Primary organic disorders

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

Sorted by prevalence (frequency of occurrence) in descending order. The prevalence indicates the frequency of the Disorder itself, not the frequency or likelihood of ADHD in the Disorder. For example, the prevalence of deficiency symptoms is quite high, but the influence of their elimination on ADHD symptoms is not significant.

• 1. Consequences of sleep disorders (sleep disorders: children 47.1 %; adults: 0.6 to 7.8 %)
• 2. Post-concussion syndrome (Consequences of a concussion) (11 to 80 %)
• 3. Deficiency symptoms (5 to 30 %)
  • 3.1. Vitamin D3 (30 %)
    • 3.2. Vitamin B12 (5 to 30 %)
    • 3.3. Zinc (11 %)
  • 3.4. Iron (10 %)
  • 3.5. Other possible deficiency symptoms
• 4. Migraine (women: 18 %, men 6 %)
• 5. Substance abuse (illegal drugs: 10 %, nicotine: 16.6 to 25.5 %)
• 6. Addiction / dependency (alcohol: 5%, gambling: 0.31%)
• 7. Thyroid problems (cumulative 7 to 14 % in women, 2.75 to 3.5 % in men)
  • 7.1. Hyperthyroidism (women 1 - 2 %, men 0.25 - 0.5 %)
  • 7.2. Underactive thyroid / hypothyroidism (from 60 years approx. 2 %)
  • 7.3. Hashimoto’s thyroiditis (women 4.5 - 9.5 %, men 0.5 - 1 %)
  • 7.4. Thyroid hormone resistance (RTH) / thyroid hormone action defect (THAD)
• 8. Restless legs syndrome (children 2 %, adults 5 to 10 %)
• 9. Prenatal damage due to alcohol, FAS (0.8 to 8.2 %)
• 10. Seizure disorders (epilepsy: 0.5 to 1 %)
• 11. Hydrocephalus (0.4 - 0.8 %; from 65 years 3 %)
• 12. Histamine intolerance, histamine intolerance (1 %, of which 80 % adults)
• 13. Prolactinomas (0.02 - 0.05 %)
• 14. Phenylketonuria (PKU) (0.0125 %)
• 15. Consequences of severe brain infections (cumulative 0.05% to 0.16%)
  • 15.1. Encephalitis (cumulative 0.03 %)
  • 15.2. Perinatal hypoxemia (0.001 to 0.009 %)
  • 15.3. Bacterial infections (cumulative 0.01% in women, 0.12% in men)
• 16. Neurofibromatosis type 1 (0.029 %)
• 17. Velocardiofacial syndrome (22q11DS) (0.01 to 0.05 %)
• 18. Cortisol disorders (cumulative 0.0042 to 0.0048 %)
  • 18.1. Hypocortisolism (adrenal insufficiency) (0.004 %)
  • 18.2. Hypercortisolism (Cushing’s syndrome) (0.0002 to 0.0008 %)
• 19. Moyamoya (0.0001 % to 0.0009 %)
• 20. Hamartoma of the hypothalamus (0.0005 %)
• 3.21. Allergies (with motor restlessness)
• 3.22. Visual and hearing impairment
• 3.23. Lesions of the left cerebral hemisphere / right PFC
• 3.24. Organic brain damage
• 3.25. Status epilepticus during sleep (ESES)
• 3.26. Traumatic or space-occupying cerebral disorders / other psychoorganic syndromes with cerebral damage and/or mental retardation
• 3.27. Bachmann-Bupp syndrome (BABS)
• 3.28. CAPRIN1 haploinsufficiency
• 3.29. KBG syndrome
• 3.30. Cystic fibrosis
• 3.31. ME/CFS, myalgic encephalomyelitis / chronic fatigue syndrome
• 3.32. Congenital myopathy and neuropathy
• 3.33. Mild Cognitive Impairment (MCI)
• 3.34. Cerebrotendinous xanthomatosis (CTX)

1. Consequences of sleep disorders (sleep disorders: children 47.1 %; adults: 0.6 to 7.8 %)¶

The annual prevalence of sleep disorders in Germany in 2008 was 0.6 % (15 to 19 years) to 6.6 % (60 years and over) for men and 0.8 % (15 to 19 years) to 7.8 % (60 years and over) for women.¹
Sleep problems with ADHD are extremely common:

• 70 - 80 % of people with ADHD suffer from sleep problems
• 20 - 30 % of people with ADHD suffer from sleep problems

A Chinese study of 23,791 schoolchildren found that 68.7% of children with ADHD had poor sleep quality, compared to 47.1% of children without ADHD²

See also: ⇒ ADHD - comorbidity, there on sleep problems

When it comes to sleep problems and ADHD, it is difficult to separate cause and effect. ADHD very often causes sleep disorders and sleep disorders often cause ADHD-like symptoms.

In the case of an ADHD diagnosis, comorbid sleep disorders should always be treated with special priority. In addition, when taking medication for sleep problems, their possible negative effect on ADHD symptoms must be taken into account, just as medication for ADHD must be checked to ensure that it does not exacerbate sleep problems. More on the treatment of sleep problems with ADHD: ⇒ Treatment of sleep problems with ADHD

• Vigilance disorders with impaired sleep-wake regulation³⁴
• Consequences of sleep apnea syndrome⁵
  “Obstructive sleep apnoea syndrome (OSAS) is the most common sleep-related breathing disorder. The prevalence is around 4% in men and around 2% in women.
  Obstructive sleep apnea (OSA) is even more common and reaches strikingly high figures, particularly when subgroups are considered. For example, there is a prevalence of around 36% in patients with diabetes mellitus or arterial hypertension, a prevalence of 50% in obese patients and a prevalence of 83% in patients with refractory arterial hypertension. It is estimated that 80 % of male and 90 % of female patients with sleep apnoea syndrome are undiagnosed and therefore untreated.”⁶
  Breathing interruptions in children’s sleep can trigger cognitive stress, causing symptoms that resemble ADHD.⁷
• Chronic lack of sleep³
• Disorders of the dream sleep phases occur within a few days:
  • Increased irritability⁸
  • Increased impulsivity⁸
  • Reduced concentration⁹
  • Reduced attention⁹
  • Disorders of the working memory¹⁰

