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Revised Diagnostic Criteria for Rett Syndrome (RTT)

Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2).

Revised diagnostic criteria for RTT.

RTT Diagnostic Criteria 2010
  • Consider diagnosis when postnatal deceleration of head growth observed.
Required for typical or classic RTT
  1. A period of regression followed by recovery or stabilization*
  2. All main criteria and all exclusion criteria
  3. Supportive criteria are not required, although often present in typical RTT
Required for atypical or variant RTT
  1. A period of regression followed by recovery or stabilization*
  2. At least 2 out of the 4 main criteria
  3. 5 out of 11 supportive criteria
Main Criteria
  1. Partial or complete loss of acquired purposeful hand skills.
  2. Partial or complete loss of acquired spoken language**
  3. Gait abnormalities: Impaired (dyspraxic) or absence of ability.
  4. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms
Exclusion Criteria for typical RTT
  1. Brain injury secondary to trauma (peri- or postnatally), neurometabolic disease, or severe infection that causes neurological problems***
  2. Grossly abnormal psychomotor development in first 6 months of life#
Supportive Criteria for atypical RTT##
  1. Breathing disturbances when awake
  2. Bruxism when awake
  3. Impaired sleep pattern
  4. Abnormal muscle tone
  5. Peripheral vasomotor disturbances
  6. Scoliosis/kyphosis
  7. Growth retardation
  8. Small cold hands and feet
  9. Inappropriate laughing/screaming spells
  10. Diminished response to pain
  11. Intense eye communication - “eye pointing”

*Because MECP2 mutations are now identified in some individuals prior to any clear evidence of regression, the diagnosis of “possible” RTT should be given to those individuals under 3 years old who have not lost any skills but otherwise have clinical features suggestive of RTT. These individuals should be reassessed every 6–12 months for evidence of regression. If regression manifests, the diagnosis should then be changed to definite RTT. However, if the child does not show any evidence of regression by 5 years, the diagnosis of RTT should be questioned.
**Loss of acquired language is based on best acquired spoken language skill, not strictly on the acquisition of distinct words or higher language skills. Thus, an individual who had learned to babble but then loses this ability is considered to have a loss of acquired language.
***There should be clear evidence (neurological or ophthalmological examination and MRI/CT) that the presumed insult directly resulted in neurological dysfunction.
#Grossly abnormal to the point that normal milestones (acquiring head control, swallowing, developing social smile) are not met. Mild generalized hypotonia or other previously reported subtle developmental alterations during the first six months of life is common in RTT and do not constitute an exclusionary criterion.
##If an individual has or ever had a clinical feature listed it is counted as a supportive criterion. Many of these features have an age dependency, manifesting and becoming more predominant at certain ages. Therefore, the diagnosis of atypical RTT may be easier for older individuals than for younger. In the case of a younger individual (under 5 years old) who has a period of regression and >/=2 main criteria but does not fulfill the requirement of 5/11 supportive criteria, the diagnosis of “probably atypical RTT” may be given. Individuals who fall into this category should be reassessed as they age and the diagnosis revised accordingly.


  1. Jeffrey L. Neul, Walter E. Kaufmann, Daniel G. Glaze, John Christodoulou, Angus J. Clarke, Nadia Bahi-Buisson, Helen Leonard, Mark E. S. Bailey, N. Carolyn Schanen, Michele Zappella, Alessandra Renieri, Peter Huppke, Alan K. Percy. Rett Syndrome: Revised Diagnostic Criteria and Nomenclature. Ann Neurol. 2010 December; 68(6): 944–950. [Medline]
  2. Percy AK, Neul JL, Glaze DG, Motil KJ, Skinner SA, Khwaja O, Lee HS, Lane JB, Barrish JO, Annese F, McNair L, Graham J, Barnes K. Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann Neurol. 2010 Dec;68(6):951-5. [Medline]
  3. Huppke P, Gärtner J. Molecular diagnosis of Rett syndrome. J Child Neurol. 2005 Sep;20(9):732-6. [Medline]

Diagnosis of Paget's Disease of Bone

Paget's disease of bone (also known as osteitis deformans) is a nonmalignant disease involving accelerated bone resorption followed by deposition of dense, chaotic, and ineffectively mineralized bone matrix.
An estimated 70% of patients who have Paget's disease have no symptoms. The diagnosis is typically found incidentally on radiographs and laboratory investigations. Clinical manifestations, when present, may be wide in spectrum.

