.

6. Steiner M, Pearlstein T. Premenstrual dysphoria and the serotonin system: pathophysiology and treatment. J Clin Psychiatry. 2000;61(suppl 12):17-21.

7. O’Hara MW. Postpartum Depression: Causes and Consequences. New York, NY: Springer-Verlag; 1995.

8. Cox JL, Conner Y, Kendell RE. Prospective study of the psychiatric disorders of childbirth. Br J Psychiatry. 1982;140:111-117.

9. Nonacs R, Cohen LS. Postpartum mood disorders: diagnosis and treatment guidelines. J Clin Psychiatry. 1998;59(suppl 2):34-40.

10. Avis NE, Bramvilla D, McKinlay SM, et al. A longitudinal analysis of the association between menopause and depression: results from the Massachusetts Women’s Health Study. Ann Epidemiol. 1994;4:214-220.

11. Huerta R, Mena A, Malacara JM, Diaz de Leon J. Symptoms at perimenopausal period: its association with attitudes toward sexuality, life-style, family function, and FSH levels. Psychoneuroendocrinology. 1995;20:135-148.

12. Soares CN, Almeida OP, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58:529-534.

13. Schneider LS, Small GW, Hamilton S, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Am J Geriatr Psychiatry. 1997;5:97-106.

14. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline and imipramine in chronic depression. Am J Psychiatry. 2000;157:1445-1452.

15. Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.

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Andrew Adesman, MD

Primary Psychiatry. 2003;10(4):55-60

 

Dr. Adesman is director of Developmental and Behavioral Pediatrics at Schneider Children’s Hospital in New Hyde Park, NY.

Disclosure: Dr. Adesman is a consultant for, advisor to, and on the speaker’s bureau for Eli Lilly, McNeil, Novartis, and Shire.

Please direct all correspondence to: Andrew Adesman, MD, Suite 130, 1983 Marcus Avenue, Lake Success, NY 11042.



Abstract

Attention-deficit/hyperactivity disorder (ADHD), if not effectively treated, is associated with considerable morbidity. Behavioral interventions and medication management remain the cornerstones of effective ADHD therapy. The National Institute of Mental Health’s Multimodal Treatment of ADHD (MTA) study demonstrated that stimulant medication, when prescribed carefully and monitored closely, is the single most effective treatment for ADHD. The MTA study likewise documented that a comprehensive behavior therapy program was also effective, albeit less so than medication. A multimodal program that combined medication and behavioral interventions resulted in the greatest overall improvement. Nonetheless, a combined approach may not be required for all patients with ADHD. Clinicians must be aware that current community approaches to medication management do not result in an optimal response. Important differences in the approach to medication management are discussed. The MTA study reinforces the need for close monitoring of clinical response to medication. Compared to children medicated in the community, the MTA-medicated children were generally treated for 12 hours (not 8 hours), were seen more frequently for follow-up (with mandated frequent teacher communication), were treated at somewhat higher doses of medication, and had their medication adjusted more frequently. In addition to elaborating on the MTA study results, this article reviews some of the other implications and limitations of the MTA for clinicians. Lastly, several of the most recently approved stimulant and nonstimulant medications for treatment of ADHD are described.

 

Introduction

Attention-deficit/hyperactivity disorder (ADHD), if not effectively treated, is associated with considerable morbidity. Children and adolescents with ADHD are at increased risk for academic failure, social rejection, behavior problems at home and school, and ultimately, low self-esteem. Although effective clinical interventions cannot eliminate the risks for academic and psychosocial impairment, delayed or ineffective treatment will almost certainly increase these risks.

Behavioral interventions and medication management remain the cornerstones of effective ADHD therapy and is the focus of this article. This article focuses primarily on the lessons to be learned from the recent Multimodal Treatment of ADHD (MTA) study and briefly reviews some of the newest medication options in treating children and adolescents with ADHD.

 

The MTA Study

The National Institute of Mental Health-sponsored MTA study represents the most extensive, well-designed prospective evaluation of different treatment approaches for children with combined type ADHD.1 The MTA study was initiated in 1994 and conducted by experienced researchers at six sites. Children 7–9 years of age with combined type ADHD, including those with comorbid anxiety and/or disruptive behavior disorders, were included in the study. Subjects were randomized to one of four treatment groups: medication management (MedMgt), behavior therapy (Behav), combined medication management and behavior therapy (Comb), and a community control (CC) group. The treatment protocols for the MedMgt and Behav groups reflected “best practice” and were provided by clinical research personnel over a 14-month period. Children in the CC group did not receive any services through the MTA study, but were encouraged to seek any services in their community which they felt their child needed.

The MTA study indisputably demonstrates that medication, when carefully prescribed and closely monitored, is the single most effective treatment of ADHD. Although the results of the MTA study cannot be fully reviewed here,2-7 there are several lessons worth noting. First of all, children in the MedMgt and Comb groups showed the greatest improvement, whereas those in the CC group experienced the least improvement. Given that two thirds (68%) of the children in the CC group were treated with medication by their local physicians, it is essential to appreciate that the act of prescribing medication for a child with ADHD does not insure an optimal outcome. The MedMgt, Comb, and CC groups were comparable with respect to ADHD severity, but there were the following key differences in the approach to medication management3,4:

12-hour dosing: One of the most significant differences between the MTA-treated children and the community-treated children was in the medication regimen itself. Children in the MedMgt and Comb groups of the MTA protocol generally received medication on a BID regimen (mean=2.9 methylphenidate doses/day) whereas those children medicated in the CC group generally received only two doses per day (mean=2.1 doses/day). To the extent that all of the children in the MTA study met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition8 criteria for ADHD, combined type, and therefore had some impairment in the home setting (not just in school), it is not surprising that treatment with medication for 12 hours was associated (along with many other factors) with a superior clinical response.

Follow-up frequency/intensity: There were significant qualitative and quantitative differences in the approach to medical follow-up of children in the MTA protocol who received medication. Medical follow-up visits for children receiving MTA-delivered medication were significantly longer than those provided in the community—30 minutes versus 18 minutes. Similarly, children in the MedMgt and Comb groups were seen much more frequently for medication follow-up than were those in the CC group—8.8 visits/year versus 2.3 visits/year.

Teacher communication: In addition to more frequent and longer medication follow-up visits, there was also more frequent teacher communication in the MedMgt and Comb groups. For the MTA-delivered medication subjects, a pharmacotherapist called each child’s teacher monthly to gain insight into the child’s functioning and thus guide medication adjustments. Clinicians in a private practice setting do not speak regularly with the teacher of a child with ADHD.

Total daily dose: The total methylphenidate dose was higher in the MTA-treated subjects than in those children treated in the community—32.8 mg/day versus 18.7 mg/day. When adjusted per dose, the mean methylphenidate dose in the MTA-treated children was 11.3 mg, whereas the average dose for children treated by community physicians was 21% lower, at 8.9 mg.

Tolerability: When carefully adjusted and closely monitored, treatment with stimulant medication was not only very effective, but it was also very well tolerated. At the conclusion of the 14-month study, 73.4% of the MTA-medicated subjects were taking methylphenidate, and an additional 10.4% were taking amphetamine; only 13.1% were not taking any medication. (A very small percentage of patients were on either pemoline, bupropion, haloperidol, or imipramine.) Of the 198 children for whom methylphenidate was the optimal treatment (based on placebo-controlled titration trial at the outset), 88% were still taking methylphenidate at the end of the 13-month maintenance period. Despite the fact that the MedMgt children generally received a 12-hour regimen at a higher dose than the CC children, they remained on medication significantly longer (9.9 months versus 5.5 months; P<.001), suggesting that stimulant therapy, when optimized and closely monitored, is also well tolerated.

 

Additional Lessons From the MTA Study

Optimal Medication Regimens

Result of the MTA study show that optimal medication regimens require periodic readjustment. There were many differences in medication dosage and monitoring between children in the CC group and those in the MedMgt and Comb groups. Although the aggregate data cited above highlights significant differences in the dosing regimen, one must also consider to what extent children required subsequent titration or medication changes.

Despite the fact that placebo-controlled dose titrations were conducted at the outset, many children required several further additional dose adjustments. For example, of the 230 children for whom an optimal treatment regimen was established (using the titration trial), only 17% remained on the same medication dosage throughout the study. The overwhelming majority of children needed a change in dose and some required a change in medication. In most instances, a dose increase was required, though some children needed a dose reduction instead. When comparing the titration dose versus the end-of-maintenance dose, the mean MPH dose increased from 30.5 mg/day (.97 mg/kg/day) to 34.4 mg/day (1.09 mg/kg/day). Not surprisingly, children who were started on a low dose following titration (<15 mg/day) were most likely to require a dose increase, whereas those who were started on a high dose initially (>35 mg/day) were more likely to experience a dose reduction over time.

The mean number of medication changes per child was 2.18 (±1.8 SD), though one child required 10 medication dosage adjustments. More than half of the children treated with medication required a medication change within 3 months into the maintenance period, and the average time interval to the first change was 4.7 months. Although dosage adjustments were made 1 month earlier in the MedMgt group than in the Comb group (4.1 months versus 5.1 months, P<.05), this was likely a protocol artifact in that changes in the behavior therapy plan had to precede any medication change, thus delaying medication changes for children in the Comb group.

Medication adjustments were not limited to the initial months of the maintenance period. Approximately 20% of children required modifications in the medication regimen at 9 months and 12% required changes at 12 months. These data collectively suggest the need to regularly monitor and adjust medication response based on frequent parent and teacher feedback.

 

Response to Stimulants

Overall, 90% (231/256) of the children who completed the titration trial responded well to either methylphenidate (79%) or dextroamphetamine (11%), indicating that most children with ADHD respond well to stimulants. This 90% overall response rate is comparable with previously cited response rates to stimulants when two different medications are tried. Dextroamphetamine was found to be helpful in approximately half of the children for whom methylphenidate was not considered appropriate at the end of the titration (12/26). Interestingly, 6 of the 26 initial methylphenidate nonresponders were later successfully treated with methylphenidate. For these children, the titration trials were considered “false negatives.” Although not common, this observation suggests that clinicians may occasionally need to revisit previously tried (and failed) medications.

 

Stimulants and Anxious ADHD Children

Investigators have previously tried to identify which children with ADHD are most likely to respond to stimulant medication. Preschool children, autistic children, and children with a comorbid anxiety disorder seem to be less likely to respond well to stimulant therapy. Although the MTA excluded preschool children and autistic children, a significant number of the children in the MTA had a comorbid anxiety disorder by parent report. During the titration trial, the children with both ADHD and
anxiety responded well to stimulant therapy.5 Although earlier studies have likewise suggested that anxious ADHD children do indeed respond to stimulants, the MTA methodology was methodologically superior to many of these other studies.

 

MTA: Interpretive Pitfalls

The results of the MTA study are somewhat complex, and media reports have at times inadvertently oversimplified or distorted their findings. By extension, some clinicians may also not fully understand or appreciate all of the results and may potentially misinterpret the lessons from these data. Professionals who treat children with ADHD must be aware of the many potential “false lessons” from the MTA.

 

Neccesity of the Multimodal Approach

Although some may be tempted to conclude from the MTA that there is no benefit to a multimodal approach, this inference is likely as simplistic as it is incorrect. Admittedly, there was no statistical or clinical difference between the MedMgt group and the Comb group when solely considering ADHD core symptom outcomes. However, some differences were suggested for other functional outcomes, such as oppositional/aggressive symptoms, internalizing symptoms, social skills, parent-child relations, and academic functioning.6 The MTA investigators describe these differences as small but likely real. An effect size of 0.27 (when comparing Comb group with MedMgt and Behav groups) did not achieve statistical significance because of design limitations of the MTA protocol. Sample-size calculations for the MTA study were predicated on 80% power to detect effect sizes of 0.4 or greater. Many critics and proponents of the MTA study have noted that focusing on the reduction of ADHD core symptoms may be too myopic, and that long-term outcome is more likely related to social skills and these other functional outcome measures.

A more powerful argument in support of the value of a multimodal approach is derived from a comparison of aggregate measures of improvement. Using factor analysis, a single composite measure of treatment outcome was developed based on the sum of the scores on 17 of the standardized baseline assessments. The Comb treatment group did significantly better than all other treatment groups, with the smallest difference noted when compared to the MedMgt group (effect size 0.28) and the greatest difference when compared to the CC group (effect size 0.70).

Two other modest advantages have been identified for the multimodal approach compared to medication alone. In the MTA trial, children in the Comb group ended treatment on a somewhat lower dose of methylphenidate than did children in the MedMgt group (31.1 mg/day versus 38.1 mg/day). It is unclear to what extent this modest dose differential (methylphenidate 7 mg) conferred any clinical advantages with respect to medication-related adverse events or overall tolerability/compliance. Also, parent ratings of satisfaction with treatment were highest for the two groups that received behavioral intervention. Satisfaction ratings were greater in the Comb treatment group than the MedMgt group. Ironically, satisfaction ratings were higher for the Behav group than the MedMgt group, despite the fact that the latter group had a more substantial clinical response to treatment.

 

The Multimodal Approach as Optimal for all Children With ADHD

Although the data suggest that children in the Comb group did have the best overall outcome, that does not necessarily mean that all children with ADHD should receive a multimodal approach. Some ADHD patients may benefit more from such a comprehensive treatment approach than others. For example, secondary analyses from the MTA study indicate that children with ADHD plus two comorbid conditions benefited more from a combined approach than did others.

Of the 579 subjects in the MTA sample, 68% had one or more comorbid conditions; 33% had a comorbid anxiety disorder, 40% had oppositional defiant disorder, 14% had conduct disorder, 4% had an affective disorder, and 10% also had a tic disorder. A quarter of the total cohort (24.7%) had both a comorbid anxiety disorder and disruptive behavior disorder; this subgroup seemed to benefit most from the multimodal approach.

Although the MTA’s multimodal treatment protocol was clearly superior to behavior therapy alone, there were only modest benefits to a multimodal approach compared to the MedMgt group. On clinical grounds alone, treatment with medication may be more than sufficient for many children with ADHD. When MTA investigators looked at a qualitative outcome measure of success (that incorporated both parent and teacher ratings of ADHD and oppositional defiant disorder symptoms at completion of treatment), 68% of the Comb children and 56% of the MedMgt children were in the normal range (compared to 34% and 25% for the Behav and CC groups respectively). Even smaller differences between the Comb and MedMgt groups were noted at the study conclusion with respect to what proportion no longer met full criteria for ADHD, combined type (90% and 88% respectively).