Common symptoms of sleep problems and ADHD:¹¹

• Motor hyperactivity, physical restlessness
• Concentration problems
• Attention problems

ADHD symptoms that are atypical of sleep problems:

• Inner restlessness (typical in atypical depression, less so in melancholic depression)
• Impulsiveness
• High flow of speech (logorrhea, polyphrasia)
• Chasing thoughts, circling thoughts
• Rapid mood swings
• Dysphoria with inactivity

Symptoms of sleep problems that are atypical for ADHD:

• Drowsiness
• (Day) tiredness

2. Post-concussion syndrome (Consequences of a concussion) (11 to 80 %)¶

Another name: post-concussion syndrome

Prevalence: probably in 1 / 10 patients with mild traumatic brain injury¹²
A concussion is the mildest form of traumatic brain injury. In the USA, an incidence of 1.15 % is assumed for concussion (3.8 million / 331 million). This would put the incidence of postconcussion syndrome at around 0.115% per year.
The prevalence is between 11 and 80 %.¹³

In uninjured adolescent athletes, ADHD appears to mimic postcommotional syndrome. Persons with ADHD report more symptoms of postconcussion syndrome than non-affected people.¹⁴ One study reported prolonged times to recovery from concussion in ADHD¹⁵, another found no differences in progression¹⁶
One study found no clustering of ADHD in 12-/13-year-old athletes with a concussion.¹⁷

3. Deficiency symptoms (5 to 30 %)¶

3.1. Vitamin D3 (30 %)¶

Prevalence of D3 deficiency:¹⁸¹⁹
* 30.2 % inadequately supplied
* 38.4 % sufficiently supplied
* 31.4 % in need of improvement or oversupplied

• A vitamin D3 deficiency also appears to be very common in ADHD.²⁰ D3 supplementation is recommended, especially in the fall/winter.

• D3 requires fat for absorption, i.e. ingestion requires that the preparations contain fat or that food is consumed at the same time. A glass of milk should suffice for this.

3.2. Vitamin B12 (5 to 30 %)¶

Prevalence of B12 deficiency:²¹¹⁹

• Young adults 5 to 10 %
• Older adults 10 to 30 %

• At an older age, concentration and attention problems due to B12 deficiency are almost phenotypical.
• B12 can be administered more safely by means of injections.
• In the meantime, B12 is also available in tablet form.
• Foods with a potentially high B12 content (spinel algae), on the other hand, cannot be dosed reliably enough.

3.3. Zinc (11 %)¶

Zinc deficiency can exacerbate symptoms of existing ADHD.²²

• Prevalence of zinc deficiency:
  • Population-wide
    • Europe: 11 %¹⁹
  • Healthy children from 1 to 3 years:
    • Western Europe: 31.3 %²³
  • in children under five years of age (Disease Control Priorities in Developing Countries 2006).
    • East Asia/Pacific: 7 %
    • Eastern Europe and Central Asia: 10%
    • Latin America and the Caribbean: 33 %
    • Middle East and North Africa: 46 %
    • Sub-Saharan Africa: 50 %
    • South Asia: 79 %
• Zinc deficiency manifests itself in a lack of T and B lymphocytes, among other things
• Zinc deficiency often goes hand in hand with vitamin A deficiency
• Zinc is involved in the Ada repair protein. This repairs (demethylates) methylated phosphate linkers in the DNA by transferring the methyl group to the cysteinate-S²⁴

3.4. Iron (10 %)¶

The prevalence of iron deficiency is difficult to determine because there is little reliable epidemiologic data on this topic, and it is also related to various related pathologic entities such as anemia, iron deficiency anemia, and isolated iron deficiency without anemia.

• Worldwide: 50 %²⁵
  • for women: 37% (42% and 25% for children)
    • non-pregnant women: 33 %
    • pregnant women: 40 %
    • In around 50% of cases, this is due to severe iron deficiency.
  • large differences depending on age, gender and world region
• Europe: 5-10 %²⁶
  • Women of childbearing age: approx. 20 %
  • Other risk groups: Infants and young children
  • Adolescents from 13 to 15: 4-8 %; mainly storage iron deficiency without iron deficiency anemia

Symptoms of iron deficiency are²⁵

• Tiredness
• Muscle weakness
• reduced physical performance
• Changes in mood and emotional behavior

Today, iron status is determined on the basis of serum ferritin. Low serum ferritin concentrations are a marker for low iron stores. Normal or elevated serum ferritin levels, on the other hand, do not rule out iron deficiency in the case of infections or inflammation.²⁷²⁸

Iron deficiency affects the dopamine metabolism²⁵

• This could be particularly harmful in infants and young adults with changes in the mesolimbic signaling pathway [30]. Iron is involved in dopaminergic signaling pathways and dopaminergic neurotransmission.
• Iron deficiency in the substantia nigra could result in reduced tyrosine hydroxylase activity and thus impaired dopamine synthesis.
• The SERT influences dopaminergic signaling
  • through its modulation of intracerebral iron homeostasis. The SERT-dependent decrease in intracerebral iron concentration influences dopaminergic and noradrenergic neurotransmission because iron is required for the conversion of phenylalanine to L-tyrosine and L-tyrosine to L-dopa and thus co-regulates dopamine synthesis.
  • by the (reversible) decrease in the density of dopaminergic D2 receptors and presynaptic DAT, which ensure presynaptic reuptake.
• Striatum:
  • Increased dopamine levels
  • Tyrosine hydroxylase increased
  • D1 receptors increased
  • Transferrin receptors increased
  • D2 receptors reduced
  • Adenosine-1 receptor reduced

3.5. Other possible deficiency symptoms¶

• Vitamin B6
• Magnesium
• Iodine

4. Migraine (women: 18 %, men 6 %)¶

Prevalence women 18 %, men 6 %
The overall symptom picture usually differs significantly from ADHD and is barely permanent.

