As our first goal, we developed criteria for progressive disorders to apply in our literature review (Table 1). Since this activity was focused on a case definition for public health surveillance of CP, in particular for the Autism and Developmental Disabilities Monitoring Network, we concentrated on disorders with progressive features typically occurring by 8 years of age.⁸ By definition, we did not consider conditions that are purely myopathies, disorders only involving the spinal cord, or peripheral neuropathies (neuromuscular disorders), since the primary pathology in these conditions is not in the brain. Progressive features were defined primarily by loss of motor skills or milestones, although descriptions of disorders often more broadly described generalized regression, deteriorating clinical courses or neuropathological findings, or normal early development with subsequent developmental delay. If a disorder was clearly a neurodegenerative condition, we decided to list it for the purposes of exclusion from surveillance, even if some of the neurologic findings progressed and others did not. Another important feature that we considered was childhood mortality; lethality alone was not a criterion for progressiveness, since some genetic conditions known for mortality due to malformations or pathophysiologic processes outside of the central nervous system can have static or even improving neurologic manifestations.

The criteria took into account what is typical or described in the majority of children with disorders in question. The rationale for this principle was our belief that when neurologic deterioration is a rare feature, typical children with certain diagnoses who might have CP-like features for reasons unrelated to the disorder should not be excluded categorically. In practice, a limitation of applying this principle was the inadequate precision of literature quantifying the occurrence of CP-like features in rare genetic conditions. The issue of the effects of available therapies on natural history also is problematic, including the spectrum of interventions from diet and medications to enzyme replacement and stem-cell transplantation. Unfortunately, with our routine surveillance procedures, without a special study it is typically difficult to ascertain variables such as treatment regimens and timing of therapies that might be important in assessing the adequacy of treatment and its relationship to the clinical outcome of a particular child.⁹ For our list of progressive disorders, we did not review the core disorders on the Recommended Uniform Screening Panel for newborns in the United States,¹⁰ since the typical outcome for these conditions has changed because treatment is routinely instituted shortly after birth, thus preventing progressive features, eg, hypotonia and intellectual disability with congenital hypothyroidism. For other conditions with more potential variability in treatment in the general population, we did not consider the effects of such therapies on natural histories, eg, hematopoietic stemcell transplantation in Krabbe disease. The rapid progress expected in the diagnosis and treatment of progressive disorders, with concomitant changes in newborn screening panels as well as clinical practice, is another caveat for the need to continuously update surveillance practices.

After developing criteria for our literature review, the next step was to identify broad categories of disorders that were likely to include individual conditions that are progressive, such as leukodystrophies and lysosomal storage diseases. Ideas for these categories sometimes were generated by a particular disorder found in CP review articles or chapters,^4,5,11–13 but we also attempted to identify potential categories through a search for progressive or degenerative disorders in published literature. Due to a lack of epidemiologic literature, we did not perform a formal meta-analysis but used standardized methods to review primarily expert literature (standard genetics textbooks, review articles, and selected online resources used in clinical practices and medical school courses). After a category of disorders was identified, we created a list of individual conditions within the category to review using overview chapters, indices, and summary tables in such literature.^14–27 Occasionally, a new class was added after a query about a particular case by field staff.

Next, we searched for information about the natural history of candidate disorders in textbooks, review articles, and online catalogs^14–27; if necessary, we evaluated primary sources of natural history data referenced therein or searched databases such as PubMed. Not uncommonly, natural history descriptions and neurologic manifestations were not mentioned in a particular review article or chapter, but only if 2 or more comprehensive sources lacked any information about a progressive course was the disorder left off our final list. A particularly important impetus for reviewing primary sources of information was when one source described a progressive neurologic feature but others did not. For example, the term progressive spasticity is used in connection with Weaver syndrome in a highly-cited textbook,¹⁸ but in a review by Opitz, Weaver, and Reynolds, this complication was described in only 1 child who also had spinal cord compression.²⁸ Similarly, as noted in Table 1, we did not consider a condition to be a progressive disorder when deterioration tended to occur from repeated strokes or seizures per se, rather than events in the brain secondary to a neurodegenerative process.

For surveillance purposes, we did not include conditions with high rates of fetal death or early mortality since the minimum age of CP diagnosis for inclusion in our monitoring program was 2 years (Table 1). For rare disorders, high rates of mortality are obviously problematic in assessing natural histories related to motor milestones, particularly when fetal or neonatal deaths are the typical outcomes. Occasionally children with such disorders will survive long enough to be ascertained by CP surveillance systems, and in fact children with some disorders described as lethal in older references are now treated surgically or with new medical interventions, and are gaining skills in special education settings. Our practice for such conditions is to make decisions about whether they should be excluded from CP surveillance on a case-by-case basis after they have been abstracted, rather than categorically labeling them as progressive disorders.

We did not include groups of conditions with well-known clinical and genetic variability, such as mitochondrial neuromyopathies. Certain mitochondrial disorders were included if they resulted in a distinct syndromic phenotype that has a relatively well-defined natural history (eg, neuropathy, ataxia, and retinitis pigmentosa). Other mitochondrial disorders such as oxidative phosphorylation defects with specific electron transport complex pathology generally were not listed, since the nature of many of these conditions leads to heterogeneity of outcomes.

Some conditions such as Leigh syndrome are also heterogeneous but have a distinctive phenotype with progressive features generally included. There are also well-defined diagnostic criteria for such conditions with presumably less variability in community diagnoses. We therefore included such conditions on our list of progressive brain disorders. Some rarer conditions, such as pontocerebellar hypoplasia, have multiple genetic subtypes (with varying natural histories) that might not necessarily be evident to nonphysician field staff, and therefore would be considered on a case-by-case basis as described above.