 

Results of a Community-Based Multimodal Approach 

Many would assume that a community-based multimodal approach would achieve the same results as in the MTA protocol. However, just as there were substantial differences in outcome for the children medicated in the community compared to those treated as part of the MedMgt or Comb groups, there will likely be substantial differences between a community-initiated multimodal approach and that provided through the MTA protocol.

Although the behavioral treatment interventions were standardized and manualized (thus permitting replication), it is unlikely that many families would be able to obtain the same package of services locally.7 Parents of children in the Behav treatment group received 8 individual and 27 group sessions that focused on behavior management techniques and how to coordinate their child’s care with the school. In addition, children in this group attended an 8-week, 5 days/week (9 hours/day) Summer treatment program. Besides sports skills, this summer program included a consistency management program, timeout from reinforcement, social reinforcement, modeling, group problem-solving, social skills training, and individualized academic skills practice. During the school year, a part-time behavioral aide was in the classroom for 12 weeks to work with the child and provide feedback to the parents using a daily report card.

Lastly, a behavior consultant provided the child’s teacher with 10–16 sessions focusing on classroom behavior management strategies. Unfortunately, health insurance plans often do not cover this extensive array of services, school districts are generally unable to provide this intensity of behavioral supports, and many communities do not have professionals with the proper training and availability to provide these intensive interventions even if funding were available. Thus, in many ways, the behavioral interventions in the MTA study were optimal, but not likely attainable for most families.

The multimodal approach in the MTA was interdisciplinary, not just multidisciplinary. There was close collaboration between the pharmacotherapist and the behavioral therapist from both a logistical and clinical standpoint. Medication management follow-up visits were scheduled to coincide with behavioral therapy sessions, and there was frequent clinical communication between the staff overseeing the medical and behavioral interventions. Although generally desired, achieving such close collaboration among professionals in a community setting is often quite difficult.

 

Efficacy of Behavior Therapy

Many are under the assumption that behavior therapy does not work. Children treated in the MTA protocol with behavior therapy showed a comparable response to those children treated with medication in the community with respect to ADHD outcomes. Although behavior therapy did not have the most robust treatment effect as a single modality, it was included as a treatment modality specifically because of the multiple prior studies that have demonstrated its efficacy.

In the MTA study, parent report of “parent-child relations” was higher in the Behav group than the CC group. When moderator variables were examined to determine if select subgroups had a differential response to the interventions provided, it was noted that in children with a comorbid anxiety disorder, behavior therapy was essentially as effective as medication management, and that the combined therapy group responded significantly better than either treatment alone.

 

Generalization of the MTA Findings

Clinicians must remember that the MTA study focused exclusively on children with ADHD, combined type, and should not be generalized to all ADHD patients. Children with ADHD, Inattentive type, were not included in this study. Children with ADHD, inattentive type typically have fewer difficulties with social functioning and are often able to focus better in a quiet home environment than in a classroom with 25 other children. Thus, whereas the MTA study clearly suggests that children with ADHD, combined type, should generally be treated with medication for school and homework (eg, 12-hour duration), the decision to treat a child with ADHD, innattentive type with medication during the after-school period should be determined on a case-by-case basis. To the extent that a significant percentage of children with ADHD also have a learning disability, clinicians’ questions to parents about a child’s difficulty completing homework should delineate between distractibility due to ADHD and learning difficulties due to an associated learning disability.

 

Medication Management

In recent years, several new medications have been approved for treatment of children with ADHD.9 Although many of these newer medications are simply improved, longer-acting preparations of familiar stimulants, these extended-release preparations do confer several advantages. With effective long-acting preparations, children with ADHD should no longer need to go to their school nurse for a mid-day dose of medication. This means that children will not have gaps in coverage in between doses, and some of the sharp daytime blood level peaks and troughs should be eliminated. Since the longer-acting stimulants (methylphenidate and mixed amphetamine salts) work beyond the 7–8 hour school day, these once-a-day dosing preparations better enable ADHD children to do their homework after school without subsequent re-dosing. This is an especially big advantage for “latchkey kids,” who will no longer need to assume responsibility for self-medication, further reducing potential for problems with adherence or diversion. In addition to improved long-acting preparations, the Food and Drug Administration has recently also approved two other medications for treatment of ADHD (dexmethylphenidate and atomoxetine), and several other preparations are currently in development.

 

Choosing a Stimulant

Methylphenidate, dextroamphetamine, and mixed amphetamine salt preparations are generally equally effective. Approximately 75% of children with ADHD respond well to any one specific stimulant medication, and 90% respond well to stimulants when more than one is tried. Although many children with ADHD respond equally well to different stimulants, some children respond better to methylphenidate than amphetamines, and for others, it is the reverse. Unfortunately, medication response cannot be predicted a priori. Thus, as in the MTA titration protocol, if a patient with ADHD does not respond well to one stimulant preparation despite adjustments in the medication regimen (eg, timing, dose), a second stimulant should be tried. Although some physicians chose amphetamine preparations as their first-line stimulant, the amphetamines do have a higher side-effect rate than methylphenidate. For this reason, it may be best to start patients on a long-acting methylphenidate preparation and switch to an amphetamine product if methylphenidate is ineffective or poorly tolerated.

Since once-a-day dosing is best for every child whenever possible, patients should be started on long-acting preparations to streamline the titration phase and to maximize confidentiality, convenience, and adherence. Some clinicians choose to start patients on short-acting preparations to minimize side effects and allow greatest dosing flexibility. Once stable, the patient should be switched to a longer-acting preparation. If a patient has a need for after-school medication coverage (all children with ADHD, combined type, and some patients with ADHD, inattentive type), a 12-hour methylphenidate stimulant preparation is recommended. If a child functions well after school (eg, many children with ADHD, inattentive type), an 8-hour extended-release methylphenidate preparation may be sufficient. Titration is often necessary, and clinicians may occasionally choose to give a child both an 8-hour and a 12-hour preparation if, for example, the child needs 12-hour coverage but less medication after school than in school.

The two main amphetamine preparations, dextroamphetamine and mixed amphetamine salts, appear to be comparable in efficacy, though there have been very few studies directly comparing the two agents. Both are available in short- and long-acting preparations: dextroamphetamine in preparations of 4 hours and 8 hours and amphetamine salts in preparations of 5–6 hours and 10–11 hours. Mixed amphetamine salts extended-release capsules are available in many different strengths (5, 10, 15, 20, 25, 30 mg) and can be given as a sprinkle, further facilitating dose titration.

Whereas all of the previously available methylphenidate preparations include methylphenidate in its racemic form (both the “d” and “I” stereoisomers), clinical studies suggest that methylphenidate’s biological activity resides with the “d” isomer. Dexmethylphenidate is a novel methylphenidate preparation in that it is only comprised of the “d” isomer. Preliminary studies suggest that dexmethylphenidate may have a somewhat longer duration of benefit and superior clinical effect compared to immediate-release racemic methylphenidate. However, it is not yet available in a long-acting preparation.

 

Nonstimulants

Atomoxetine was recently approved by the FDA for the treatment of ADHD in children (>6 years of age), adolescents, and adults.10 This medication is a selective norepinephrine reuptake inhibitor, though it has been shown in animals to also have dopaminergic activity in the prefrontal cortex. Unlike stimulants, where there is a relatively close relationship between half-life and clinical duration of action, there is a sharp dissociation between atomoxetine’s pharmacokinetic and pharmacodynamic profile.

Atomoxetine is metabolized by the 2D6 pathway of the cytochrome P450 system. The drug’s half-life is approximately 5 hours in patients who are “extensive metabolizers” (94% of the general population), but much longer (20.4 hours) in the small percentage of individuals who are “poor metabolizers.” Interestingly, the clinical duration of benefit is substantially longer than the half-life.

In several double-blind, placebo-controlled trials with atomoxetine, improvement was noted compared to placebo on school teacher ratings as well as on parent questionnaires. Benefit was noted by parents not only after school but also, to some extent, in the evening and the following morning (prior to the next day’s medication). In children, gastrointestinal side effects, such as decreased appetite, stomach ache, and vomiting, are most common. These side effects may be minimized if given with a meal or if the daily dose is divided into two doses (eg, breakfast and dinner).

It is recommended that patients treated with atomoxetine be started on a low dose, and titrated to the target dose after at least 3 days. The recommended dose is generally based on weight. In children and adolescents who weigh under 70 kg, the starting dose is 0.5 mg/kg/day and the target dose is 1.2 mg/kg/day. For individuals who weigh >70 kg, the starting dose is 40 mg and the target dose is 80 mg. The total daily dose in children and adolescents should not exceed 1.4 mg/kg/day or 100 mg/day, whichever is less. Some clinical benefit is likely to be seen within a few days of starting the medication. However, full clinical response may take several weeks.

Atomoxetine appears to have several potential advantages compared to the stimulants. Nonetheless, it is premature to consider it a preferred first-line medication for youth with ADHD. To begin with, although atomoxetine is FDA-approved as a “once-a-day” therapy for children and adolescents with ADHD, there are limited data specifically looking at its efficacy and tolerability when prescribed in that manner. Atomoxetine is said to have a 70% response rate (when including QD and BID studies together). Although this response rate is similar to the stimulants when considered individually, it is much lower than the stimulants collectively. More importantly, there have been no well-designed direct comparisons between any of the stimulants and atomoxetine. Although atomoxetine is said to have a comparable effect size to the stimulants (0.7 s.d.), well-controlled double-blind trials are needed to assess the relative efficacy and tolerability of this new medication.

If children or adolescents with ADHD do not respond well to treatment with stimulants or atomoxetine, other medications may be helpful. Although not approved for the treatment of ADHD, clinical studies have shown bupropion, a2-agonists (clonidine, guanfacine), and tricyclic antidepressants to be effective in some youths with ADHD. In general, these medications do not have as robust an effect size as the stimulants. These medications are sometimes used in conjunction with the stimulants as well, although there are very few studies evaluating the safety and efficacy of combining medications for treatment of ADHD. For example, there have been a few cases of sudden death reported in children taking clonidine and stimulants concurrently. However, these were rare events and atypical clinical cases, so it is unclear to what extent these medications can be used together safely.

 

Conclusion

Effective treatment of ADHD is essential. Medication, when prescribed carefully and monitored closely, is the single most effective treatment for ADHD. Clinicians must be mindful of their prescribing practices and the extent to which their medication management routines deviate from those followed in the MTA protocol. Children in the MTA study were more likely to be on a 12-hour medication regimen with close follow-up and titration as needed. Community physicians in the MTA study did not communicate with the teachers as regularly and did not meet with the family as frequently.

In the MTA study, behavioral interventions were not as effective as medication when optimized. However, the addition of behavior therapy to medication not only led to increased parent satisfaction with the treatment protocol, but also resulted in some additional benefits beyond the core symptoms of ADHD. Unfortunately, many factors preclude families from receiving a multimodal treatment approach as provided in the MTA study. Nonetheless, the availability of new long-acting stimulants and the recent release of other medications should enable concerned and caring physicians to provide children and adolescents with effective treatment of ADHD.  PP

 

References

1. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086.

2. Jensen PS, Hinshaw SP, Swanson JM, Greenhill LL, Conners CK. Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers. Dev Behav Pediatrics. 2001;22:60-73.

3. Vitiello B, Severe JB, Laurence MS, Greenhill L, Arnold LE. Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA. J Am Acad Child Adolesc Psychiatry. 2001;40:188-196.

4. Greenhill LL, Abikoff H, Arnold LE, Cantwell D, Conners CK. Medication treatment strategies in the MTA study: relevance to clinicians and researchers. J Am Acad Child Adolesc Psychiatry. 1996;35:1304-1313.

5. March JS, Swanson JM, Arnold LE, Hoza B, Conners CK. Anxiety as a predictor and outcome variable in the Multimodal Treatment Study of Children with ADHD (MTA). J Abnorm Child Psychol. 2000;28:527-541.

6. Conners CK, Epstein JN, March JS, Angold A, Wells KC. Multimodal treatment of ADHD in the MTA: an alternative outcome analysis. J Am Acad Child Adolesc Psychiatry. 2001;40:159-167.

7. Barkley R. Commentary on the Multimodal Treatment Study of Children with ADHD. J Abnorm Child Psychol. 2000;29:595-599.

8. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC. American Psychiatric Association; 1994.

9. Adesman A. New medications for treatment of children with attention-deficit/hyperactivity disorder: review and commentary. Pediatr Ann. 2002;31:514-522.

10. Strattera [package insert]. Indianapolis, IN: Eli Lilly; 2002.

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Karen Pierce, MD

Primary Psychiatry. 2003;10(4):77-80

 

Dr. Pierce is assistant professor of psychiatry in the Department of Psychiatry at Northwestern University and medical director of the Children’s Partial Hospitalization Program at Children’s Memorial Hospital in Chicago, IL.

Disclosure: Dr. Pierce is on the speaker’s bureau for Eli Lilly, Novartis, and Ortho-McNeil.

Please direct all correspondence to: Karen Pierce, MD, Children’s Memorial Hospital, Box 10, 2300 Children’s Plaza, Chicago, IL 60614; Tel: 773-525-1218; Fax: 773-525-8925; E-mail: kpierce@childrensmemorial.org


Abstract

Attention-deficit/hyperactivity disorder (ADHD) is being recognized as prevalent in adulthood. However, there is a lack of extensive research and thorough physician training of adult ADHD. The recent awareness of the chronicity of childhood symptoms of ADHD continuing throughout the lifespan makes this an important topic. This disorder is complicated by the fact that comorbid psychiatric problems accompany the ADHD symptoms. Physicians often overlook symptoms of inattention, distractibility, and impulsivity in adulthood. This article reviews prevalence of ADHD in adults as well as diagnosis and treatment options.

 

Introduction

With increased awareness of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, research1and clinical experience has indicated that many young people with ADHD continue to have symptoms as adults. An increasing number of adults present to clinics with symptoms of ADHD.2Recognition of this disorder in adults can be complex due to the difficulty of obtaining and understanding the impact of ADHD symptoms in one’s life and the coexistence of other psychiatric conditions. Obtaining an accurate past history of symptoms is difficult and often misleading. The limitation of a strict adherence to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)3 definition of ADHD adds to the frustration. This article highlights the incidence and prevalence of adult ADHD, provides information on how to diagnose the disorder, and reviews effective treatments.

 

Prevalence

ADHD is common among adults. Estimates of occurrence of ADHD in adulthood range from 1% to 6%.4 Occurrence of adult ADHD can be difficult to study as some of the core symptoms of ADHD remit with age. Although the rate of hyperactivity and impulsivity declines with age, inattention symptoms often remain. In adult epidemiology studies, the incidence of ADHD is approximately 4.7%.5,6 The lowest incidence of adult ADHD was reported by Heiligenstein and Keeling7 at 4.0%.