5. Substance abuse (illegal drugs: 10 %, nicotine: 16.6 to 25.5 %)¶

Among adults with ADHD, the prevalence of substance abuse is 33.5%.²⁹ The risk of substance abuse among adults with ADHD in the USA is 1.7 to 7.9 times higher.³⁰

If aggressive and oppositional defiant behavior and low self-esteem are present in addition to ADHD, the probability of substance abuse is significantly increased, while no more frequent substance abuse was found in adolescent people with ADHD without these additional symptoms.³⁵³⁶

In our opinion, substance abuse is much more likely to be a consequence of ADHD than the cause of a full ADHD symptom picture. In rarer cases, it is comorbid. Treatment with stimulants very often eliminates the addictive tendency in ADHD. Modern dosage forms of stimulant medications are barely suitable for abuse as a drug (e.g. Vyvanse: prodrug of amphetamine bound to lysine, which is only very slowly converted to the active ingredient in the intestine).

In the Continuous Performance Test, people with ADHD showed more responses to correct timing compared to those with substance abuse.³⁷

6. Addiction / dependency (alcohol: 5%, gambling: 0.31%)¶

Prevalence: Present in 24.9% of adults with people with ADHD.³⁸

Alcohol:³³

• Dependence
  • Men 4.8 %
  • Women 2 %
• Abuse
  • Men 4.6 %
  • Women 1.5 %

In Berlin, 5.0% of respondents aged 15 to 64 met the criteria for alcohol dependence according to DSM-IV (men: 6.4%, women: 3.5%).³⁹

In Germany, the prevalence of gambling addiction is 0.31% and the prevalence of problematic gambling behavior is 0.56%.⁴⁰
A study of n = 97 gambling addicts found an ADHD rate of 26.0 % and an ASD rate of 29.8 %.⁴¹

In the case of comorbidity of ADHD and addiction, there is an increased probability that ADHD is the causal cause of the addiction and not addiction the cause of ADHD. This was shown at least for smoking, cannabis and probably also alcohol.⁴²

One study found that increased polygenic risk scores (PRS) for ADHD also increased the likelihood of addiction by 20%. There were no differences with regard to the intensity of the addiction (use, abuse, dependence) or the type of addictive substance (alcohol, cannabis, other illegal drugs). Conversely, the ADHD-PRS explained only 0.2% of the probability of addiction compared to other risk factors.⁴³

One study showed an ADHD prevalence of 16.7% in severe addicts compared to 2.5% in the control group.⁴⁴
Even more significant was the fact that 53% of severe addicts had socially disturbed behavior in childhood or adolescence (up to 15 years), as measured by the SKID-II (control subjects with 2.5%).⁴⁵ An earlier Disorder of Social Behavior (OR = 35.1) compared to childhood hyperkinetic behavior (OR = 5.7) is by far the greater risk factor for severe addiction.⁴⁶
This indicates to us that addiction plays a role predominantly in ADHD-HI and less in ADHD-I.
The preference for addictive substances indicates a more frequent use of cannabis products among people with (former) hyperkinetic behavior. There appears to be no significant difference for opiates, cocaine, amphetamines, sedatives and hallucinogens.⁴⁷
Although a joint occurrence of hyperkinetic and socially disturbed behavior is associated with an early first use of illegal drugs, statistically only an earlier and increased use of nicotine could be proven.⁴⁷
Adults with ADHD and addiction had a lower age of onset of substance use and used as an addictive substance:⁴⁸

• more frequently: alcohol, cannabis, methamphetamine, tramadol
• less frequently: methylphenidate, methadone, ecstasy, morphine, hypnotics

Long-term abuse of dopaminergic drugs (cocaine, amphetamines) leads to prolonged downregulation of dopamine levels. Withdrawal symptoms then correspond to ADHD symptoms. ⁴⁹ Against this background, the question arises as to whether ADHD medications (stimulants), which are known to have no intoxicating effect, could be helpful in the withdrawal of dopaminergic drugs.
People with ADHD with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants.⁵⁰

Common symptoms of addiction / substance abuse and ADHD:¹¹

• Impulsiveness
• (Inner) restlessness, motor hyperactivity
• Concentration problems
• High flow of speech (logorrhea, polyphrasia)

ADHD symptoms that are atypical for addiction / substance abuse:

• Chasing thoughts, circling thoughts
• Attention problems
• Dysphoria with inactivity
• Mood swings

Symptoms of addiction / substance abuse that are atypical for ADHD:

• Substance abuse:
  • Excessive consumption of a substance, even if there are serious Consequences
• Addiction / dependence:
  • Excessive consumption to the point of dependence on the drug
  • Very difficult to stop

7. Thyroid problems (cumulative 7 to 14 % in women, 2.75 to 3.5 % in men)¶

Among other cognitive deficits, hyperthyroidism can also cause inattention and hyperarousal. Depending on the degree of hypothyroidism, the cognitive effects can range from mild impairment of memory and attention to complete dementia.⁵¹⁵²

The THRA gene encodes the thyroid receptor alpha, TRα1, TRHB the thyroid receptor isoforms TRβ1 and TRβ2.
The pituitary hormone TSH (thyroid-stimulating hormone) stimulates the thyroid gland to produce thyroxine (T4; prohormone) and then triiodothyronine (T3). The thyroid hormones (T3 and T4) in the blood in turn regulate the pituitary release of TSH within the hypothalamic-pituitary-thyroid axis, which is mediated by the receptor isoform TRβ2.