Symptoms of Paget's Disease
  • Bone pain from microfractures or osteoarthritis; if the jaw is involved, teeth may become loose
  • Headaches and loss of hearing or vision from pressure on nerves, brain, or spinal cord and reduced blood flow
  • Pain or neuropathy from pressure on nerves
  • Increased head size, bowing of a limb, or curvature of the spine
  • Hip pain
  • Damage to cartilage of joints, which may lead to osteoarthritis
  • Heart failure (only in severe cases, especially in patients with heart disease)
  • Kidney stones (more common in patients with Paget's disease)
  • Sarcoma, in less than 1% of patients with Paget's disease

Patients with bone pain caused by Paget's disease usually describe the pain as continuous. Unlike osteoarthritis, pagetic bone pain usually increases with rest, on weight bearing, when the limbs are warmed, and at night. Paget's disease can cause osteoarthritis if the affected section of bone is near a joint.
A variety of deformities may occur, including kyphosis; shortened or bowed limbs; leonine facies; frontal bossing of the forehead; dental abnormalities; and, in severe cases, an enlarged cranium that may be difficult to hold erect.

Biochemical Markers
There are many biochemical markers for Paget's disease, but the two most important are total serum alkaline phosphatase and urinary pyridinoline. These markers may be normal in patients with the monostotic form of Paget's disease (15% of patients) therefore, serum bone-specific alkaline phosphatase measurements may be useful. Urinary hydroxyproline is no longer considered an accurate marker of activity or extent of the disease.

Radiographs include both lytic (early) and sclerotic findings. Many patients are diagnosed incidentally in the asymptomatic phase by plain radiographs that show localized enlargement of bone. These radiographs often have a high specificity because of their classic nature, but a low sensitivity. Bone scans can be used to increase the sensitivity in patients suspected of having Paget's disease; however, the bone scan is less specific and should be interpreted cautiously. Once a diagnosis of Paget's disease is confirmed, repeat radiographs are required only to monitor degeneration around weight-bearing joints. Computed tomography and magnetic resonance imaging are not necessary.

Radiologic Findings in Patients with Paget's Disease
  • Osteoporosis circumscripta in skull
  • Flame-shaped lesions in long bones
  • Osteolytic lesions near thickened lesions
  • Sclerotic bone
  • Bowed limbs
  • Fractures, including “banana” or “chalk” transverse fractures
Bone scintigraphy
  • Areas of increased uptake of technetium-99m
  • “Mouse face” pattern on scan of affected vertebra
If the results of the biochemical markers and radiography are inconclusive, a biopsy of the affected bone may be indicated in rare cases.

  1. Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Paget's disease of bone. Am Fam Physician. 2002 May 15;65(10):2069-72. [Medline]
  2. Whyte MP. Clinical practice. Paget's disease of bone. N Engl J Med. 2006 Aug 10;355(6):593-600. [Medline]
  3. Ralston SH. Clinical practice. Paget's disease of bone. N Engl J Med. 2013 Feb 14;368(7):644-50. [Medline]

Intravenous Immune Globulin in Autoimmune and Inflammatory Diseases

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agent in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent non-exclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors and several cell surface immunocompetent molecules. IVIg also has an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis.

Diseases for Which Intravenous Immune Globulin Has Been Shown to Be Beneficial

FDA-approved indications
  • Primary immunodeficiency disease
  • Chronic lymphocytic leukemia
  • Pediatric HIV infection
  • Kawasaki’s disease
  • Allogeneic bone marrow transplantation
  • Chronic inflammatory demyelinating polyneuropathy
  • Kidney transplantation involving a recipient with a high antibody titer or an ABO-incompatible donor
  • Multifocal motor neuropathy
Additional approved indications with criteria

Neuromuscular disorders
  • Guillain–Barré syndrome
  • Relapsing–remitting multiple sclerosis
  • Myasthenia gravis
  • Refractory polymyositis
  • Polyradiculoneuropathy
  • Lambert–Eaton myasthenic syndrome
  • Opsoclonus–myoclonus
  • Birdshot retinopathy
  • Refractory dermatomyositis
Hematologic disorders
  • Autoimmune hemolytic anemia
  • Severe anemia associated with parvovirus B19
  • Autoimmune neutropenia
  • Neonatal alloimmune thrombocytopenia
  • HIV-associated thrombocytopenia
  • Graft-versus-host disease
  • Cytomegalovirus infection or interstitial pneumonia in patients undergoing bone marrow transplantation
Dermatologic disorders
  • Pemphigus vulgaris
  • Pemphigus foliaceus
  • Bullous pemphigoid
  • Mucous-membrane (cicatricial) pemphigoid
  • Epidermolysis bullosa acquisita
  • Toxic epidermal necrolysis or Stevens–Johnson syndrome
  • Necrotizing fasciitis
* This is an abbreviated list of conditions approved under Medicare Part D or Aetna Clinical Policy Bulletin (2012). Criteria include medical certainty of diagnosis, medical necessity owing to the failure of usual treatments, contraindications to usual treatments, rapid progression or relapse, documentation of progress, and attempts to adjust drug dosages without improvement. FDA denotes Food and Drug Administration, and HIV human immunodeficiency virus.