Several predictors of persistence for ADHD into adulthood include positive family history of ADHD, psychosocial adversity, and comorbid disorders such as conduct disorder, oppositional defiant disorder, and mood/anxiety disorders.8 Another reason that adult ADHD is often overlooked may be due to the way we define remission and categorize the symptoms. Adults may not have the required number of DSM-IV symptoms to meet full criteria but may have enough disability to be functionally impaired.3 Longitudinal studies of children with ADHD have revealed that 60% no longer meet diagnostic criteria (syndromatic remission), 30% continue to have symptomatic remission (subthreshold symptoms), and only 10% achieve full functional remission.2

An interesting discussion by Biederman and colleagues9 explored the curious data showing that ADHD in adults have a more equal gender distribution than in childhood. In children the gender ratio of ADHD favors males at 4:1 to females at 9:1. Biederman and colleagues9 postulated that since boys have a greater tendency to demonstrate disruptive behavior disorders than girls, the disorder is diagnosed more in boys during childhood. Further studies in females at younger ages are required to fully understand this phenomenon. Perhaps by diagnosing more adult women with ADHD, we can better calculate the prevalence of the disorder in young girls.

 

Impact

ADHD carries great impact as indicated in recent studies.6 Nonmedicated adults with ADHD often suffer from the cumulative effects of a lifetime of ADHD-associated behaviors. Pomerleau and colleagues10 studied 71 adults with ADHD (55 males, 16 females; mean age=34 years) and found higher rates of smoking compared with controls. Results of the study suggest that smokers with ADHD find exceptional difficulty quitting (despite numerous attempts to quit) compared with the general population. In addition, individuals with untreated ADHD are more prone to abuse substances.11 Children with ADHD?who are untreated typically begin drinking 3 years earlier than their peers.11 Adults with ADHD are at risk for increased medical costs, increases job changes, and are more often self-employed.12 They have jobs with lower status and fail to achieve or be promoted. They struggle with vocational, academic, or social demands. Barkley and colleagues12 demonstrated increase in traffic accidents in adults and adolescents with ADHD not related to knowledge about driving rules or safety in a driving lab.

ADHD is a heterogeneous condition that has a heritable component. The genetic basis for the etiology of ADHD has a heritability of .75%.13 Often, adults first get diagnosed when their children are diagnosed with the disorder and receive intervention.14 Completing ADHD symptom checklists on their child reveals that they, too, suffer with many of the same problems. The pathophysiology of ADHD shown by both anatomic and functional studies may lie within the frontosubcortical system.15 Structural neuroimaging studies reveal problems in the frontal cortex, prefrontal cortex, corpus collosum, globus pallidus, vermis of the cerebellum, and the caudate nucleus.15 Functional imaging continues to investigate and validate these findings and show decreased cerebral metabolism. These tests are for research purposes only and do not help to confirm the diagnosis.

 

Making the Diagnosis

An ADHD diagnosis is made by a clinical exam. There are no laboratory tests or psychological tests that confirm a clinical presentation. Since ADHD is a performance-based disability, the procedure to assess this can be subjective. Can a medical student or an intern attain that level of education and suddenly develop ADHD? How about a second-time mother who gets overwhelmed, distracted, and first presents with symptoms after having no symptoms with the first child? Many adults with ADHD were able to get by until multi-level high performance tasks needed to be juggled and completed. A thorough interview becomes important with specific questions about impairment. In assessment of ADHD, one needs to carefully observe the person’s motor activity and their attention when not directly engaged. Planning to be engaged in paperwork during the interview can expose inattention and distractibility. There are adult rating scales for ADHD available to confirm a diagnosis.16

There are 18 symptoms defined by DSM-IV to diagnose ADHD.3 Adults may present these symptoms differently than children.3,7 Adults tend to be self-referred, rarely presenting to the clinician with behavior that disrupts others the way many children present. Spouses and employment personnel note less productivity, missing deadlines, being late for work, poor financial management, or forgetfulness. Interpersonal skills suffer as impatience, being quick to become angry, and excessive talking interfere with the reciprocal nature of relationships.

The inattention in adults may manifest as inattention to details. They may make lists and then forget to check what is on it and miss the task.14 Many adults with ADHD can read a magazine or brief article but not a whole novel. They may regularly read the encyclopedia because the entries are concise. Adult ADHD patients report inner restlessness and becoming easily overwhelmed. Over-commitment to activities and poor time management may round out the picture. In adolescents and adults, symptoms of hyperactivity can take the form of restless feelings and difficulty engaging in quiet or sedentary activities. Adults can be extremely fidgety but in a socially acceptable way, like wiggling their toes or drumming their fingers quietly. Shifts in sitting and walking around the consulting room are also signs of ADHD. Other symptoms may include impulsive job changes, driving too fast, traffic violations, or an excess of smoking or caffeine consumption.

For a diagnosis of ADHD, symptoms must occur frequently, persist for at least 6 months, and be inconsistent with the developmental level.3 Careful history including job performances, academic achievement, and the pattern of relationships can establish the chronicity of the symptoms. An adult with ADHD may be fortunate to have kept one job but when asked about the job it becomes obvious that the duties are changed frequently (eg, an emergency room physician). It is important to ask about the person’s work and conduct an assessment of their performance within the job. One may deny symptoms of ADHD until it becomes obvious; for example, when the secretary is on vacation, inattention, disorganization, and forgetfulness may become more apparent.

Perhaps the most difficult DSM-IV criteria to establish in adults is that the symptoms must cause impairment prior to 7 years of age.3 Retrospective history is often inaccurate, as adults have trouble remembering childhood symptoms. There is no evidence that 7 years of age is the magic number for the onset of the disorder, but rather represents the long-standing nature of the illness and its impact on functioning. Gathering old report cards or communicating with the parents to establish history and chronicity can be helpful. ADHD symptoms may present later when the task complexity increases such as in college or in professional school. One DSM-IV criteria for ADHD is some impairment from the symptoms in two or more settings, such as school, work, or home.3 To establish problems functioning in two or more areas, reports from spouses, children, and work relations can be helpful both to establish the diagnosis and to enlist help during the treatment phase.

The DSM-IV states that impairment is required in order to make a psychiatric diagnosis. There must be evidence of impairment in social, academic, or occupational functioning.3 This can create controversy, and good clinical judgment is helpful. However, it is not always easy to judge what constitutes impairment. For example, a gifted student may achieve B’s and C’s in college, or a busy housewife may forgets her errands and have to go to the store three to four times a day to complete a task. Both of these individuals are significantly achieving below the individual’s expectation and would meet the impairment criteria. This should be carefully documented before treatment begins as these symptoms will be markers for treatment interventions.

Another DSM-IVcriteria is the exclusionary diagnosis.3 More often in adults, ADHD is not considered in the presence of coexisting conditions. Frontal lobe functioning is impaired in many diseases and psychiatric diagnoses. Often, the ADHD symptoms are missed because focus is on the other disease state.

The three subtypes of ADHD are defined in DSM-IV as the inattentive type, hyperactive-impulsive type, and the combined type.3 Most often, adults present with the inattentive subtype. Those with the combined type usually have a strong history of symptoms throughout their childhood, with little remission. Impulsive irritability and hyperactivity still occur in adults but may present in a more socially acceptable way than the disruptive behaviors of childhood.

 

Comorbidity

Comorbidity is commonplace in people with ADHD. Studies in children show increased rates of anxiety, depression, and substance use. Adults must be screened for ADHD symptoms and other psychiatric disorders. Among patients with ADHD, antisocial personality disorder occurs in 12% to 27%, alcohol and drug dependence in 27% to 46%, major depressive disorders in 17% to 31%, and anxiety disorders in 32% to 50%.17 Often when depression or an anxiety disorder in an adult clears, underlying issues with executive functioning and attention can be found. Demoralization from the underachievement that a chronic attention disorder presents is common. Feelings of inadequacy, a sense of failure, and underachievement can lead to depressive symptoms. Not being able to read a book because of inattention, distractibility, or missing deadlines can be humiliating. This should be differentiated from depression. In addition, substance abuse must be treated and understood as a separate disorder or possibly a way to self-medicate symptoms of ADHD.

 

Treatment

Treatment of ADHD should improve the patient’s functional outcomes. As ADHD is a chronic disorder, impairment will be very individualized and so should treatment. Before a treatment plan is undertaken, care must be taken to identify target symptoms and measure severity. Developing a list of symptoms to be treated or using a standardized rating scale of severity is a way to establish treatment markers.

There are three components for treatment of adult ADHD: (1) education of patients and caregivers to create a framework for understanding and managing behavior; (2) psychosocial interventions to improve socialization and interpersonal interactions; and (3) pharmacologic interventions to treat physiologic manifestations of the disorder.

Education is the first step to easing miscommunications and misconceptions of adult ADHD. Referral to support groups or national organizations can be helpful. Often, newly diagnosed adult patients need to reframe their lives and their past with the new knowledge that has been gained. Understanding the disorder and its impact can provide great relief to the patient.

 

Psychosocial Intervention

Psychosocial interventions with a person’s support group are beneficial. There are no studies on psychosocial treatment of adults, but any of the management techniques used with children may be helpful. Adults can set up a reward system for each task that is completed. Employers, spouses, and significant others benefit from knowledge that is gained about the chronicity of the disorder and the impact on one’s life. Systems to improve organization such as computer systems or lists can be mainstays of treatment.

Behavioral treatment works when it is constantly implemented. Like pharmacotherapy, when behavior treatment ends, so does the symptom relief. Employers can insist on weekly meetings to keep things on track. A very successful businessman with ADHD may flounder when his boss stops their weekly phone reports, and improve once the procedure is reinstated. Simple plans to keep things in the same place or to dedicate daily time to organization are also beneficial.

A recent development in ADHD is the concept of coaching. Coaches establish working relationships with clients to help promote organization and time management. The concept of coaching is to help individuals with ADHD set goals, accept limitations, acknowledge strengths, develop social skills, and create strategies that help to manage their lives. Coaches have varied educational and professional backgrounds and should be screened and interviewed. The American Coaching Association is an organization that can partner a person with ADHD with a coach.18

 

Pharmacologic Intervention

Pharmacologic treatment studies in adults have been limited (Table).19-31 Stimulants have been the standard treatment for an adult with ADHD. Studies have shown that stimulants work on core symptoms in adult ADHD.19-23

The two classes of stimulants that come in both short-acting and long-acting forms are methylphenidate23 and amphetamines.30 The advantages of the stimulants are their effectiveness in reducing core symptoms such as impulsivity, and increasing patient compliance. Stimulants have been used for a long time to treat ADHD and safety and efficacy data is established.19-31 They may also improve social functioning and academic performance. The limitations include the lack of continuous relief, diversion and abuse potential, and tolerability and safety. The adverse effects of stimulants are similar for all but there is individual variation between patients and agents. Side effects occur most frequently during initiation of therapy and with dosage increases. Side effects such as headache, abdominal pain, and decreased appetite tend to decrease over time. With adults, monitoring blood pressure and pulse is important as these agents may increase heart rate and blood pressure.17

The dosage range for adults varies and can be assessed with rating scales and feedback from the patient. The methylphenidate dose is about 15–20 mg every 4 hours during the period that the symptoms should be treated. The dose ranges from 60–80 mg/day depending on the symptom list. Some patients want pharmacology during the work day while others want their social time under control with medication. The long-acting stimulants methylphenidate HCl, and amphetamine extended release, have been shown to be efficacious in adults.17

A new medication that has been studied in adults is atomoxetine, a norepinephrine reuptake inhibitor that has been shown to alleviate symptoms of ADHD.32 The side-effect profile of atomoxetine is similar to the stimulants but these side effects are usually transient. The dosage range for atomoxetine for adults is 80–100 mg.32

Other medications which have been tried with adults include tricyclic antidepressants, bupropion, and venlafaxine. These are not approved by the Food and Drug Administration for use in ADHD and studies of these agents are limited and inconclusive.

 

Conclusion

ADHD is a chronic disorder, not only for children and adolescents but adults as well. With continuing symptoms into adult life,33 impairment may impact the functioning of an adult with attention symptoms. Careful screening for this disorder in adults will lead to proper intervention and an improved quality of life in those who suffer from ADHD.  PP

 

References

1. Goldman L, Genel M. Diagnosis and treatment of attention deficit/hyperactivity disorder in children and adolescents. JAMA. 1998;279:1100-1107.

2. Faraone SV, Biederman J, Spencer T, et al. Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry. 2000;48:9-20.

3. Diagnostic and Statistical Manual of Mental Disorders. 4th ed text-revision. Washington, DC: American Psychiatric Association;2000:85-93.

4. Biederman J. Attention-deficit/hyperactivity disorder: a lifespan perspective. J Clin Psychiatry. 1998;59(suppl 7):4-16.

5. Schweitzer JB, et al, Attention-deficit hyperactivity disorder. Med Clin North Am. 2001;85:757-777.

6. Murphy K, Barkley RA. Attention deficit hyperactivity disorder in adults: comorbidites and adaptive impairments. Compr Psychiatry. 1996;37:393-401.

7. Heilegenstein E, Keeling RP. Presentation of unrecognized attention deficit hyperactivity disorder in college students. J Am Coll Health. 1995;43:226-228.

8. Biederman J, Faraone S, Milberger S, et al. Predictors of persistence and remission of ADHD into adolescence: results from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351.

9. Biederman J, Faraone SV, Mick E, et al. Clinical correlates of ADHD in females: findings from a large group of girls ascertained from pediatric and psychiatric referral sources. J Am Acad Child Adolesc Psychiatry. 1999;38:966-975.

10. Pomerleau OF, Downey KK, Stelson FW, et al. Cigarette smoking in adult patients diagnosed with attention deficit hyperactivity disorder. J Subs Abuse. 1995;7:373-378.

11. Simkin DR. Adolescent substance use disorders and comorbidity. Pediatr Clin North Am. 2000;49:463-477.

12. Barkley RA, Murphy KR, DePaul GR, et al. Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functions. J Int Neuropsychol Soc. 2002;8:655-672.

13. Hudziak JJ, Heath AC, Madden PF. Latent class factor analysis of DSM-IV ADHD: A twin study of female adolescents. J Am Acad Child Adolesc Psychiatry, 1998;34:848-857.

14. Faraone SV, Biederman J, Mick E. Symptom reports by adults with attention deficit hyperactivity disorder: are they influenced by attention deficit hyperactivity disorder in their children? J Nerv Ment Dis. 1997;185:583-584.

15. Casey BJ, et al. Implication of right fronto-striatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997;36:374-383.