See also the guidelines of the ADHD Working Group of Pediatricians and Adolescent Doctors, as of 2014.⁵³

7.1. Hyperthyroidism (women 1 - 2 %, men 0.25 - 0.5 %)¶

Prevalence: 1-2 % in women, 0.25 - 0.5 % in men⁵⁴⁵⁵³

ADHD-like symptoms can be:⁵⁶

• Nervousness
• Aggression
• Irritability
• Increased anxiety up to and including fearfulness
• (Extreme) jumpiness
• Difficulty to relax
• Sleep disorders
• Hyperactivity⁵⁷

Other symptoms that are not typical of ADHD can be:⁵⁶

• Sweating
• Palpitations
• Atrial fibrillation
• (Severe) tremor
• Diarrhea
• Severe weight loss
• Tiredness
• Weakness
• Additionally occurring psychosis
• High blood pressure⁵⁷
• Oily skin⁵⁷
• Hyperventilation⁵⁷
• Cravings⁵⁷
• TSH low, fT3 high, fT4 high

7.2. Underactive thyroid / hypothyroidism (from 60 years approx. 2 %)¶

From the age of 60, around 2% of the population are affected by hypothyroidism.³

ADHD-like symptoms can result from hypothyroidism⁵⁸
Hypothyroidism becomes more common with increasing age (usually a consequence of Hashimoto’s autoimmune thyroiditis).

Hypothyroidism often develops slowly, which is why symptoms are difficult to recognize.

Healthy 4-year-old children with thyroid-stimulating hormone levels in the upper normal range have a higher risk of ADHD than children with low free thyroxine levels. Thyroid disorders are more common in women than in men. As ADHD continues to show a possible association with thyroid hormone receptor insensitivity (see below), a role of thyroid hormones in the development and manifestation of ADHD in women and girls should be further investigated.⁵⁹

Symptoms of an underactive thyroid can include⁵⁷

• Constipation
• Weight gain
• Blemished skin
• Freeze
• Lack of drive
• Weepiness
• Increased need for sleep
• Low blood pressure
• Difficult breathing
• Loss of appetite
• TSH high, fT3 low, fT4 low

Hyperthyroidism does not preclude treatment with methylphenidate, but requires particular caution, especially strict monitoring of thyroid levels, pulse and blood pressure.

7.3. Hashimoto’s thyroiditis (women 4.5 - 9.5 %, men 0.5 - 1 %)¶

Hashimoto’s (Hashimoto’s lymphomatous goiter) is an autoimmune disorder that causes hypothyroidism⁵⁸
The prevalence of Hashimoto’s in Germany is around 5 to 10 %. Prevalence and incidence increase with age. Women in the 3rd-5th decade of life are affected about 10 to 20 times more frequently than men.⁶⁰

ADHD-like symptoms can be:⁵⁶

• Depressive moods
  • Apathy
  • Rapid exhaustion
  • Concentration disorders.

Other symptoms that are not typical of ADHD can be:⁵⁶

• Tiredness
  • In extreme cases: delusions / suicidal thoughts
  • Weight gain
  • Slowed heartbeat
  • Slowed reflexes
  • Decreased libido.

It is reported that adrenal insufficiency (reduced cortisol production by the adrenal gland) often leads to thyroid insufficiency. Treatment of the thyroid gland with thyroxine then increases the cortisol demand on the adrenal gland. However, if the adrenal gland is already so weakened that the increased cortisol production completely overwhelms it, a collapse of the adrenal gland can result, which further reduces cortisol production, which is why the adrenal gland should be considered and treated before thyroxine treatment.⁶¹

An attenuated cortisol stress response is often present in ADHD-HI. *⇒ Cortisol and other stress hormones in ADHD *This could be a sign of mild adrenal insufficiency. However, this is often likely to be caused by pituitary weakness due to CRH receptor downregulation. To differentiate from adrenal insufficiency, see ⇒ Hypocortisolism (adrenal cortical insufficiency) In this article.
However, adrenal collapse due to thyroxine therapy is not reported as typical in ADHD.

7.4. Thyroid hormone resistance (RTH) / thyroid hormone action defect (THAD)¶

The β-thyroid receptors (TRβ) in the pituitary gland control the down-regulation of thyroid stimulating hormone (TSH), which leads to reduced production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Thyroid hormone resistance (RTH) / thyroid hormone action deficiency (THAD) is an overall rare, hereditary syndrome, but the most common syndrome with reduced sensitivity to thyroid hormones.⁶²
Mutations in the β gene of the thyroid receptor (Thrb, formerly just called RTH) can impair the receptors’ ability to bind T3⁶³
There is an imbalance between

• the resistance of tissues that predominantly express thyroid hormone receptor β isoforms 1 and 2 and
• overstimulation of tissues that mainly express the thyroid hormone receptor α isoform
  In functional receptors, the mutant receptors form homo- and heterodimers that lack the ability to act on genomic response elements. The result of this dominant negative effect is that TSH is not downregulated (thyroid hormone resistance (RTH)).

THRB mutation thyroid hormone resistance has the following typical symptoms:

• normal⁶⁴⁶⁵ or elevated levels of triiodothyronine/free thyroxine and non-suppressed thyroid-stimulating hormone⁶²⁶⁵
• Sinus tachycardia⁶²⁶⁶ at rest⁶⁵
• Short stature⁶⁵
• Osteoporosis⁶⁵
• Hearing loss
• Goitre⁶⁶⁶⁴ or goitre (enlargement of the thyroid gland)⁶²
• ADHD⁶²⁶⁴
  • in 70 % of children with thyroid hormone resistance⁶⁷
  • entire spectrum of ADHD symptoms
  • Foggy Brain⁶⁴
  • suggests that mechanisms downstream of the TRβ receptor may be responsible for the manifestation of behavioral phenotypes in both disorders

THRA mutation thyroid hormone resistance has the following typical symptoms:⁶²

• mental retardation of varying degrees
• Short stature with reduced subischial leg length
• chronic constipation
• Bradycardia

8. Restless legs syndrome (children 2 %, adults 5 to 10 %)¶

Prevalence:⁶⁸

• Children 2 %
• Adults 5 - 10 %

Restless legs correlates with ADHD symptoms.³⁴
Intensive sugar consumption can cause twitching in the limbs (especially in the legs) - especially in people who do not tolerate sugar well - which is similar to a mild form of restless legs and can make it difficult to fall asleep.

