Regression in Adolescents and Adults with Down Syndrome

Where do I go from here?

 Of course, many other medical and psychiatric conditions should be ruled in or out as part of the evaluation. The differential diagnosis for a developmental regression is broad an d includes: 

• Catatonia 

• Mental health diagnoses: depression, schizophrenia, anxiety disorder

• Tourette's/ tic disorder

• Wilson’s Disease

•  Medication side effects 

• Hydrocephalus 

• Stroke(s)

• Infections – encephalitis, hepatitis

• Endocrine conditions like hypothyroidism, celiac disease

• Autoimmune diseases & autoimmune encephalopathies (Autoimmune encephalitis, Graves’ disease, other)

• More rare conditions such as

  • Intermediary metabolism disorders – MMA - Methylmalonic aciduria and homocystinuria, cblC type, 

  • Homocystinuria, glutaric aciduria, carnitine metabolism disorder 

  • Dopamine metabolism disorder – low HVA and 5HIAA metabolites in CSF 

  • Folate receptor Alpha Defect -causes cerebral folate transport deficiency with disturbed myelin metabolism. Should show up with hypomyelination on MRI

Because this entity is poorly understood, the Down Syndrome Medical Interest Group (an international organization that meets yearly) has been working on developing standard protocols for work up and treatment. 

There are many studies that can be considered in the evaluation of an individual who has regressed. Many start with basic labs, which can provide a lot of information and rule in/out a lot of more common medical conditions. Laboratory evaluation of more rare conditions should be considered based on the individual characteristics of the case

An MRI (magnetic resonance imaging) of the brain with and without contrast, as well as an EEG (electroencephalogram) are minimum studies that should be obtain to evaluate for encephalitis, seizure disorder, strokes, etc. An LP is generally recommended, as mounting evidence suggest that a sub-section of these patients have a neuroinflammatory condition that may respond to steroids and IVIG. A polysomnographic sleep study should also be part of the basic work up, as studies have shown that sleep apnea can worsen regression symptoms. 

 Basic Bloodwork Studies:  

•  Complete metabolic panel

• Complete blood count with differential 

• Vitamin D level

• Hemoglobin A1c - done and normal

• Urinalysis 

• Thyroid function: Thyroid Stimulating Hormone, Free T4 , 

• Thyroid antiborides: Thyroglobulin Ab and Thyroid (TPO) Peroxidase Ab 

• Iron studies

• Erythrocyte sedimentation rate

•  C-reactive protein (CRP)

• Creatine Kinase

• B12 level 

• Folate level 

• Ceruloplasmin and Copper level

• Serum homocystine, total 

• Celiac serology 

•  ANA - note this is positive in some individuals with Down syndrome without lupus. Therefore, if positive, please obtain the followign labs

  • Anti-cardiolipin antibodies IgG, M & A 

  • Lupus Anti Sta Clot         

  • DNase B Ab 

  • Anti-cardiolipin antibodies IgG, M & A 

• Streptolysin O Ab (ASO) 

  • note, if symptoms are primarily motor tics and obsessive behavior that are suggestive of a PANS diagnosis, consider sending a Cunningham panel: titers against D1 and D2 Dopamine and Tubulin. CaM Kinase II looks at activation of that enzyme by the patient’s serum to gauge level of autoimmune response. All of these measure autoimmunity.  

Additional testing that can be considered:

• Carnitine panel (i.e. an acylcarnitine profile plus free and total carnitine)

• RPR (ruling out tertiary syphilis)

• Methylmalonic acid, serum quantitative urine organic acids 

Autoimmune encephalitides can cause behavioral changes, though usually it leads to abnormalities in the EEG. A variety of tests can be considered, including:

• Serum Paraneoplastic autoantibody evaluation, serum panel 

• IgG NMDAR antibodies – neuro–autoimmune disease arising from production of aby targeting   synaptic proteins.  Can be paraneoplastic or not. Detected better in CSF

• GAD (Glutamic Acid decarboxylase Ab)

• Voltage-Gated Potassium Channel (VGKC)

• AMPAR 

• GABA –B receptor, etc

• Consider Mayo panel (profile tests + reflex tests)

There is mounting evidence that some patients with Down syndrome presenting with regression have a treatable neuro-inflammatory condition. to properly rule this out, a lumbar puncture should be performed and the following studies should be sent:

Basic studies

•  Routine CSF measures: opening pressure, cell counts, glucose, pH, lactate, protein 

• Serum & CSF IgG (IgG quotient)

•  Serum & CSF albumin (albumin quotient). These are now ordered as Mayo Multiple Sclerosis Panel

•  Oligo bands (CSF & serum) 

CSF studies for neurologic disorders that can cause similar symptoms 

• Medical Neural Genetics (MNG) lab in Atlanta – get their forms and tubes.

• Neurotransmitter levels from CSF - (5-hydroxyindoleacetic acid, homovanillic acid, 3-0-methyldopa)

• To test for a Dopamine metabolism disorder – low HVA and 5HIAA metabolites in CSF 

• CSF Methyltetrahydrofolate to test for Folate receptor Alpha Defect that causes cerebral folate    transport deficiency with disturbed myelin metabolism. Should show up with hypomyelination on MRI 

• Neopterin (HPLC Fluorescence) –indicator of CNS immune activation

• Mayo now packages this as their CSF Neurotransmitter Profile III 

• Paraneoplastic autoantibody panel CSF, IgG ab – Mayo   (profile tests + reflex tests).  

• IgG NMDAR antibodies – neuro –autoimmune disease arising from production of antibodies targeting synaptic proteins.  Can be paraneoplastic or not. 

• GAD (Glutamic Acid decarboxylase Ab) 

• Voltage-Gated Potassium Channel (VGKC) =    pmol/liter (nl = 0-31) (better detected in serum)

• AMPAR

• GABA –A receptor

Treatment of Down syndrome Regression/ Down syndrome disintegrative disorder

 Treatment of regression in Down syndrome should be initiated as soon as possible, as delays in treatment are associated with worse outcomes. 

Available treatment options:    

• Lorazepam – GABA agonist; increase by 2 mg every 3-5 days up to 16 mg. Consider a lorazepam challenge - 1.5-2 mg IV lorazepam test in clinic.Parents to take notes on behavior over next 24 hours. 

• ECT– GABA agonist; requires series of closely spaced treatments, often needs repeat series and/or maintenance. This has also been found to be effective

Other: 

? Menentine – NMDA glutamate antagonist (down regulate NMDA receptor)

? Nuedexta 20/10. A glutamate antagonist. Start 1 capsule in the morning; increase to bid in a week if tolerated. 

? N-acetylcysteine (NAC) – multiple effects (reverses ? glutamate, ?oxidative stress, antiinflammatory)

? Parkinson drugs: L-dopa (Sinemet), Anticholinergic drugs.

? Minocycline – crosses blood brain barrier, anti-inflammatory, may act as NMDA receptor antagonist; 100mg po  BID with careful times regarding meals and drinking and staying upright to obviate reflux and GI distress. 

In general, neuroleptics are avoided

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