16. Multi-Health Systems. Conners’ Adult Attention Deficit Rating Scale (CAARS). North Tonawanda, NY: Multi-health Systems Inc.; 1994:138.

17. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002(suppl 2):26S-48S.

18. The ADDA Guiding Principles for Coaching Individuals With Attention Deficit Disorders. Available at: http://www.add.org/content/coach/ coachingguidlines2.htm. Accessed: March 2003.

19. Mattes JA, Boswell L, Oliver H. Methylphenidate effects on symptoms of attention deficity disorder in adults. Arch Gen Psychiatry. 1984;41:1059-1063.

20. Wender PH, Reimherr FW, Wood D, Ward M. A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. Am J Psychiatry. 1985;142:547-552.

21. Gualtieri CT, Ondrusek MG, Finley C. Attention deficit disorders in adults. Clin Neuropharmacol. 1985;8:343-356.

22. Shekim WO, Antun F, Hanna GL, McCracken JT, Hess EB. S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: preliminary results from an open trial. Psychopharmacol Bull. 1990;26:249-253.

23. Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapey K. A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention-deficit disorder. Arch Gen Psychiatry. 1995;52:434-443.

24. Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. Am J Psychiatry. 1996;153:1147-1153.

25. Wilens TE, Biederman J, Spencer TJ, et al. Controlled trial of high doses of pemoline for adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 1999;19:257-264.

26. Paterson R, Douglas C, Hallmayer J, Hagan M, Krupenia Z. A randomised, double-blind, placebo-controlled trial of dexamphetamine in adults with attention deficit hyperactivity disorder. Aust N Z J Psychiatry. 1999;33:494-502.

27. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol. 2000;10:311-320.

28. Horrigan JP, Barnhill LJ. Low-dose amphetamine salts and adult attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2000;61:414-417.

29. Spencer T, Biederman J, Wilens T, et al. Efficacy of a mixed amphetamine salts compound in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2001;58:775-782.

30. Taylor FB, Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2001;21:223-228.

31. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108:E83.

32. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53:112-120.

33. Weiss G, Hechtman L, Milroy T, et al. Psychiatric status of hyperactives as adults: a controlled prospective 15-year follow-up of 63 hyperactive children. J Am Acad Child Psychiatry. 1985;24:211-220.

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Karen Pierce, MD

Primary Psychiatry. 2003;10(4):69, 70,75,76

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Alison M. Kerr, FRCP
 
Primary Psychiatry. 2003;10(2):59-62

 

Dr. Kerr is senior lecturer and honorary consultant in pediatrics and learning disability at the academic centre in the Department of Psychological Medicine at Glasgow University in Scotland.

Acknowledgments: Dr. Kerr is pleased to acknowledge advice on the content of this paper from Anthony Charman, PhD, Fiona Knott, PhD, Bronwen Burford, PhD, and Jill Clayton-Smith, MD.

Disclosure: Dr. Kerr’s work has been supported by the Rett Syndrome Association United Kingdom, Rett Syndrome Association Scotland, International Rett Syndrome Association, RSRF, the University of Glasgow, and the families of people with Rett syndrome.

Please direct all correspondence to: Alison M. Kerr, FRCP, Gartnavel Hospital, Great Western Road, Glasgow, United Kingdom, G12 OXH; Tel: 011-44-141-211-0281; Fax: 011-44-141-357-4899; E-mail: amk5m@clinmed.gla.ac.uk


 

Abstract

How should the physician provide for people with Rett disorder? From a newly described entity that was presumed to be rare in 1966, Rett disorder has become one of most characterized developmental disorders. Over 1 in 10,000 females are diagnosed with the disorder, which is among the most common genetic causes of combined profound intellectual and motor disability in women. Primary care practitioners, neurologists, and psychiatrists carry the responsibility of detecting the condition in infancy, offering support to the family, and monitoring the progress of the child and adult through a series of age- and stage-related difficulties. These difficulties include epilepsy, poor central cardiorespiratory regulation, movement disorder, nutritional problems, a tendency to joint contractures and scoliosis, severe intellectual disability, agitation, lack of speech, and evident enjoyment of non-speech communication and musical interaction. Discovery of the causative mutations in the methyl-CpG-binding protein-2 gene allows positive identification and has demonstrated a wide range in clinical severity. A unique combination of defects in control of both mind and movement provides fresh insights on the development of the brain. This article briefly reviews recent discoveries and their relation to behavior. A table compares possible early signs in Rett syndrome, Angelman, and autism.

Introduction

Whereas some diseases destroy the brain, many developmental disorders impact specific functions and demonstrate vulnerabilities that depend on the characteristics of particular neural networks. Rettis a prime example of such a disorder and, as incomplete as our knowledge of the subject is, the present knowledge brings fresh insights to understanding the brain.

Andreas Rett1 distinguished the syndrome in 1966. Children with Rett disorder tend to be attractive and they love face-to-face contact. While personalities are most endearing, the unsteady posture, agitation, hand stereotypy, and color changes with abnormal breathing indicate severe problems in regulating movement, thought, and vital functions. Minimum estimated prevalence in the United Kingdom is 1 in 10,000 females at 14 years of age2 and the remarkably good survival (deaths are 1.2%/year)3 indicates that the disorder probably accounts for more than 1 in 10 women with profound disability.4

Genetics of Rett Disorder

The causative mutations on methyl-CpG-binding protein-2 (MECP2) usually arise in the male germ cell due to its numerous cell divisions.5,6 Offspring receiving a paternal X chromosome must be female. This explains why most cases are female but recurrences are rare. Since every female cell expresses only one of its two X chromosomes, the defective X is usually active in half the cells of the body. This causes typical/classic Rett disorder. If one X is used preferentially (skewed X inactivation) then the disorder may be exceptionally severe or mild. The risk to any offspring of a woman with a mutation is 50%. Severe XY male cases occur when the mutation affects every cell.7 In Klinefelter’s syndrome (XXY) the disorder can presents in its classic form.8 A mild male form may be seen if mutation occurs after fertilization, affecting a proportion of cells (somatic mosaic).9

The several types and many sites of mutation on MECP2 affect clinical severity, but in females the X-inactivation pattern chiefly determines outcome.10 A MECP2 mutation has been reported to cause a disabling neurologic disorder in a kindred’s males but not females.11 In about 15% of classic and 50% of atypical cases a mutation is not found.7,10 It is expected that still unidentified mutations may affect the same neural mechanisms. Initial diagnostic confusion with Rett disorder may occur in metabolic and brainstem disease.12 Rett disorder is often confused with Angelman’s syndrome and autistic disorder, causing particular diagnostic difficulty. Subtle differences in the early symptoms may distinguish these indicating differences in the neural mechanisms involved (Table).13,14

Pathogenesis of Rett Disorder

The MECP2 gene is believed to contribute to regulation of the activity of other genes15 with an important role in the development and maintenance of cortical connections.16-19

A recently developed mouse model for Rett disorder bears considerable likeness to human disease and is currently being used in research.17,18 Human brain growth is suboptimal, especially in the frontal, parietal, and temporal cortex where dendritic territories are reduced.19

From their study of disturbed sleep rhythms, Nomura and colleagues20 and Nomura and Segawa20,21 suggested that hypofunction of the monoamines, noradrenaline, and serotonin is present as early as 36 weeks of gestation.At 2 years of age, deficient brain-derived growth factor has been demonstrated22 and serotonin receptors are increased in the brainstem23 suggesting defective serotonin supply or activity. Throughout early childhood, levels of glutamate are raised24 and cortical receptors are increased, decreasing later.25 This period of increased excitatory neurotransmitter level coincides with a regressive, hyperactive period in the child.

Early Presentation and Diagnosis

A newborn child with Rett disorder appears well grown with a normal head circumference but is exceptionally placid. Experienced caregivers soon notice hypotonic or occasionally stiff posture, reduced mobility, and, as the year progresses, increasing repetitive movements and lack of exploration.26 However, there is real progress along with the early signs of developmental deviation, which explain some late diagnoses. Development usually plateaus around 10–12 months of age when confusion with Angelman’s syndrome is common (Table).

In most children 1–3 years of age there is a regressive period when hand use and communication decline. The child often becomes agitated with unexplained crying and hand use is replaced with stereotyped twisting or patting, frequently in the hair or mouth. At this stage confusion may arise with autism (Table). After some months the respiratory rhythm becomes erratic with spells of shallow, deep, and apneustic breathing, and breath holding. The electroencephalogram (EEG) becomes abnormal with bursts of slow large amplitude waves, sometimes with spikes, accentuated in sleep.26,27

Regression is a time of high stress for the brain and measures supportive of the neurones seem justified but there is no evidence that these affect the course or severity of the disease. Formal trials are now required using objective outcome measures.28 In severely affected males, the presentation is contracted into a few months, with death possibly due to cardiorespiratory arrest.29

Characteristics of Rett Disorder

Epilepsy

Epilepsy occurs in over half of patients with Rett disorder.26 Their EEG is generally reported “normal” or “immature,” initially becoming abnormal towards the end of regression, with bursts of slow waves and spikes, increased during sleep.27 It may be difficult to distinguish atypical epileptic seizures from the much more frequent “vacant spells” due to poor autonomic regulation.27,30,31 Breathing rhythm is labile, with any one child showing several awake rhythms.30,31 Rhythms are grouped into those which are inadequate for gas exchange (feeble breathing); those which delay the onset of expiration common in the youngest girls (apneustic breathing); vigorous breathing often with hyperventilation, and Valsalva breathing where increased pressure in the chest interrupts venous return to the heart—common in older people.30,31 Non-epileptic vacant spells may occur during each type of breathing and may cause sudden deaths.3,30,31 Uncoordinated expiration causes aerophagy. Prolongation of the cardiac QT interval has been reported.32,33

Posture and Mobility

Many Rett disorder patients learn to walk independently, some quite late is life, and most walk with support. However, as initial hypotonia gives way to hypertonia and dystonia there is a tendency for the limbs to adopt dystonic postures. Without physiotherapy and careful positioning this leads to joint contractures with loss of mobility. Experience with the British cohort26 suggests that deterioration may be prevented in all but the most severe if there is due attention to therapy and the individual is encouraged to be active. Scoliosis is common and more difficult to prevent, progressing rapidly during growth spurts.34 Osteoporosis is common in young and active children.35

Nutrition and Growth

Nutritional and growth difficulties are implicated in half the deaths reported in the British survey.3 Most Rett disorder patients are dependent on others to feed them, posture may be awkward, chewing is either poor or absent, mouth closure is weak, and abnormal respiration makes timing of the swallow difficult. Gastro-oesophageal reflux is common and constipation almost universal.26,36 Habit toilet training is frequently possible26 and final stature is usually reduced.37

Hand Behavior, Communication, and Understanding

The marked hand stereotypy that aids in diagnosis is obligatory, repetitive, fixed, and exacerbated by agitation. Involuntary movements also affect the limbs, trunk, and face. Although voluntary hand use improves, after regression it remains poor. However, opportunities presented directly to touch, sight, and hearing such as wind, water, musical sounds, contact with responsive musical instruments, and close face-to-face “conversational” contact, seem to release useful movement (Figure).26,29 Poor voluntary control of movement and the confusion which is evident in Rett disorder patients makes it difficult to assess the level of understanding and many families feel that their daughters’ understanding is in advance of their ability to communicate.

Although 70% of girls in the British survey29 developed some speech initially, only 15% continued after regression. A few patients with mild Rett disorder can sign although speech is absent. Puberty and fertility in Rett disorder patients appear normal and the preference for human contact makes them vulnerable to physical and sexual abuse.26

Conclusion

With many questions still unanswered, it is known that in the Rett disorder patients, the genetic fault impacts on the autonomic, motor, and cognitive integrative systems in the brain. The neuronal differentiation on which these systems depend begins in the brainstem due to agents which may change their role or disappear later and the effects on dendritic and synaptic development continue to unfold as the infant grows. Investigation of the Rett mouse will be crucial to detection at the earliest stage of the disorder.17,18

The individual with Rett disorder is aware, interested, and involved yet deprived of means of expression. To this incapacity is added physiologically driven agitation and an involuntary movement disorder which mimics intentional movement. To serve patients with Rett disorder adequately, the physician must understand what is affected and what is spared by the disorder, tailoring assessments and care to particular needs. (See page 32 for a routine Rett disorder medical supervision checklist).

Further insight into the mind of the person with Rett disorder deserves close examination of behavior in the first year of life since the abilities displayed then seem eclipsed rather than destroyed by the subsequent regression.26 Sensitive and objective methods should be adopted to track the perceptions and responses of the individual. PP

References

1. Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr. 1966;116:723-726. [German].

2. Kerr AM. Rett Syndrome British Longditudinal Study (1982-1990) and 1990 survey. In: JJ Roosendaal, eds. Mental Retardation and Medical Care. Zeist: Uitgeverij Kerckbosch: 1992:143-145.

3. Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL. Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry. 1997;6:71-74.

4. Kerr AM, Mitchell JM, Robertson PE. Short fourth toes in Rett syndrome: a biological indicator. Neuropediatrics. 1995;26:72-74.

5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Franke U, Zoghbi HY. Rett Syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185-188.

6. Girard M, Couvert P, Carrie A, et al. Parental origin of de novo MECP2 mutations in Rett Syndrome. Eur J Hum Genet. 2001;9:231-236.

7. Shahbazian MD, Zoghbi HY. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol. 2001;14:171-176.

8. Salomao Schwartzman J, Zatz M, dos Reis Vasquez L, et al. Rett Syndrome in a boy with a 47, XXY karyotype. Am J Hum Genet. 1999;64:1781-1785.

9. Clayton-Smith J, Watson P, Ramsden S, Black GC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet. 2000;356:830-832.

10. Amir RE, Van den Veyver IB, Schultz R, et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann Neurol. 2000;47:670-679.

11. Meloni I, Bruttini M, Longo I, et al. A mutation in the Rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet. 2000;67:982-985.

12. Hagberg B, Witt-Engerstrom I. Early stages of the Rett syndrome and infantile neuronal ceroid lipofuscinosis—a difficult differential diagnosis. Brain Devel. 1990;12:20-22.

13. Maestro S, Muratori F, Cavallaro MC, et al. Attentional skills during the first 6 months of age in autistic spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2002;41:1239-1245.

14. Osterling JA, Dawson G, Munson JA. Early recognition of 1-year-old infants with autism spectrum disorder versus mental retardation. Dev Psychopathol. 2002;14:239-251.

15. Nan X, Campoy FJ, Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88:471-481.

16. Kaufmann WE, Naidu S, Budden S. Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome. Neuropediatrics. 1995;26:109-113.

17. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett Syndrome. Nat Genet. 2001;27:322-326.

18. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001;27:327-331.

19. Armstrong D, Dunn JK, Antalffy B, Trivedi R. Selective dendritic alterations in the cortex of Rett syndrome. J Neuropathol Exp Neurol. 1995;54:195-201.

20. Nomura Y, Segawa M, Hasegawa M. Rett syndrome—clinical studies and pathophysiological considerations. Brain Devel. 1984;6:475-486.

21. Nomura Y, Segawa M. The monoamine hypothesis in Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:205-226.

22. Rikonnen R. Neurotrophic factors in the pathogenesis of Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:125-129.

23. Armstrong DA, Kinney H. The neuropathology of the Rett Disorder In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:57-84.

24. Lappalainen R, Rikonnen R. High levels of cerebrospinal fluid glutamate in Rett Syndrome. Pediatr Neurol. 1996;15:213-216.

25. Blue M, Johnson M. Amino acid receptor studies in Rett syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:115-118.

26. Kerr AM, Witt Engerstrom I. The clinical background to the Rett disorder In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:1-26.

27. Cooper R, Kerr AM, Amos P. Rett syndrome: critical examination of clinical features, serial EEG and video-monitoring in understanding and management. Eur J Pediatr Neurol. 1998;2:127-135.

28. Ellaway C, Williams K, Leonard H, Higgins G, Wilcken B, Christudoulou J. Rett syndrome: randomised controlled trial of L-carnitine. J Child Neurol. 1999;14:162-167

29. Kerr AM, Belichenko P, Woodcock T, Woodcock M. Mind and Brain in Rett disorder. Brain Dev. 2001;23:S44-S49.

30. Julu PO, Kerr AM, Apartopoulos F, et al. Characterisation of breathing and associated autonomic dysfunction in the Rett Disorder. Arch Dis Child. 2001;85:29-37.

31. Julu PO. The central autonomic disturbance in Rett Syndrome. In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:131-181.

32. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT in Rett Syndrome. Arch Dis Child. 1999;80:470-472.

33. Glaze DG, Schultz RJ. Autonomic dysfunction and sudden death in Rett Syndrome: prolonged QTc intervals and diminished heart rate variability In: Kerr AM, Witt Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press; 2001:251-255.

34. Loder RT, Lee CL, Richards BS. Orthopaedic aspects of Rett Syndrome: a multicenter review. J Ped Orthop. 1989;9:557-562.

35. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett Syndrome. Dev Med Child Neurol. 1999;41:323-328.

36. Morton RE, Bonas R, Minford J, Kerr A, Ellis RE. Feeding ability in Rett syndrome. Dev Med Child Neurol. 1997;39:331-335.

37. Holm VA. Physical Growth and development in patients with Rett Syndrome. Am J Med Genet. 1986;(suppl 1):119-126.


Articles

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Rett Syndrome:
The Challenge of the Pathology

By Dawna Duncan Armstrong MD, FRCP
 
Primary Psychiatry. 2003;10(2):63-66

 

Dr. Armstrong is professor of pathology and pediatrics in the Department of Pathology at Baylor College of Medicine in Houston, Texas.

Disclosure: This work was partially supported by National Institute of Health grant #HD40301, the International Rett Association, and the Harvard Brain Tissue Resource.

Please direct all correspondence to: Dawna Duncan Armstrong, MD, Baylor College of Medicine, Department of Pathology, 1 Baylor Plaza, Houston, TX 77030; Tel: 832-824-1873; Fax: 832-825-1032; E-mail: dawnaa@bcm.tmc.edu


 

Abstract

What is the neuropathology of Rett syndrome, a common cause of severe mental handicap in girls and some boys? The definition of the neuropathology of Rett syndrome has been problematic. It is believed that its primary lesion probably resides in the synaptic apparatus of selected neurons. An x-linked gene for methyl-CpG-binding protein-2 (MECP2) has been identified to be abnormal in 80% of Rett syndrome patients. The protein belongs to a family of methyl-binding proteins, the members of which are variously distributed and have different specific functions. We are now at an enviable state of knowledge in our study of the biology of Rett syndrome. We have an excellent probe, MECP2, with which to explore the subtle serious alterations in the Rett syndrome brain. We have a diagnostic test for 80% of cases. There is a literature and experience with the methyl-binding proteins, and there are powerful molecular technologies that may help elucidate the role of MECP2’s interaction with developmentally regulated proteins that are critical for brain maturation and function.

Introduction

Rett Syndrome,1 the most frequent disorder associated with profound mental handicap in girls,2 has an incidence of 1/10,000–23,000.3 It is primarily a sporadic disorder with a classic phenotype,4 but there are also familial cases,5-7 and atypical forms.

In the classic Rett syndrome, an apparently healthy baby girl fails in her infancy to reach “normal” motor milestones. A deceleration in the growth of head circumference is the first objective sign, but because most of the girls have a global growth delay, there is not an obvious microencephaly or an immediately identified central nervous system (CNS) abnormality.8,9 The infant may begin to walk in an awkward manner, to show some hand automatisms, and to use words. Near the end of infancy there is a dramatic and, for the parents, a sudden deterioration in behavior, with crying, inconsolability, and lack of communication.10 This time period, which may vary in its duration, is designated as the “period of regression” because following this frightening and dramatic episode, there is a loss of skills, particularly of hand use and speech. Thereafter, there does not appear to be any further motor development.11

The girls live in a dependent way, requiring full care. They mature sexually,12 and are burdened with malfunction of the nervous system that may result in seizures,13 breathing irregularities,14 sleep disturbances,15 gastrointestinal disorders,16 and circulatory failure.17 Their nutrition is problematic and scoliosis frequently develops. The girls live into adulthood but with an increased risk for sudden death.18 Most girls and women with Rett syndrome live at home where they establish communication with their families by behavior and vocalizations that are interpretable by their devoted caregivers. The two conditions that are considered in the clinical differential diagnosis of the classic Rett syndrome are Angelman’s syndrome and Batten’s disease.

Atypical cases of Rett syndrome include boys who may exhibit failure to develop beyond the newborn period,19 or the very rare boy who may show the development, postures, and behavior of atypical Rett syndrome girl.20,21 Some girls are designated as atypical because they retain simple speech, or have limited hand use.

The classification of individuals with Rett syndrome has become more problematic since the discovery of abnormalities in the gene methyl-CpG-binding protein-2 (MECP2).22 To date, approximately 80% of girls with the clinical diagnosis of Rett syndrome have been found to have alterations in the MECP2 gene. However, there are 20% of girls with the clinical diagnosis of Rett syndrome in whom no abnormalities of MECP2 have been found. Also, there are some cases of children with abnormalities of MECP2 who carry a different clinical diagnosis, eg, autism, Angelman’s syndrome, and boys with mental retardation.23-26 The explanation for these problematic clinical and genetic associations is being sought.

In the cases of the girls with clinical features of Rett syndrome who have no detectable MECP2 abnormalities, it is hypothesized that unexplored regions of MECP2 (for example, the promoter regions or the 3 prime region) may be the sites of mutations or other abnormalities that have not been explored. There is also the possibility that other chromosomes have abnormalities that produce a Rett syndrome phenotype.27

The identification of mutations in MECP2 in children with clinical manifestations of other types of pervasive disorders of brain development is excitingly provocative and suggests that studies of the biology of MECP2 may provide a probe into the understanding of these other conditions.

Pathology

Defining the pathology of Rett syndrome has been challenging. The time of onset is not known, and this remains a critical question for early diagnosis and possible intervention. The infant “seems” normal at birth and the diagnosis is not suspected until later in infancy.28 It has been debated whether the pathologic process is progressive or whether some changes, such as scoliosis, muscle atrophy, and osteoporosis are the secondary effects of an early motor deficit. The clinical disorder suggests that there are lesions at every level of the CNS, with particular involvement of the motor and sympathetic systems.29 However, it is not known whether there is a primary site of pathology whose influence in the immature brain is responsible for a faulty generalized development, or whether there is a single mechanisms that interrupts neuronal function at all levels of the CNS.

The phenotypes and prognosis for girls with Rett syndrome has been carefully observed and it is the clinical criteria that are utilized for making the diagnosis of classic Rett syndrome.30 The clinical-pathologic correlations of Rett syndrome were focused on several hypothesis before the gene was identified. The first hypothesis was based upon clinical observations and the second upon pathologic observations. Now, with knowledge of a specific protein abnormality, a new study of geno-phenotype and clinical-pathologic correlation has begun.31,32

The first clinical description of Rett syndrome, by Andreas Rett,33 described girls with mental and motor delay and abnormalities of ammonia metabolism. Twenty years later, a study by Hagberg and colleagues1 recognized the same disorder which they named “Rett syndrome,” in recognition of the earlier report, and which they defined as a progressive disorder with autism, ataxia, and mental retardation. The abnormalities in ammonia were not observed in this larger group of patients.

Observations of the neuropathology of Rett syndrome have been accumulated on a case-by-case basis. Jellinger and colleagues34,35 made the first significant observations, defining the small size of the Rett syndrome brain, and the decreased amounts of melanin in the pars compacta of the substantia nigra. The subsequent pathologic examinations have not identified in the Rett syndrome brain any of the characteristic neuropathologies that have been observed in other progressive brain disorders of children, ie, there is no primary storage material, no consistent abnormalities of the myelin, or obvious hydrocephalus.8,36

With no morphologic correlation for a deteriorating brain disease, the essential pathology of the syndrome was reconsidered and it was hypothesized that the small brain size could represent a disorder of development, rather than atrophy. This theory had several attractions; it explained the infant-like capabilities of the girls, their patterns of blood flow,37,38 their electroencephalogram,39 some of their neurotransmitter studies,40-48 and the relative stability of the girls’ condition following the regression stage. However, the period of regression and the attainment of sexual maturity are not completely explained by a pervasive developmental arrest hypothesis. The identification of the abnormalities in the MECP2 protein in Rett syndrome now focuses Rett syndrome investigations on the question of how the altered biology of MECP2 could underlie the pathogenesis of brain pathology in Rett syndrome.

The early morphologic studies of Rett syndrome were concerned with the question of whether Rett syndrome represented a disorder of all body systems. The clinical presentation of Rett syndrome appears to involve many organs; respiratory, with episodes of hyperventilation or apnea14; cardiac, with unexplained sudden death18; gastrointestinal, with constipation and abdominal bloating; and musculoskeletal, with scoliosis.49 The small size of the Rett syndrome child suggests that generalized growth failure is a prominent feature.9 Studies of nutrition and endocrine function have been undertaken,50,51 and there is no definite consistent abnormality of the endocrine system identified. Studies regarding skeletal abnormalities are not complete.28

Autopsy studies of Rett syndrome have not revealed any characteristic pathology in any body system apart from the decreased size of organs compared with standards established for age. However, when organ weight is correlated with body length in Rett syndrome, it is only the brain that is significantly decreased in weight. The average Rett syndrome brain weight is about 950 g, the weight of a 12-month-old infant. This brain weight does not correlate with the age of the Rett syndrome child or adult at death. That is, there is no age-related decline in weight that would suggest that the brain is undergoing atrophy.52

Magnetic resonance imaging studies of Rett syndrome patients at various ages also failed to demonstrate atrophy.53 This identification of a selective effect on brain size supports the idea that Rett syndrome is primarily a disorder of the brain and nervous system.

Recent studies of MECP2 identify that its expression is highest in the CNS,54 so that its lack of activity in Rett syndrome will presumably determine the neuropathology of Rett syndrome. The normal low level of MECP2 expression in other organs endorses the idea that Rett syndrome is a disorder of the CNS.

Neuropathology

As suggested above, apart from decreased size, there is no obvious brain abnormality. The cerebral hemispheres are relatively slightly smaller than the cerebellar hemispheres, (D.D.A., unpublished data, 2003) but the gross appearance is that of a small normal brain. Studies of selected regions of the cerebral cortex using golgi impregnations have identified a decreased size of dendritic arborizations in layers three and five of the frontal, motor, and temporal cortex. This altered dendritic length affects the basal dendrites more than the apical dendrites, except in the motor cortex.

The relative decrease in dendritic branching is not correlated with the age of the Rett syndrome patient, reinforcing the idea that in Rett syndrome it is a failure of development of dendrites, rather than atrophy of dendrites.55 The trisomy 21 brain, which has been reported to show abnormalities of dendritic structure, does not exhibit the same alterations observed in Rett syndrome.56 Thus, there may be selective alteration in neuronal dendrites because of MECP2 deficiency and the resulting effects on synaptic function may be the basis for the Rett syndrome symptomatology.57

There have been a few studies illustrating decreased spines and synapses in Rett syndrome.58,59 Studies of neuronal numbers in Rett syndrome have also been limited to few subjects and few regions. Jellinger and colleagues34 showed a normal compliment of neurons in the substantia nigra. Bauman and colleagues60 showed decreased size and increased packing density of neurons in the hippocampus. Belichenko61 found a normal neuronal compliment in the speech cortex. Neurochemical studies have defined alterations, usually deficiencies, in structural proteins and neurotransmitters in the Rett syndrome brain and cerebrospinal fluid (CSF).40,41,43,46,47,62-64 Microtubule-associated protein 2 is deficient in the subplate neurons, and in its cortical expression.65 The cortical expression of cyclooxygenase-2 is also abnormal.66 Substance P is reduced in brainstem neurons, particularly those involved with the sympathetic nervous system, and in the CSF.67 Nerve-growth factor immunoreactivity and other trophic-like factors are reduced in the CSF of Rett syndrome.68

Studies of neurotransmitters metabolites and receptors in Rett syndrome patients reveal altered expression that are age related. The catecholamines in the CSF are decreased in the youngest Rett syndrome girls.69 The expression of glutamate receptors in brain is elevated during the earliest stage of Rett syndrome, leading to the suggestion that the associated elevations in glutamate may produce a toxic effect which could be responsible for the regression and the onset of seizures in the Rett syndrome child.70 There has been a demonstration of reduced acetylcholine in the Rett syndrome brain71 and there are preliminary studies of elevated serotonin receptors in the regions of the Rett syndrome brainstem, suggesting that there is an immaturity of that system.72

The pathoetiology and the effects of abnormalities in most of the essential neurotransmitters in Rett syndrome remains a challenging problem. Correction of the altered biochemical milieu in the Rett syndrome brain may alleviate some of the distressing symptoms for the patient, but to date the complexity and our incomplete knowledge of the biochemical alterations preclude intervention. Mouse models of MECP2 mutations and deletions provide opportunity to study this.73-75

MECP2 in the Human Brain

MECP276 expression begins after the completion of organogenesis. At 10 weeks gestation it can be identified in the nuclei of some brain stem neurons and in the Cajal Retzius neurons of the immature cortex. Thereafter, the numbers of MECP2 positive cells (probably mostly neurons) increases so that at 40 weeks gestation some neurons of all brain regions express MECP2. After birth there is an increasing number of neurons which express the protein. The expression of MECP2 in individual neurons is variable. Some neurons show an intense immunoreactivity, while others show less.