A lower frequency of D4.7R is suspected in restless legs, while this gene variant is more common in ADHD.⁶⁹

In restless legs, treatment with L-dopa is often helpful in the short term, but can be detrimental in the long term.
Treatment with D4 agonists is also being discussed⁶⁹

9. Prenatal damage due to alcohol, FAS (0.8 to 8.2 %)¶

Other names: Fetal alcohol syndrome, embryofetal alcohol syndrome, alcohol effects, FAE, FAS, FASD, alcohol embryopathy

Prevalence: 0.8 to 8.2 % of all births, with around 10 % of all cases developing full symptoms.⁷¹ Long-term studies of children with FAS (fetal alcohol syndrome) found that 47.2 %⁷², 67.6 %⁷³ or 70 %⁷⁴ also had ADHD.

Around 15 to 30% of all mothers continue to drink alcohol during pregnancy.⁷¹ The risk to the unborn child is considerable.
This problem is also considered a possible cause of ADHD.⁷⁵ The risk of ADHD among people with FAE/FAS was increased 10-fold.⁷⁶

10. Seizure disorders (epilepsy: 0.5 to 1 %)¶

The prevalence of epilepsy is 0.5 to 1 %.⁷⁸

Source⁵³

• Pyknolepsy³
• Seizure disorder with absences or complex partial seizures³⁴
• Epilepsy-related seizures (absences)⁷⁹

11. Hydrocephalus (0.4 - 0.8 %; from 65 years 3 %)¶

Prevalence: 0.4 - 0.8 %, > 65 years: approx. 3 %⁸⁰

Children with hydrocephalus have an almost threefold risk of ADHD.⁸¹
In old age, hydrocephalus often occurs comorbidly with Alzheimer’s disease and vascular dementia.

12. Histamine intolerance, histamine intolerance (1 %, of which 80 % adults)¶

The prevalence of histamine intolerance is given as 1%. However, 80% of people with ADHD are said to be adults.⁸²
The main physical symptoms of histamine intolerance are⁸³⁸⁴⁸⁵

• Psychological symptoms
  • Depression
  • depressive moods
  • Winter depression
  • Mood swings
  • States of exhaustion
  • increased sensitivity (acoustic, visual, tactile, temperature, emotional, etc.)
  • Sleep disorders, wakefulness
  • Tension, feeling of restlessness, states of agitation, arousal, nervousness, overexcitement

• Nervous system
  • Headache, cluster headache
  • Migraine
  • Dizziness (vertigo), seasickness, motion sickness

• Muscle tension

• Endocrine system
  • Menstrual cramps: Period pain, menstrual pain, dysmenorrhea
  • Increased PMS symptoms
• Digestive tract, gastrointestinal tract
  • Diarrhea (diarrhea, soft stools, diarrhea), indigestion
  • Abdominal cramps, stomach pain
  • Flatulence, meteorism, bloating, intestinal winds, flatulence
  • Recurrent cystitis
  • Nausea, nausea
  • Vomiting, vomitus
• Cardiovascular system
  • Palpitations (synonyms: rapid heartbeat, tachycardia), up to and including panic attacks
  • Low blood pressure, sudden drop in blood pressure (hypotension, drop in blood pressure)]
  • Additional heartbeats (extra beats, extrasystoles)
  • Cardiac arrhythmia, heart stumbling, arrhythmias, heart problems
  • Palpitations, palpitations
• Skin, mucous membranes, respiratory tract
  • Stuffy or runny nose (synonyms: blocked nose, runny nose, runny nose, rhinorrhea, non-allergic rhinitis, runny nose, nasal obstruction)
  • Sneezing, sneezing irritation
  • Narrowing of the airways (synonyms: Bronchoconstriction, bronchoconstriction, bronchial constriction and bronchial obstruction): e.g. shortness of breath (breathlessness, dyspnea), asthma, bronchospasm
  • Flushing, red face, flush
  • Itching, pruritus, scratching
  • Erythema, reddening of the skin
  • Hives, nettle rash, urticaria, urticarial exanthema
  • Edema, water retention, swelling of the eyelids
  • Conjunctivitis, inflammation of the conjunctiva of the eye, eye inflammation

13. Prolactinomas (0.02 - 0.05 %)¶

Prevalence: 30 to 50 / 100000 (0.02 to 0.05 %)

Prolactinomas are prolactin-secreting (benign) tumors
⇒ ADHD neurotransmitters - messenger substances

14. Phenylketonuria (PKU) (0.0125 %)¶

Other names; Følling’s disease, Fölling’s disease, phenylpyruvic acid oligophrenia, oligophrenia phenylpyruvica, hyperphenylalaninemia
Prevalence; 1 / 8,000 (0.0125 %)

People with ADHD often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^8687888990

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the phenylalanine hydroxylase gene). PKU leads to a significant excess of phenylalanine (hyperphenylalaninemia). As phenylalanine and tyrosine pass through the blood-brain barrier via the same transporters, and these transporters have a higher affinity for phenylalanine, too little tyrosine reaches the brain if there is an excess of phenylalanine in the blood. Tyrosine is a precursor for dopamine, from which noradrenaline and adrenaline are further produced. Excess phenylalanine in the blood therefore leads to a lack of dopamine, noradrenaline and adrenaline in the brain.⁹¹In addition, excess phenylalanine causes changes in cerebral myelin and protein synthesis as well as reduced levels of serotonin in the brain.⁹² ADHD and phenylketonuria therefore have the common feature of a dopamine deficiency ^{88 9394}