  1. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012 Nov 22;367(21):2015-25. [Medline]
  2. Jolles S, Sewell WA, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol. 2005 Oct;142(1):1-11. [Medline]

Typical Laboratory Abnormalities in Alcoholic Liver Disease (ALD)

Alcoholic liver disease (ALD) encompasses a spectrum of injury, ranging from simple steatosis to frank cirrhosis.

Typical Laboratory Abnormalities in ALD
Serum enzymes
  • AST >>> ALT: Both usually <300 IU/L
  • Alkaline phosphatase (ALP) and g-glutamyl transpeptidase (GGT): Both usually elevated to a variable degree
Metabolic alterations
  • Hyperglycemia
  • Hypertrygleridemia
  • Hyperuricemia
  • Electrolyte abnormalities: low potassium, magnesium and phosphorus
Tests of liver function
  • Serum albumin, prothrombin time, and serum bilirubin usually normal until significant liver injury present
Hematological abnormalities
  • Mild anemia common (usually macrocytic)
  • Platelets (normal to markedly decreased)
  • Elevated white blood cell count: Leukemoid reactions associated with alcoholic hepatitis

Abbreviations: AST, aspartate aminotransferase;  ALT, alanine aminotransferase

  1. O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol. 2010 Jan;105(1):14-32. [Medline]
  2. McCullough AJ, O'Connor JF. Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol. 1998 Nov;93(11):2022-36.[Medline]

Diagnostic Criteria for Dementia with Lewy Bodies (DLB)

Synucleinopathies, with and without dementia, encompass a wide range of diseases including Parkinson's disease, multiple system atrophy, rapid eye movement (REM) sleep behavior disorder, and dementia with Lewy bodies (DLB). DLB is a neurodegenerative disorder resulting in slowly progressive and unrelenting dementia until death.

Diagnostic Criteria for Dementia with Lewy Bodies (DLB)
Central feature
  • Progressive dementia: deficits in attention and executive function are typical. Prominent memory impairment may not be evident in the early stages.
Core features:
  • Fluctuating cognition with pronounced variations in attention and alertness.
  • Recurrent complex visual hallucinations
  • Spontaneous features of Parkinsonism.
Suggestive features:
  • REM sleep behaviour disorder (RBD), which can appear years before the onset of dementia and Parkinsonism.
  • Severe sensitivity to neuroleptics occurs in up to 50% of DLB patients who take them.
  • Low dopamine transporter uptake in the brain's basal ganglia as seen on SPECT and PET imaging scans.
Supportive features:
  • Repeated falls and syncope (fainting).
  • Transient, unexplained loss of consciousness.
  • Autonomic dysfunction.
  • Hallucinations of other modalities.
  • Visuospatial abnormalities like depth perception, object orientation, directional sense and illusions
  • Other psychiatric disturbances like systematized delusions, aggression and depression.
A probable DLB diagnosis requires either:
  • Dementia plus two or more core features, or
  • Dementia plus one core feature and one or more suggestive features.
A possible DLB diagnosis requires:
  • Dementia plus one core feature, or
  • Dementia plus one or more suggestive features.

  1. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec 27;65(12):1863-72. [Medline]
  2. Weisman D, McKeith I. Dementia with Lewy bodies. Semin Neurol. 2007 Feb;27(1):42-7.[Medline]

Cervical-Cancer Screening Guidelines

The incidence of cervical cancer, as well as mortality rates from the disease, has decreased over the past 30 years because of widespread screening with cervical cytology. The American College of Obstetricians and Gynecologists (ACOG) recently published a clinical management guideline on cervical cytology screening.