There is a debate about whether MECP2 expressed in cytoplasm. There are regional differences in the expression of MECP2, and some neuronal cell types express less than other (eg, granule neurons express less than pyramidal neurons).We do not understand the significance of the variation in cellular MECP2 expression in relation to function. MECP2 belongs to a family of methyl-binding proteins each of which has different functions and which is differently expressed in the brain.77 These questions are under active investigation.

Conclusion

The pathogenesis of the structural and functional pathology in Rett syndrome remains unknown. It appears that, in classic Rett syndrome with random x-inactivation, the girl will have approximately 50% of the normal amount of MECP2. This amount is not enough for normal brain function. Understanding the mechanisms by which MECP2 deficiency alters neuronal dendrites and synapses, and of how intervention for MECP2 deficiency may be possible, is the exciting challenge for investigators studying Rett syndrome and related disorders. PP

References

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2. Hagberg B. Rett’s syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatr Scand. 1985;74:405.

3. Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett syndrome: A population based registry. Pediatrics. 1993;91:445-449.

4. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol. 1988;23:425-428.

5. Zoghbi HY, Percy AK, Schultz R, Fill C. Patterns of X chromosome inactivation in the Rett syndrome. Brain Dev (Tokyo). 1990;12:131-135.

6. Zoghbi HY, Ledbetter DH, Schultz R, Percy AK, Glaze DG. A de novo KX;3 translocation in Rett syndrome. Amer J Med Gen. 1990;35:148-151.

7. Anvret M, Wahlstrom J, Skogsberg P, Hagberg B. Segregation analysis of the X-chromosome in a family with Rett syndrome in two generations. Amer J Med Gen. 1990;37:31-35.

8. Armstrong D. The neuropathology of the Rett syndrome. Brain Dev. 1992;14(suppl):S89-S98.

9. Schultz R, Glaze DG, Motil KJ, et al. The pattern of growth failure in Rett syndrome. Am J Dis Child. 1993;147:633-637.

10. Percy AK. Rett syndrome. Curr Opin Neurol. 1995;8:156-160.

11. Nomura Y, Segawa M. Motor Symptoms of the Rett Syndrome: Abnormal tone, posture, locomotion and stereotyped movement. Brain Dev. 1992;14(suppl):S21-S28.

12 Engerstrom W, Forslund M. Mother and daughter with Rett Syndrome [letter]. Dev Med Child Neurol. 1992;34:1022-1023.

13. Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. 1998;106:79-83.

14. Kerr AM. A review of the respiratory disorder in Rett syndrome. Brain Dev. 1992;114(suppl): S43-S45.

15. Glaze DG, Frost JD, Jr., Zoghbi HY, Percy AK. Rett’s syndrome: characterization of respiratory patterns and sleep. Ann Neurol. 1987; 21:377-382.

16. Motil KJ, Schultz RJ, Browning K, Trautwein L, Glaze DG. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. 1999;29:31-37.

17. Johnsrude C, Glaze D, Schultz R, Frideman R. Prolonged QT intervals and diminished heart rate variability in patients with Rett syndrome [Abstract]. Pacing Clin Electrophysio. 1995;18:889.

18. Sekul EA, Moak JP, Schultz RJ, Glaze DG, Dunn JK, Percy AK. Electrographic findings in Rett syndrome: An explanation for sudden death? J Pediatr. 1994;125:80-82.

19. Schanen C, Francke U. A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. Am J Hum Genet. 1998;63:267-269.

20. Salomao SJ, Zatz M, dos R, et al. Rett syndrome in a boy with a 47,XXY karyotype. Am J Hum Genet. 1999;64:1781-1785.

21. Armstrong J, Pineda M, Aibar E, Gean E, Monros E. Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation. Ann Neurol. 2001;50:692.

22. Amir RE, Van dV, I, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185-188.

23. Kleefstra T, Yntema HG, Oudakker AR, et al. De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia. Clin Genet. 2002;61:359-362.

24. Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C et al. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001;10:941-946.

25. Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B et al. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet. 2001;38:224-228.

26. Beekman RP, Hofstee N, Smeitink JAM, Poll-The BT, Duran M. Rett syndrome in a patient with medium chain acyl-CoA dehydrogenase deficiency. Eur J Pediatr. 1994;153:264-266.

27. Clarke A, Schanen C, Anvret M. Towards the genetic basis in Rett syndrome. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England: Oxford University Press; 2001:27-56.

28. Kerr AM. Early clinical signs in the Rett disorder. Neuropediatrics. 1995;26:67-71.

29. Julu P. The central autonomic disturbances in Rett syndrome. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder in the Developing Brain. Oxford, England: Oxford University Press, 2001:131-182.

30. Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, September 11, 2001. Eur J Paediatr Neurol. 2002;6:293-297.

31. Hoffbuhr KC, Moses LM, Jerdonek MA, Naidu S, Hoffman EP. Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype. Ment Retard Dev Disabil Res Rev. 2002;8:99-105.

32. Shahbazian MD, Zoghbi HY. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol. 2001;14:171-176.

33. Rett A. Cerebral atrophy associated with hyperammonemia. In: Vinken PW, Bruyn GW, eds. Handbook of Clinical Neurology. New York, NY: Elsevir/North Holland Biomedical Press; 1977:305-325.

34. Jellinger K, Seitelberger F. Neuropathology of Rett syndrome. Amer J Med Gen. 1986;24:259-288.

35. Jellinger K, Armstrong D, Zoghbi HY, Percy AK. Neuropathology of Rett syndrome. Acta Neuropathol. 1988;76:142-158.

36. Bauman ML, Kemper TK. The neuropathology of Rett syndrome is pervasive throughout the brain. Neurology. 1991;41:306

37. Yoshikawa H, Fueki N, Suzuki H, Sakuragawa N, Masaaki I. Cerebral blood flow and oxygen metabolism in Rett syndrome. J Child Neurol. 1991;6:237-242.

38. Nielsen JB, Friberg L, Lou H, Lassen NA, Sam ILK. Immature pattern of brain activity in Rett syndrome. Arch Neurol. 1990;47:982-986.

39. Glaze DG, Frost JD, Zoghbi HY, Percy AK. Rett syndrome: correlation of electroencephalographic characteristics with clinical staging. Arch Neurol. 1987;44:1053-1056.

40. Nomura Y, Segawa M, Higurashi M. Rett syndrome and early catecholamine and indolamine deficient disorder. Brain Dev (Tokyo). 1985;7:334-341.

41. Zoghbi HY, Percy AK, Glaze DG, Butler IJN, Riccardi VM. Reduction of biogenic amineic levels in the Rett syndrome. N Eng J Med. 1985;313:921-924.

42. Zoghbi HY, Milstien S, Butler IJ, et al. Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome. Ann Neurol. 1989;25:56-60.

43. Wenk GL, Naidu S, Casanova MF. Altered neurochemical markers in Rett syndrome. Neurol. 1991;41:1753-1756.

44. Wenk GL, Naidu S, Moser H. Altered neurochemical markers in Rett syndrome. Ann Neurol. 1989;26:467.

45. Johnston MV, Hohmann C, Blue ME. Neurobiology of Rett syndrome. Neuropediatrics. 1995;26:119-122.

46. Wenk GL, O’Leary M, Nemeroff CB, Bissette G, Moser H, Naidu S. Neurochemical alterations in Rett syndrome. Dev Brain Res 1993;74:67-72.

47. Wenk GL. Alterations in dopaminergic function in Rett syndrome. Neuropediatrics. 1995; 26:123-125.

48. Nielsen JB, Bertelsen A, Lou HC. Low CSF HVA levels in the Rett syndrome: A reflection of restricted synapse formation? Brain Dev. 1992;14(suppl):S63-S65.

49. Kerr A, Witt-Engerstrom I. The clinical background of the disorder. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England: Oxford University Press. 2001:1-16.

50. Holm VA. Physical growth and development in patients with Rett syndrome. Amer J Med Gen. 1986;24:119-126.

51. Motil KJ, Schultz RJ, Wong WW, Glaze DG. Increased energy expenditure associated with repetitive involuntary movement does not contribute to growth failure in girls with Rett syndrome. J Pediatr. 1998;132:228-233.

52. Armstrong D, Dunn JK, Schultz R, et al. Organ growth in Rett Syndrome post mortem examination analysis. Pediatr Neurol. 1999;20:125-129.

53. Reiss AL, Faruque F, Naidu S, et al. Neuroanatomy of Rett syndrome: A volumetric imaging study. Ann Neurol. 1993;34:227-234.

54. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11:115-124.

55. Armstrong D, Dunn JK, Antalffy B, Trivedi R. Selective dendritic alterations in the cortex of Rett syndrome. J Neuropath Exp Neurol. 1995;54:195-201.

56. Armstrong DD, Antalffy B, Dunn JK. Quantitative golgi studies of dendrites in Rett syndrome and trisomy 21. J Neuropath Exp Neurol. 1996;55:630.

57. Johnston MV, Jeon OH, Pevsner J, Blue ME, Naidu S. Neurobiology of Rett syndrome: a genetic disorder of synapse development. Brain Dev. 2001;23(suppl 1):S206-S213.

58. Belichenko PV, Dahlstrom A. Studies on the 3-dimensional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and lucifer yellow microinjections. J Neurosci Methods. 1995;57:55-61.

59. Belichenko PV, Hagberg B, Dahlstrom A. Morphological study of neocortical areas in Rett syndrome. Acta Neuropatho. 1997; 93:50-61.

60. Bauman ML, Kemper TK, Arin DM. Microscopic observations of the brain Rett syndrome. Neuropediatrics. 1995;26:105-108.

61. Belichenko PV. The morphologic substrate for communication. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England; Oxford University Press: 2001:277-302.

62. Perry TL, Dunn HG, Ho HH, Crichton JU. Cerebrospinal fluid values for monoamine metabolites, gamma aminobutyric acid, and other amino compounds in Rett syndrome. J Pediatr 1988;112:234-238.

63. Lekman A, Witt-Engerstrom I, Holmber B, Percy AK, Svennerholm L, Hagberg B. Cerebrospinal fluid and urine biogenic amine metabolites in Rett syndrome. Clinic Genetics. 1990;37:173-178.

64. Budden SS, Myer EC, Butler IJ. Cerebrospinal fluid studies in the Rett syndrome: Biogenic amines and beta-endorphins. Brain Dev (Tokyo). 1990;12:81-84.

65. Kaufmann WE, Naidu S, Budden S. Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome. Neuropediatrics. 1995;26:109-113.

66. Kaufmann WE, Worley PF, Taylor CV, Bremer M, Isakson PC. Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome. Brain Dev. 1997;19:25-34.

67. Deguchi K, Antalffy BA, Twohill LJ, Chakraborty S, Glaze DG, Armstrong DD. Substance P immunoreactivity in Rett syndrome. Pediatr Neurol. 2000;22:259-266.

68. Riikonen RS. Neurotrophic factors in the pathogenesis of Rett syndrome. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England: Oxford University Press; 2001:127-130.

69. Percy AK. Neurochemistry of the Rett syndrome. Brain Dev. 1992;14(suppl):S57-S62.

70. Blue ME, Naidu S, Johnston MV. Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Ann Neurol. 1999;45:541-545.

71. Wenk G. Selective changes in Rett syndrome neurochemistry: Findings of normal dopaminergic and decreased cholinergic function. Eur Child Adolesc Psychiatry. 1997;6:S87-S88.

72. Armstrong D, Kinney HC. The neuropathology of the Rett disorder. In: Kerr A, Witt-Engerstrom I, eds. Rett Disorder and the Developing Brain. Oxford, England: Oxford University Press; 2001:58-84.

73. Shahbazian M, Young J, Yuva-Paylor L, et al. Mice with truncated MECP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron. 2002;35:243-254.

74. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001;27:327-331.

75. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001;27:322-326.

76. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11:115-124.

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Articles

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Linda S. Kahn, PhD, and Uriel Halbreich, MD
 
Primary Psychiatry. 2003;10(2):41-45

 

Dr. Kahn is research assistant professor, and Dr. Halbreich is professor of psychiatry, research professor of OB/GYN, and director of biobehavioral research in the BioBehavioral Program at the State University of New York in Buffalo.

Disclosure: Dr. Halbreich has received grant support from Pfizer and Eli Lilly. Dr. Kahn reports no financial, academic, or other support of this work.

Please direct all correspondence to: Uriel Halbreich, MD, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Hayes C Annex, Suite 1, 3435 Main Street, Building 5, Buffalo, NY 14214-3016; Tel: 716-829-3811; Fax: 716-829-3812; E-mail: urielh@acsu.buffalo.edu

 



Abstract

How are premenstrual syndromes (PMS) identified and diagnosed, and what are the best approaches to treatment?PMS is a self-reported condition encompassing a broad array of symptoms which physicians must distinguish from other affective and general medical conditions in women. The hallmark of PMS is the cyclical occurrence of symptoms premenstrually, and their alleviation and remission shortly following the onset of menses. The pathophysiology of PMS involves multiple factors—particularly genetic vulnerability, environmental inputs, and the interaction between gonadal hormone fluctuations and neurotransmitters. For women with very mild symptoms, conservative nonpharmacologic treatment is recommended, including exercise, healthy nutrition, relaxation, and social support. For women with moderate to severe symptoms, especially if these symptoms are mood- and behavior-related, a variety of efficacious treatment options are available, with selective serotonin reuptake inhibitors being the treatment of choice.

Introduction

Premenstrual syndromes (PMS) are a broad, diversified cluster of emotional, behavioral, and physical symptoms that occur cyclically for a time span ranging from several days to over 2 weeks before menses. Symptoms subside shortly after the beginning of the menstrual period. Most women experience some symptoms premenstrually, particularly physical symptoms, at some time in their reproductive years (when a woman is menstruating), but they do not perceive these symptoms as either distressing or debilitating.1 It has been reported that 35% of women may have moderate PMS symptoms which do not meet standard diagnostic criteria, but may necessitate treatment,2,3 while 3% to 9% of women have dysphoric PMS severe enough to warrant pharmacologic treatment.4,5 These women may experience marked disruptions in work, relationships, productivity, and quality of life. These disruptions underscore the need to recognize and appropriately treat premenstrual syndromes. This review will briefly summarize current assessment guidelines, diagnostic criteria, and treatment aspects of premenstrual syndromes.