Treatment with sapropterin improved ADHD symptoms in a pharma-funded study in phenylketunorie.⁹⁵ A study also suggests BH4 treatment for ADHD, which is helpful for PKU⁹⁴

15. Consequences of severe brain infections (cumulative 0.05% to 0.16%)¶

Sources⁷⁹⁹⁶⁴

15.1. Encephalitis (cumulative 0.03 %)¶

Prevalence:⁹⁷
Autoimmune encephalitis 13.7/100,000 (0.0137 %)
infectious encephalitis 11.6/100,000 (0.0116 %)
viral encephalitis 8.3/100,000 (0.0083 %)

Brain infection with inflammatory changes caused by invading microorganisms.
Encephalitis destroys the cells in the substantia nigra that produce dopamine.
The people with ADHD affected by the encephalitis epidemic from 1914 to 1917 showed typical symptoms of ADHD as the disease progressed. Children developed hyperactive motor skills, adults Parkinson’s symptoms.
The symptoms are consequences of the dopamine deficiency that characterizes ADHD. These symptoms have been reproduced in animal experiments as a result of impaired dopamine production.⁹⁸

See also Viral infections as a cause of ADHD in the article Age-independent physical stress as an environmental cause of ADHD in the chapter Development.

15.2. Perinatal hypoxemia (0.001 to 0.009 %)¶

Prevalence: 1 to 9 / 100,000 (0.001 to 0.009 %)((Hypoxic-ischemic encephalopathy (HIE), Orpha.net))

Oxygen deprivation during birth is one of the main causes of early childhood brain damage (ECBD).
In animal experiments, led to the death of dopamine-producing cells in the substantia nigra and thus to a decrease in dopamine levels of up to 70 %.⁹⁹
Hypoxemia is associated with excess adenosine. Adenosine inhibits dopamine.

15.3. Bacterial infections (cumulative 0.01% in women, 0.12% in men)¶

• Meningitis: inflammation of the meninges
  • Prevalence: 0.5 / 100,000 (0.0005 %)¹⁰⁰
• Brain abscesses: 0.3-1.3 /100,000 per year (0.0003% to 0.0013%)
  • Local infection of the brain tissue. Begins as focal encephalitis (cerebral phlegmon, “cerebritis”). Gradually develops into a collection of pus with a connective tissue capsule
• Syphilis (prevalence 11.5 / 100,000 (0.115 %) in men, 0.9/100,000 (0.009 %) in women)

16. Neurofibromatosis type 1 (0.029 %)¶

Other names: Von Recklinghausen’s disease, Recklinghausen’s disease, neurofibromatosis Recklinghausen, peripheral neurofibromatosis
With a prevalence of around 1:3500 (0.029 %), it is one of the most common hereditary neurological diseases. Neurofibromatosis type 1 shows malformations of the skin and the central nervous system. Neurofibromatoses are nerve tumors.

Among 128 persons with ADHD (53.1 % girls), 28.9 % (37/128) were found to have ADHD, including 20 ADHD-C, 15 ADHD-I and 2 ADHD-HI. ADHD and ASD occur more frequently in neurofibromatosis type 1 ¹⁰¹¹⁰²
Other comorbidities of neurofibromatosis type 1 were macrocephaly (head circumference more than 2 SDs above the age average, 37.5 %), headache (18.6 %), cognitive impairment (7.8 %), motor deficits (6.2 %) and epilepsy (4.68 %). MRI revealed T2-weighted hyperintensities in the basal ganglia and/or cerebellum (70.5 %), optic nerve gliomas (25.8 %), plexiform neurofibromas (9.3 %), Chiari malformation type 1 (6.7 %), arachnoid cysts (5 %), gliomas of the central nervous system (3.1 %).¹⁰³

Diagnostic criteria - at least 2 of the following symptoms:¹⁰⁴

• Six or more café-au-lait spots (CAL) > 5 mm in diameter prepubertal and > 15 mm postpubertal.
• Freckling in the armpit or groin region.
• Two or more neurofibromas of any type or one plexiform neurofibroma (PNF)
• Glioma of the visual pathway
• Two or more iris nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs) detected as irregular bright nodules by optical coherence tomography (OCT) or near infrared imaging (NIR imaging).
• Specific bony lesions such as sphenoid dysplasia, anterolateral bowing of the tibia or pseudarthrosis of the long tubular bones.
• A heterozygous pathogenic (= disease-causing) NF1 variant with an allele frequency of 50 % in normal tissue such as leukocytes.

In 5 to 11% of people with NF-1, this is due to a microdeletion syndrome of neurofibromatosis type 1.
In 57 persons with ADHD with NF-1 microdeletion syndrome:¹⁰⁵

• 28 people with ADHD type 1, 4 type 2, 2 type 3, 9 atypical deletions and 14 persons with undetermined deletions
• in 33 out of 41 (80.5 %) learning difficulties
• 39 out of 49 (79.6 %) developmental delays
• expressive and/or receptive language delays in 35 of 49 (71.4 %)
• in 38 out of 56 (67.9 %) describable facial features
• in 23 of 42 (54.8 %) ADHD
• in 25 of 57 (43.8 %) plexiform neurofibromas
• in 3 of 57 (5.2 %) malignant peripheral nerve sheath tumors
• IQ decreased (between 50 and 96; 22 people with ADHD studied, 21 of whom were adults). Of the adults had:
  • 14 out of 21 (66.7 %) have a high school diploma
  • 4 out of 21 (19.0 %) had some college experience.