Cervical-Cancer Screening Guidelines *
Age group
Screening Recommendation
<21 yr
Do not screen.
21–29 yr
Perform cytologic testing alone every 3 years.
30–65 yr
Perform cytologic and HPV cotesting every 5 years (preferred), or perform cytologic testing alone every 3 years (acceptable).**
>65 yr
Discontinue screening if there has been an adequate number of negative screening results previously
(3 consecutive negative cytologic tests or 2 consecutivenegative cotests in the past 10 years, with the most recent test in the past 5 years) and if there is no history of HSIL,*** adenocarcinoma in situ, or cancer.
Women who have undergonehysterectomy
Discontinue screening if the patient has undergone a totalhysterectomy with removal of cervix and if there is no history of HSIL, adenocarcinoma in situ, or cancer.
* The three major sets of screening guidelines were issued by the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Multisociety Guidelines Group; the American College of Obstetricians and Gynecologists; and the U.S. Preventive Services Task Force (USPSTF). The guidelines agree on most recommendations, including the recommended age at the start of screening (21 years), the age at which screening can be discontinued if the history of negative screening is adequate (>65 years), and the recommended interval between tests. Specifically, cotesting at a 5-year interval is either preferred or acceptable for women 30 to 65 years of age, whereas cytologic testing alone every 3 years is acceptable for women 21 to 65 years of age. HSIL denotes high-grade squamous intraepithelial lesions.
** The terms “preferred” and “acceptable” are not included in the USPSTF Recommendation Statement.
*** HSIL includes cervical intraepithelial neoplasia grade 3 and cases of grade 2 that stain positive for p16.

  1. Schiffman M, Solomon D. Clinical practice. Cervical-cancer screening with human papillomavirus and cytologic cotesting. N Engl J Med. 2013 Dec 12;369(24):2324-31.[Medline]
  2. Tatsas AD, Phelan DF, Gravitt PE, Boitnott JK, Clark DP. Practice patterns in cervical cancer screening and human papillomavirus testing. Am J Clin Pathol. 2012 Aug;138(2):223-9. [Medline]
  3. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 2012;62:147-72. [Medline]
  4. Moyer VA. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;156:880-91. [Medline]
  5. ACOG Practice Bulletin number 131: screening for cervical cancer. Obstet Gynecol 2012;120:1222-38. [Medlione]

Prevention of Sensitizer-Induced Occupational Asthma

Primary, secondary, and tertiary preventive measures may reduce the incidence and severity of sensitizer-induced asthma.

Prevention of Sensitizer-Induced Occupational Asthma
Primary prevention
  • Avoid introducing predicted new sensitizing agents into the workplace (efficacy as primary prevention currently theoretical).
  • Avoid use of known sensitizing agents if safer alternatives are available.
  • Modify the physical or chemical form of known sensitizers to reduce risk of exposure (e.g., less volatile preparations, polymerized products, and latex gloves with a low-protein and low-powder content).
  • Reduce exposure to work sensitizers by means of occupational hygiene measures (e.g., use of robotics, containment, ventilation, and respirators).
  • Educate workers in the use of safe practices at work.
  • Monitor and control levels of exposure to workplace sensitizers.
Secondary prevention (early detection)
  • Institute medical-surveillance programs for workers at risk, consisting of preplacement and periodic respiratory questionnaires, with spirometry and immunologic tests as indicated.
  • Ensure that health care providers have adequate knowledge of occupational asthma and consider it early in the evaluation of all adults with asthma symptoms, leading to early diagnosis and management of occupational asthma.
  • Educate workers about the risks of occupational asthma through workplace programs, information provided by health care providers, and public-education programs (e.g., from news media, lung associations, and Web-based programs).
Tertiary prevention (appropriate treatment)
  • Evaluate symptomatic workers early and obtain an accurate diagnosis.
  • Remove workers from further exposure to the implicated agent after a confirmed diagnosis, when possible.
  • Control other triggers and use pharmacologic measures if necessary.
  • Assist the patient with a workers’ compensation claim when applicable, to limit the socioeconomic effects of the diagnosis.
  • Monitor the patient’s asthma in future work locations to ensure safe placement.
  1. Tarlo SM, Lemiere C. Occupational asthma. N Engl J Med. 2014 Feb 13;370(7):640-9.[Medline]
  2. Heederik D, Henneberger PK, Redlich CA; ERS Task Force on the Management of Work-related Asthma. Primary prevention: exposure reduction, skin exposure and respiratory protection. Eur Respir Rev. 2012 Jun 1;21(124):112-24.[Medline]

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