Definition

There is no current consensus on the definition of PMS. During the 1950s, the term “premenstrual syndrome” became associated with the physical and psychological symptoms occurring up to 2 weeks prior to menses and remitting after the onset of menstruation.6 Since then, distinct diagnostic criteria were developed by the American Psychiatric Association,7 the World Health Organization,8 and the American College of Obstetricians and Gynecologists.9

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV)7 criteria for premenstrual dysphoric disorder (PMDD) is the most rigorous, and requires the prospective confirmation of at least 5 of 11 total symptoms, and work/school, home, or social impairment (Table 1). PMDD is considered to be the most severe form of PMS because its symptoms mirror those of major depressive disorder, even though they are of a shorter and cyclic duration.10 However, the overlap between severe PMS and PMDD has been estimated to be approximately 79%.6,11

The International Classification of Diseases, Tenth Edition8 includes PMS (or premenstrual tension syndrome) under “pain and other conditions associated with female genital organs and menstrual cycle,” and its criteria are less formulated than that of the DSM-IV. The American College of Obstetrics and Gynecology criteria require the presence of one affective or somatic symptom during the 5 days prior to menses in the three previous menstrual cycles.

Etiology and Pathophysiology

The etiology of PMS probably involves multiple factors, including diversified genetic vulnerability, sensitivity to hormonal fluctuations, possible imbalance between rate of fluctuation of gonadal hormones (but not in their absolute levels) and changes in function of the brain and other organs.12-14 There is evidence suggesting that sensitivity to cyclic hormonal changes may have a genetic basis.15

Gonadal steroids, estrogen and progesterone, have been postulated as the main contributing factors to PMS since Frank’s landmark research during the early 1930s.16 Other hypotheses include decreased estrogen levels, decreased progesterone levels, and differences in estrogen progesterone level ratios. Particular focus was given to low progesterone, which became a rationale for progesterone suppository treatment—one of the most publicized treatment modalities for PMS.17 However, that treatment modality has not been confirmed by well-controlled studies. It has been suggested that most women with PMS might have increased, not decreased, levels of progesterone.18,19

Others believe that the levels of gonadal hormones in women with PMS are normal.20,21 However, these women might have differences in cyclicity or rate of fluctuations as well as increased sensitivity to “normal” fluctuations.19 Changes occurring during the early luteal phase might be as significant as those occurring during the symptomatic period itself.19 The reports that women do not have PMS in anovulatory cycles,22,23 that suppression of ovulation is a very effective treatment modality,24-26 and that hysterectomy and bilateral oophorectomy dramatically improve severe PMS symptoms27 support the notion that fluctuations in gonadal hormones and other ovulation-related processes are important factors in the pathobiology of PMS. Gonadal hormones probably interact with neurotransmitters and other processes that are putatively involved in regulation of mood and behavior.

Research undertaken since the 1980s has implicated serotonin and other neurotransmitters in the pathophysiology of PMS and PMDD.10,12,28 Animal studies have demonstrated that serotonergic neurons in the brain “modulate aspects of behavior also regulated by sex steroids.”28,29 This includes not only sexual behavior, but also aggression/irritability—a common PMS symptom.28 At the same time, the sex steroids estrogen, progesterone, and testosterone influence brain serotonergic activity and neurotransmission.28 Serotonergic dysfunction in PMS also has been postulated, based on decreased platelet uptake of serotonin,30 blunted response to serotonin agonists,31 and consistent therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of PMS.32

It has also been suggested that γ-aminobutyric acid (GABA) and the GABAA receptor may also be involved in the etiology of PMS. Women with PMDD and a past history of major depressive disorder (MDD) were found to have low plasma GABA levels. In women with PMDD but no past MDD, plasma GABA levels decreased from the nonsymptomatic, mid-follicular phase to the symptomatic, late luteal phase.33 The GABAA receptor is influenced by progesterone, and some of its metabolites. Progesterone and estrogen also interact with serotonergic and noradrenergic systems. These interactions are probably of importance in the pathophysiology of PMS/PMDD.

Symptomatology

Up to 300 different premenstrual complaints have been reported in patients with PMS,34 but only a few are consistent complaints assessed and identified in epidemiological studies. The most common include irritability, tension, depression, bloatedness, mastalgia, and headache.35-37 Clinically, the most commonly identified symptoms are depressed mood, mood swings, anxiety/tension, anger/irritability, low interest, decreased concentration, poor energy and changes, mostly increases, in sleep, appetite, and physical symptoms.38 The hallmark of PMS is the cyclical occurrence of symptoms premenstrually and their subsequent alleviation and remission with the onset of menses. Any symptom that appears during the premenstrual period may be considered to be related to PMS.

Many chronic disorders, both physical and psychiatric, are exacerbated premenstrually, or fluctuate in severity during the menstrual cycle and involve diversified body systems.39 Their main common denominator is the cyclicity, timing, the association with the menstrual cycle and the possible association with changes in gonadal hormones’ functions. These include neurological disorders, lung diseases, diseases of metabolism and enzymes, immune and autoimmune disorders, and gynecological disorders.39

Differential Diagnosis

There are no current diagnostic laboratory tests or other objective measurements to identify PMS. Rather, the diagnostic process relies mostly on prospective self-reporting of symptoms—optimally for two menstrual cycles. Several instruments, including the Daily Rating Form,40,41 have been developed and administered to patients to be used for self-reporting.

The Daily Rating Form, along with a self-questionnaire on medical, obstetric, gynecological, and psychiatric history, can be mailed ahead of time to the patient before her first office visit. The first visit should be scheduled for the late-luteal symptomatic phase. During this visit, the physician should review the patient’s self-report in detail, take a history, and differentiate PMS or PMDD from other possible disorders (Table 2). Routine biological tests should be undertaken to rule out other possible underlying medical conditions (Table 3). Tests include thyroid function, chemistry panel, liver function tests, complete blood count, and urinalysis. Although none of these tests are specific for PMS, they are administered to rule out other medical conditions.



The physician should also take a personal and family history of mood disorders or other mental problems. Many women who seek treatment for PMS actually have chronic disorders or an exacerbation of chronic MDD, dysthymic disorder, panic disorders, and other dysphoric disorders.42 These situations must be distinguished from PMS to develop an adequate treatment plan.

Treatment of Premenstrual Syndrome

A variety of treatment modalities are available for PMS. Conservative, nonpharmacologic treatment is recommended for women with mild PMS. This includes changes in life style, exercise, general healthy nutrition, relaxation, and social support.6,9,10,43

For women with moderate to severe PMS or PMDD, SSRIs are the first line of treatment because they are both effective and tolerated (Table 3).9,44 Several double-blind, placebo-controlled studies32,45-47 have demonstrated the efficacy of continuous administration of fluoxetine 20 mg/day for PMS and PMDD. The efficacy of continuous administration of sertraline 50–100 mg/day for PMDD has also been amply demonstrated.48-50 Fluoxetine and sertraline are approved by the Food and Drug Administration for PMDD indications. Paroxetine and citalopram have also proven effective form of treatment.51

Recent evidence suggests that intermittent administration of low-dose SSRIs during the luteal phase significantly improves both psychological and physical premenstrual symptoms even within the first cycle of treatment.52,53 Administration of long-acting, once weekly fluoxetine 90 mg, at the beginning and mid-luteal phase is probably equally effective.54

Anxiolytics may be administered during the luteal phase of the menstrual cycle for women with PMS and persistent anxiety that does not abate after a trial of SSRIs.6 Alprazolam, a short-acting benzodiazepine with antidepressant properties, has been shown to be effective in the management of PMS and PMDD at a dose of 2.25–0.5 mg TID which is administered during the luteal phase.11,55,56 However, these medications should be used with caution for long-term management of PMS and PMDD, due to their unfavorable side-effect profile and addictive potential.10

The link between PMS/PMDD symptomatology and the fluctuations of sex steroids associated with ovulation has led to the development of hormonal interventions, which should be considered second-line pharmacologic treatment.44 The goal of these therapies is to suppress ovulation, thereby reducing or eliminating PMS symptoms. The most well-known hormonal therapies include gonadotropin-releasing hormone (GnRH) agonists, danazol, progesterone, estrogen, and oral contraceptives. GnRH agonists induce a temporary, “medical oophorectomy.” Several studies reported complete resolution of premenstrual symptoms during GnRH therapy.23,24,57,58 The hypoestrogenic state induced by GnRH administration may result in postmenopausal symptoms as well as decreased bone mineral density and risk of osteoporosis during long-term treatment. Due to these concerns, several studies have evaluated “add-back” estrogen-progestin supplementation in patients treated with GnRH.59-61 However, these medications may precipitate mood symptoms, at least during the initiation of treatment, among women with severe PMS or PMDD.6,62

Danazol, an androgen derivative, has been shown to reduce symptoms of PMS, in dosages sufficient to suppress ovulation.26 However, significant side effects, including weight gain, mood changes, fluid retention, and acne, have prevented danazol from becoming a widely accepted treatment for PMS/PMDD.

Progesterone has long been advocated as a treatment for severe premenstrual symptoms.63 The rationale for progesterone therapy was the apparent temporal relationship between PMS symptoms and decreases in plasma progesterone levels, but empirical support for this theory is lacking.64,65 Moreover, double-blind, placebo-controlled trials of progesterone supplementation for the treatment of PMS have not demonstrated efficacy.21,66

Several controlled studies have reported the effectiveness of estrogen alone or with cyclical progesterone in the treatment of severe PMS.67-69 The suppression of ovulation seems to be a key factor in the efficacy of high-dose estrogen therapy, which must be cycled with progesterone to avoid endometrial hyperplasia.70 However, the addition of progesterone may precipitate a partial return of symptoms.

Some oral contraceptives have been used to treat PMS symptoms, even though their effectiveness has not been well-established.71-73 The goal of oral contraceptive therapy is to reduce hormonal fluctuations which might contribute to premenstrual dysphoria. However, findings of clinical trials on the use of oral contraceptives for PMS treatment have been inconsistent.74

Several randomized trials have suggested possible therapeutic benefits from dietary supplementation with calcium,75,76 magnesium,77 Vitamin B6,78 chasteberry,79 and other alternative therapies.44,80 A recent compreh ensive review80 evaluated randomized control trials of complementary/alternative therapies for PMS and found pervasive methodological problems. Further investigations on alternative therapies need to be undertaken before any of them can be considered viable treatment modalities.

Conclusion

PMS is quite prevalent in the general population. It is a self-reported, subjective disorder that requires the ruling out of other affective and general medical conditions to determine appropriate diagnosis and treatment. Women with mild symptoms should be encouraged to pursue nonpharmacologic therapy. For women with moderate to severe symptoms, several efficacious treatment options are available, with intermittent-luteal phase SSRIs as the treatment of choice for PMDD, and suppression of ovulation as a second-line treatment. PP

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38. Hurt SW, Schnurr PP, Severino SK, et al. Late luteal phase dysphoric disorder in 670 women evaluated for premenstrual complaints. Am J Psychiatry. 1992;149:525-530.

39. Halbreich U. Menstrually related disorders–towards interdisciplinary international diagnostic criteria. Cephalalgia. 1997;17 (suppl 20):1-4.

40. Endicott J, Nee J, Cohen J, Halbreich U. Premenstrual changes: Patterns and correlates of daily ratings. J Affect Disord. 1986;10:127-135.

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43. Johnson WG, Carr-Nangle RE, Bergeron KC. Macronutrient intake, eating habits, and exercise as moderators of menstrual distress in healthy women. Psychosomatic Medicine. 1995;57:324-30.

44. Pearlstein T, Steiner M. Non-antidepressant treatment of premenstrual syndrome. J Clin Psychiatry. 2000;61:22-27.

45. Menkes DB, Taghavi E, Mason PA, Spears GF, Howard RC. Fluoxetine treatment of severe premenstrual syndrome. Br Med J. 1992;305:346-347.

46. Stone AB, Pearlstein TB, Brown WA. Fluoxetine in the treatment of late luteal phase dysphoric disorder. J Clin Psychiatry. 1991;52:290-293.

47. Wood SH, Mortola JF, Chan YF, Moossazadeh F, Yen SS. Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study. Obstet Gynecol. 1992;80:339-344.

48. Yonkers KA, Halbriech U, Freeman E, et al. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. A randomized controlled trial. Sertraline Premenstrual Dysphoric Collaborative Study Group. JAMA. 1997;278:983-988.

49. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch Gen Psychiatry. 1999;56:932-939.

50. Pearlstein TB, Halbreich U, Batzar ED, et al. Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with sertraline or placebo. J Clin Psychiatry. 2000;61:101-109.

51. Dimmock PW, Wyatt KM, Jones PW, O’Brien PM. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet. 2000;356:1131-1136.

52. Halbreich U, Bergeron R, Yonkers KA, Freeman E, Stout AL, Cohen L. Efficacy of intermittent, luteal phase sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2002;100:1219-1229.

53. Cohen L, Miner C, Brown E, et al. Premenstrual daily fluoxetine for premenstrual dysphoric disorder: a placebo-controlled, clinical trial using computerized diaries. Obstet Gynecol. 2002;100:435-444.

54. Miner C, Brown E, McCray S, Gonzales J, Wohlreich M. Weekly luteal-phase dosing with enteric-coated fluoxetine 90 mg in premenstrual dysphoric disorder: a randomized, double-blind, placebo- controlled clinical trial. Clin Ther. 2002;24:417-433.

55. Harrison WM, Endicott J, Rabkin JG, Nee JC, Sandberg D. Treatment of premenstrual dysphoria with alprazolam and placebo. Psychopharmacol Bull. 1987;23:150-153.

56. Harrison WM, Endicott J, Nee J. Treatment of premenstrual dysphoria with alprazolam. A controlled study. Arch Gen Psychiatry. 1990;47:270-275.

57. Freeman EW, Sondheimer SJ, Rickels K. Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study. Psychopharmacol Bull. 1997;33:303-309.

58. Sundstrom I, Nyberg S, Bixo M, Hammarback S, Backstrom T. Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen. Acta Obstet Gynecol Scand. 1999;78:891-899.

59. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin [see comments]. J Clin Endocrinol Metabol. 1991;72:252A-252F.

60. Adashi EY. Long-term gonadotrophin-releasing hormone agonist therapy: the evolving issue of steroidal ‘add-back’ paradigms. Hum Reprod. 1994;9:1380-1397.