NF1 children with ADHD and children with primary ADHD show similar deficits in attention and executive functions.
NF-1 showed a slower reaction time and greater learning difficulties.¹⁰⁶

17. Velocardiofacial syndrome (22q11DS) (0.01 to 0.05 %)¶

Other names: CATCH 22, Cayler cardiofacial syndrome, Di George syndrome, DiGeorge sequence, microdeletion 22q11.2, monosomy 22q11, Sedlackova syndrome, Sphrintzen syndrome, syndrome of conotruncal anomaly with facial dysmorphia, Takao syndrome

22q11.2 deletion syndrome (DS)¹⁰⁷

The prevalence of velocardiofacial syndrome is 1 - 5 / 10,000 (0.01 to 0.05 %)¹⁰⁸

18. Cortisol disorders (cumulative 0.0042 to 0.0048 %)¶

18.1. Hypocortisolism (adrenal insufficiency) (0.004 %)¶

Sources:¹⁰⁹¹¹⁰

Addison’s disease: Prevalence: 4/100,000 (0.004 %).
Weaker forms are much more common.

Since the basal cortisol level is slightly reduced in ADHD (in ADHD-HI as in ADHD-I), ADHD could be described as very weak adrenal insufficiency (adrenal insufficiency).

18.2. Hypercortisolism (Cushing’s syndrome) (0.0002 to 0.0008 %)¶

Prevalence: 8/1,000,000 in men (0.0008%), 2/1,000,000 in women (0.0002%)¹¹¹

• ACTH-dependent form (80% of cases)
  • Micro- or macroadenoma of the anterior pituitary gland produces ACTH (= Cushing’s disease)
  • (mostly malignant) tumors outside the pituitary gland (often bronchial carcinomas) as the cause of ectopic ACTH production
• ACTH-independent form (20% of cases)
  Overproduction of glucocorticoids (cortisol) and mineralocorticoids by the adrenal cortex
  • Adrenal cortical adenoma (pure cortisol overproduction)
  • Adrenal carcinoma (increased cortisol and androgen production)
  • Nodular hyperplasia of the adrenal cortex

19. Moyamoya (0.0001 % to 0.0009 %)¶

Moyamoya is particularly common in Japan.
Prevalence
Worldwide: 1 / 1,000,000 to 9 / 1,000,000 (0.0001 % to 0.0009 %)¹¹²
Japan: 1 / 30,000 to 1 / 9,500 (0.0033 % to 0.0105 %)
Incidence Japan: 1 / 280,000 to 1 / 89,000

Moyamoya is a narrowing or occlusion of cerebral arteries that leads to relative anemia (stroke and transient ischemic attack) in the brain. Many small compensatory vessels form as bypass circuits.
Moyamoya can be associated with symptoms that can be confused with ADHD.¹¹³

20. Hamartoma of the hypothalamus (0.0005 %)¶

Prevalence: 1 / 200,000 (0.0005 %)¹¹⁴

A hamartoma is a tumor-like, benign tissue change due to incorrectly differentiated or dispersed germinal tissue. A hypothalamic hamartoma can produce a variety of hormones and cause ADHD symptoms, conduct disorder, oppositional defiant disorder, antisocial behavior, tantrums, intellectual regression, cognitive disorders, premature puberty, obesity and epilepsy. 60% of people with ADHD develop externalizing disorders (especially in boys and epilepsy) and 30% develop internalizing disorders.¹¹⁵¹¹⁶ MPH can significantly improve ADHD caused by a hypothalamic hamartoma, as can treatment with a gonadotropin-releasing hormone (GnRH) analog.¹¹⁷ In severe cases, stereotactic laser surgery may be helpful.¹¹⁸

3.21. Allergies (with motor restlessness)¶

Source³

3.22. Visual and hearing impairment¶

Sources⁵³³

3.23. Lesions of the left cerebral hemisphere / right PFC¶

• Attention selection impairs¹¹⁹
  • E.g. in situations that require quick decisions between relevant and irrelevant stimuli
  • Frequently increased number of errors in choice-response tasks or extended response times

Lesions of the OFC have been known since the case of Phineas Gage (Harlow 1848) and are associated with specific symptoms:¹²⁰

• often dramatic changes in personality
• impulsive
  • often reckless, risky behavior
  • frequent conflicts with the law
  • disinhibited in terms of instinctive behaviors
  • Problems with drive control
• irritable
• quarrelsome
• Tendency to crude humor
• Disregard for social and moral principles
• severe attention deficit disorder
  • strong distractibility due to external or internal stimuli

The OFC normally has inhibitory functions. These take place via efferents to:¹²⁰

• Hypothalamus
• Basal ganglia
• other neocortical areas, e.g. in the PFC

Patients with lesions of the right frontal cortex often show ADHD-like behavior.¹²¹

3.24. Organic brain damage¶

Source³

3.25. Status epilepticus during sleep (ESES)¶

Other names: Bioelectric status epilepticus during sleep, CSWS, CSWS syndrome, ESES syndrome, Epileptic encephalopathy with continuous spike-wave discharges during slow-wave sleep
Prevalence: unknown. Orphane Disorder (rare).¹²²

Epilepsy with continuous spike-wave discharges during sleep (CSWS) is a rare epileptic encephalopathy in children. It is characterized by seizures, electroencephalographic patterns of status epilepticus during sleep (ESES) and cognitive developmental regression.¹²³

ESES is associated with symptoms similar to ADHD. In one study, treatment with ACTH reduced ADHD symptoms by an average of 67%.¹²⁴ Another study by the same authors found similar improvements with ACTH in ADHD and stuttering.¹²⁵

3.26. Traumatic or space-occupying cerebral disorders / other psychoorganic syndromes with cerebral damage and/or mental retardation¶

Source⁵³

3.27. Bachmann-Bupp syndrome (BABS)¶

Bachmann-Bupp syndrome (BABS) is characterized by¹²⁶

• pronounced alopecia
• global developmental delay in the moderate to severe range
• Hypotension
• non-specific dysmorphic features
• Behavioral problems
  • ASS
  • ADHD
• Feeding problems
• Hair
  • usually present at birth
  • can be sparse
  • may have unexpected color
  • falls out in large clusters in the first weeks of life
• Seizures at the beginning of later childhood (rare)
• Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated levels of N-acetylputrescine) indicates BABS.
Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variants of the ODC1 gene.