61. Leather AT, Studd JW, Watson NR, Holland EF. The treatment of severe premenstrual syndrome with goserelin with and without ‘add-back’ estrogen therapy: a placebo-controlled study. Gynecol Endocrinol. 1999;13:48-55.

62. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209-216.

63. Dalton K. The Premenstrual Syndrome. Springfield, Ill: Charles C. Thomas; 1984.

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65. Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Eng J Med. 1991;324:1174-1179.

66. Rapkin AJ, Chang LC, Reading AE. Premenstrual syndrome: a double blind placebo controlled study of treatment with progesterone vaginal suppositories. J Obstet Gynecol. 1987;7:217-220.

67. Magos AL, Brincat M, Studd JW. Treatment of the premenstrual syndrome by subcutaneous estradiol implants and cyclical oral norethisterone: placebo controlled study. Br Med J Clin Res Ed. 1986;292:1629-1633.

68. Watson NR, Studd JW, Savvas M, Garnett T, Baber RJ. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet. 1989;2:730-732.

69. Smith RN, Studd JW, Zamblera D, Holland EF. A randomized comparison over 8 months of 100 micrograms and 200 micrograms twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndrome. Br J Obstet Gynaecol. 1995;102:475-484.

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Facial Paralysis and Bell’s Palsy in Children: Current Diagnostic Concepts and Management Controversies

Michael S. Salman, MSc, MRCP

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Primary Psychiatry. 2003;10(2):67-70

 

Dr. Salman is a clinical research fellow in the Division of Neurology at the Hospital for Sick Children in Toronto.

Disclosure: The author reports no financial, academic, or other support of this work.

Acknowledgment: Dr. Salman would like to thank Dr. Daune MacGregor for editing and appraising the manuscript, and for her general and continuous support.

Please direct all correspondence to: Michael S. Salman, MSc, MRCP, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8; Tel: 416-813-1500; Fax: 416-813-6334; E-mail: michael.salman@sickkids.ca


 

Abstract

How is facial paralysis in children different from adults? Facial paralysis is uncommon in children. Before making the diagnosis of Bell’s palsy (acute idiopathic facial weakness), a prompt search for other causes must be made, especially when the child is <2 years of age, with facial weakness that progresses 3 weeks after onset or fails to improve within a few weeks, and is recurrent or bilateral. There is evidence that implicates herpes simplex virus and, to a lesser extent, varicella zoster virus reactivation in the pathogenesis of Bell’s palsy in children. This may explain its excellent prognosis in that age group. Management includes supportive treatment, such as artificial tears and eye patching. The current medical literature does not provide evidence for significant benefit from the use of steroids in pediatric Bell’s palsy. A trial involving a larger number of children is needed to document if steroids provide moderate benefit in Bell’s palsy. There is not enough information to recommend the routine use of acyclovir in pediatric Bell’s palsy, however, there is some evidence of benefit for using acyclovir in facial paralysis caused by varicella zoster virus reactivation.

Introduction

Bell’s palsy is defined as acute idiopathic facial muscle paralysis. It is a diagnosis of exclusion and its annual incidence is about 20/100,000.1 Bell’s palsy in the pediatric population has a different natural history, differential diagnosis, and different prognosis than in adults and, hence, deserves special consideration. This review attempts to address these issues with emphasis on establishing the correct diagnosis and reviewing evidence-based medical literature regarding management of Bell’s palsy.

Facial paralysis has been described since ancient times. In 1821, Sir Charles Bell2 drew attention to the anatomical course and function of the facial nerve. His name was linked to facial nerve paralysis at a time when nocause can be found.

Anatomy of the Facial Nerve

The facial corticobulbar tracts descend from the facial cortical motor area through the corona radiata and the internal capsule. The tracts then pass through the ventromedial lower pons, near the corticospinal tract, and descend mainly to the level of the upper medulla. The fibers decussate in the upper medulla and ascend in the dorsolateral medulla to synapse mainly in the contralateral facial nucleus.3

The facial motor nucleus supplying the upper facial muscles receive bilateral cortical innervation from the appropriate motor cortex. The lower facial muscles receive innervation from the contralateral motor cortex. A unilateral cortical (upper motor neuron) lesion spares the upper facial muscles and causes weakness of the contralateral lower facial muscles. This is seen in pediatric strokes caused by middle cerebral artery occlusion. Lesions affecting the facial motor nucleus and nerve cause weakness of all facial muscles ipsilaterally.

The facial nerve nucleus lies dorsolaterally in the caudal pons and upper medulla. The facial nerve leaves the brainstem at the pontomedullary junction. It enters the apex of the petrous part of the temporal bone with the eight cranial nerve and gives branches to the lacrimal gland, and stapedius muscle in the inner ear, sensation to the auricular skin, and the sublingual/submandibular salivary glands, and supplies the anterior two thirds of the tongue with taste fibers. Just before exiting the skull through the stylomastoid foramen, the facial nerve lies close to the inner ear and mastoid air cells. Finally, the facial nerve innervates the muscles of facial expression ipsilaterally.4

Adult Versus Pediatric Facial Paralysis

Children represent approximately 10% of the total number of cases with facial paralysis.5,6 Bell’s palsy accounts for approximately 50% of the adult cases and approximately 35% of the pediatric cases.6

The natural history of Bell’s palsy in adults is less favorable than in children. Adult studies report complete resolution in 70% to 80% of cases,7 compared with 90% to 96% of pediatric cases.8.9 This probably relates to the etiology of the disease, which is likely to be viral in origin in the pediatric population. Therefore, it is not surprising that the disease course and response to treatment in children is different than in their adults counterparts.

Clinical Presentation of Bell’s Palsy

A prodromal viral illness precedes the onset of Bell’s palsy by 1–4 weeks in 60% of cases. The onset of the paresis is abrupt and can progress over 1–7 days (but not weeks or months) to complete paralysis. The paresis involves all the ipsilateral facial muscles, including the forehead muscles. There is no predilection to either side of the face.5 Eyelid closure and blinking are asymmetrical, leaving the cornea vulnerable to dryness and exposure keratitis. The subject’s smile is asymmetrical, which is especially noticeable when looking at the alae nasi (nasal folds between the nares and the corner of the lips). Facial muscle twitching is not seen. The paresis can be accompanied by mild facial pain or otalgia (50%), subjective altered sensation over the affected side of the face (40%) or tongue (20%), and change of taste (50%).10,11

Facial Nerve Function Evaluation

In some case reports, photographs of the face have been used to show the degree of facial paralysis.6,11,12 Few clinical tools have been developed to assess the function of the facial nerve in a more standardized way. This is of particular importance in clinical trials evaluating the effect of different treatment modalities. The Adour/Swanson grading scale gives a facial paralysis recovery profile.13The House-Brackmann Facial Nerve Grading System14 has gained more popularity in clinical trials.15-17  The House-Brackmann Facial Nerve Grading System has six grades; grade I is normal, while there is total paralysis in grade VI.

Another practical tool is the Facial Nerve Cooperative Study Group Score of the Ministry of Health and Welfare of Japan, where it has been used in patients with Bell’s palsy.18 The score is based on 10 clinical observations including asymmetry of the face at rest, wrinkling of the forehead, blinking of the eyes, closing the eyes lightly and tightly, closing one eye, movement of the alae nasi, grinning, whistling, and closing the lip tightly. More recently, the Sunnybrook Facial Grading System was shown to be reliable when applied by novice users.19  

Diagnosis

When a child presents with facial paralysis, it is important to avoid labeling it as Bell’s palsy until other causes have been considered and excluded (Table 1).20-29 This is especially important in children <2 years of age.A thorough history and clinical examination will help identify congenital, traumatic, and infective causes, which account for the majority of cases in the first 2 years of life.

Important symptoms that may help in localizing the site of the lesion along the course of the facial nerve include lacrimation, which can be quantified using the Schirmer tear test (dry eyes indicate involvement of the facial nerve at or proximal to the geniculate ganglion), hyperacusis (sensitivity to sound), salivation (dry mouth), and loss of taste (indicates distal involvement of the facial nerve).

Congenital absence of the orbicularis oris muscle, found at the corners of the mouth, is a common source of diagnostic confusion in early infancy and is frequently mislabeled as Bell’s palsy. It causes asymmetrical smile or cry. However, forehead muscles, eye closure (seen during crying or sleeping), and blinking are all symmetrical and normal.

Möbius syndrome causes facial diplegia due to aplasia of the facial nerve nuclei. It is associated with bilateral sixth cranial nerve palsy (the eyes are unable to move laterally even with oculocephalic head maneuver), deafness, palatal and lingual palsy, deficiency of the pectoral muscles, and extremities defects (syndactyly, missing or extra digits). Special attention must be paid to examining the central nervous system for evidence of brainstem and other cranial nerves involvement (eg, deafness, vertigo, dizziness, vomiting, difficulty swallowing).

The external auditory canal and tympanic membrane must be examined for evidence of varicalla zoster virus vesicles, seen in Ramsay-Hunt syndrome (herpes zoster oticus). The timing of the vesicle appearance tend be delayed in children.23 Hence, Ramsay Hunt syndrome may be initially indistinguishable from Bell’s palsy.24 The presence of tinnitus, hearing loss, nausea, vomiting, vertigo, and nystagmus, though less common in children than adults with Ramsay Hunt syndrome, may aid in making the correct diagnosis.23

The presence of mastoid bone redness and tenderness should be established or excluded. Bilateral parotid gland inspection and palpation should be done to evaluate asymmetrical enlargement caused by infiltrating mass or tumor recurrence.

Unless the history or clinical exam reveals additional abnormal and unexpected findings, no further tests are indicated for the diagnosis of Bell’s palsy. Some experts suggest doing a complete blood count to exclude the presence of leukemia because facial paralysis is an unusual presenting sign of leukemia. Table 2 lists the investigations that may aid the physician in the diagnosis of facial paralysis.

Recurrent or Bilateral Facial Paralysis

Recurrent or bilateral facial paralysis is uncommon and accounts for approximately 6% to 12% of all cases in both the adult and the pediatric population.10,30 The rate of full clinical recovery is approximately 70%, which is lower than in unilateral Bell’s palsy.30 Prompt search for other causes is recommended, eg, Möbius syndrome, Lyme disease and other infections, Guillain-Barré syndrome, myasthenia gravis, leukemia, and trauma. Melkersson-Rosenthal syndrome is a rare familial disease that causes bilateral, or alternating and recurrent facial paralysis accompanied by facial edema and transversely fissured tongue (cheilitis).

Pathophysiology of Bell’s Palsy

Many patients with Bell’s palsy have been found to have rising antibody titers to herpes simplex virus.31 Different pathophysiological processes have been suggested,31 including active viral invasion or immune processes causing demyelination and facial nerve swelling. Other mechanisms include vascular ischemia and heredity (based on few case reports with familial recurrence of facial paralysis). In early life, the anatomy of the skull makes the facial nerve more susceptible to damage by infections and trauma.32

Treatment of Bell’s Palsy

Supportive Treatment

Supportive measures include the use of artificial tear drops and patching the affected eye especially at night to prevent dryness, exposure keratitis, and subsequent corneal ulceration.

Medical Treatment

Recent systematic reviews7,33-35 in adult onset Bell’s palsy suggested that steroids are probably effective in improving facial functional outcome, especially if the paralysis is complete.34 A Cochrane systematic review, with stricter inclusion criteria,36 concluded that steroids were not beneficial. These systematic reviews did not analyze the pediatric cases separately.

A recent pediatric systematic review by Salman and MacGregor37 failed to find evidence for benefit from trials involving the use of steroids in pediatric Bell’s palsy. In the only randomized, controlled pediatric trial in Bell’s palsy,17 the outcome was not improved with steroids use. This study was not double-blinded or placebo-controlled.

Acyclovir is an antiviral drug that is used to treat herpes simplex and varicella zoster viral infections. There are reports showing benefits in Ramsay-Hunt syndrome21 and in patients with zoster sine herpete (acute facial paralysis associated with varicella zoster virus reactivation without vesicles).38 The routine use of acyclovir in Bell’s palsy is not proven and cannot be recommended. In one systematic review7 it was concluded that acyclovir in combination with steroids may be possibly effective in improving facial functional outcome in adult patients. A recent Cochrane review on the subject has been retracted.39,40

Steroids and/or acyclovir may confer moderate rather than significant benefits in Bell’s palsy. Such an effect would only be detected in trials with a large large number of participants. The effect of steroids and/or acyclovir should be tested in severely affected patients with complete paralysis. Specific benefits in this group may be seen, but this remains to be established in a purpose-designed clinical trial.

Other treatments have been used in Bell’s palsy and include Vitamin B12,18 acetyl carnitine,41 hyperbaric oxygen,42 and pentoxiphylline.33 These treatments have been previously reviewed.33 There is a lack of evidence for their benefit in pediatric Bell’s palsy.

Surgical Treatment

Many surgical techniques have been advocated to improve facial nerve function in patients with facial paralysis12 and there is no evidence to support surgical decompression in patients with Bell’s palsy.7

Prognosis

In the pediatric age group, the prognosis for full recovery is excellent in approximately 95% of cases. The remainder recover partially, especially if their paralysis was complete at the onset. The blink reflex and electroneuronography (nerve conduction and electromyography) of the facial nerve have been used to aid prognosis.4,8

Long-term complications with facial paralysis may occur (Table 3).43 Surgical techniques aimed at improving function, plastic surgery aimed at improving facial appearance and facial muscle functioning, ie, smiling and cosmesis, are available and have been reviewed recently.4

What is New in Bell’s Palsy?

A significant number of children with Bell’s palsy have rising antibody titers against herpes simplex virus and as such, they are not truly idiopathic. Some cases of herpes simplex virus-seronegative with acute periphral facial paralysis are caused by varicella zoster reactivation in the geniculate ganglion without vesicular rash (zoster sine herpete).44,45 The use of tests for the rapid diagnoses of varicella zoster virus suggests that the early use of acyclovir in the appropriate settings may aid in the full recovery from facial paralysis.38 Magnetic resonance imaging is used to delineate the site of the facial-nerve lesion accurately46 and to aid prognosis.47

Conclusion

Facial paralysis in the pediatric age group has many etiologies, especially during the first 2 years of life. Herpes simplex and, to a lesser extent, varicella zoster viruses may account for many cases of Bell’s palsy (the idiopathic group). The use of acyclovir in such cases is controversial as there is usually a significant time delay before these viruses are detected. The prognosis of pediatric Bell’s palsy without treatment is excellent. The use of steroids in Bell’s palsy does not result in significant benefit. Larger clinical trials are needed to show if steroids confer moderate benefits and better functional recovery. Further trials are needed to investigate the use of acyclovir in pediatric Bell’s palsy. PP

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