3.28. CAPRIN1 haploinsufficiency¶

Haploinsufficiency of the CAPRIN1 gene is an autosomal dominant disorder associated with loss-of-function variants in cell cycle-associated protein 1 (CAPRIN1).
The CAPRIN1 protein regulates the transport and translation of neuronal mRNAs that are crucial for synaptic plasticity, as well as mRNAs encoding proteins that are important for cell proliferation and migration in different cell types.
CAPRIN1 variants with loss of function were associated with the following symptoms:¹²⁷

• Speech impediment/speech delay (100 %)
• mental disability (83 %)
• ADHD (82 %)
• ASS (67 %)
• Breathing problems (50 %)
• Anomalies of the limbs and skeleton (50%)
• Developmental delays (42%)
• Feeding problems (33 %)
• Seizures (33 %)
• Eye problems (33 %)

3.29. KBG syndrome¶

KBG is a rare monogenetic syndrome. Genetic variants in ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 people with ADHD, 24% were diagnosed with ADHD.((Guo L, Park J, Yi E, Marchi, Hsieh, Kibalnyk, Moreno-Sáez, Biskup, Puk, Beger, Li Q, Wang K, Voronova, Krawitz, Lyon (2022): KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients. Eur J Hum Genet. 2022 Aug 15. doi: 10.1038/s41431-022-01171-1. Epub ahead of print. PMID: 35970914. n = 25
KBG goes hand in hand with:

• Macrodontia
• pronounced craniofacial features
• Short stature
• Skeletal anomalies
• global developmental delay
• Seizures
• mental disability

3.30. Cystic fibrosis¶

Cystic fibrosis is associated with increased ADHD symptoms.¹²⁸ Reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%.¹²⁹

Cystic fibrosis correlates with mutations in the CFTR gene¹³⁰, which has been identified as a gene candidate for ADHD.¹³¹

3.31. ME/CFS, myalgic encephalomyelitis / chronic fatigue syndrome¶

Myalgic encephalomyelitis / chronic fatigue syndrome is a severe neuroimmunological disease. A high degree of physical disability is a common consequence.¹³²

Prevalence:
17 million people with ADHD worldwide
250.000 people with ADHD (including 40,000 children / adolescents) in Germany before the COVID-19 pandemic (0.31 %)
500.000 people with ADHD after the COVID-19 pandemic (0.62 %)
25 % can no longer leave the house
60 % are unable to work

ME/CFS is an independent, complex clinical picture. The symptom of fatigue, on the other hand, is a common accompanying symptom of chronic inflammatory diseases.

Symptoms of ME/CFS:

• physical symptoms
  • severe fatigue (physical weakness)
    • significant restriction of the activity level- neurocognitive symptoms
  • Muscle twitching
  • Muscle cramps
  • massive sleep disorders
• autonomic symptoms
  • Orthostatic intolerance.
    • Palpitations
    • Dizziness
    • Drowsiness
    • Fluctuations in blood pressure
  • Consequences: e.g. no longer able to stand or sit for long periods of time
• immunological symptoms
  • strong feeling of illness
  • painful and swollen lymph nodes
  • Sore throat
  • Respiratory tract infections
  • increased susceptibility to infections
• Post-exertional malaise (PEM)
  • pronounced and persistent intensification of all symptoms after minor physical or mental exertion
  • pronounced weakness
  • Muscle pain
  • flu-like symptoms
  • Deterioration of the general condition
  • typically occurs even after low levels of stress
    • Brushing your teeth
    • Showers
    • Cooking
    • walk a few steps
  • for severely affected people, even turning over in bed or the presence of another person in the room can trigger PEM
• Pain symptoms
  • pronounced pain
    • Muscle pain
    • Joint pain
    • Headache
• neurocognitive symptoms
  • “Brain Fog”
    • Concentration problems
    • Memory problems
    • Word-finding disorders
  • Increased sensitivity
    • Hypersensitivity to sensory stimuli
    • Very severely affected people often have to lie in darkened rooms and can only communicate in a whisper

Trigger:

• Infectious diseases
  • Epstein-Barr virus
  • Influenza
  • SARS
  • COVID-19
• Gonorrhea
• Endometriosis and PDMS
• Nutrient deficiencies (vitamins, trace elements)

Path:

• unexplained
• possible:
  • Autoimmune disease
  • severe disorder of the energy metabolism

Biomarkers:

• none known

Diagnostics:

• using established clinical criteria catalogs

Treatment:

• there is currently no approved curative treatment or cure
• Pacing
  • helps with ME/CFS as well as ADHD or ASA
  • Overloading is “punished more severely” with ME/CFS

Differences between ME/CFS and ADHD / ASD / depression:

• ADHD: problems usually already as children, but no later than 16 to 18; ME/CFS: problems usually not already throughout life
• ME/CFS: gradual, usually undulating deterioration over years until at some point there is no energy left at all
• no depressive states
  • no strong deterioration in sentiment
  • Depression: severe cognitive impairment and reduced drive; ME/CFS: cognitive impairment due to temporary or permanent “brain fog”
  • Ability to vibrate is preserved in ME/CFS
  • People with ADHD do not perceive themselves as depressed and do not appear depressed
  • Depression; drive is lacking and is missed; ME/CFS: drive present, energy for implementation is lacking or implementation leads to overload (sometimes only hours later)

Martin Winkler considers exhaustion in ADHD in the context of a regulation-dynamic model. He distinguishes between ADHD / neurodivergence:

• Cognitive exhaustion
  • Consequences: Mental fatigue due to constant demands on attention and concentration, especially in inappropriate environments
    • reduced performance
    • reduced attention span
    • increased distractibility
• Emotional exhaustion
  • Emotional regulation requires increased effort
    • Consequences: depletion of emotional resources
      • increased irritability
      • Mood swings
      • Feeling of being overwhelmed
• Physical exhaustion
  • Constant tension and effort to concentrate / control impulsive behavior,
    • Consequences: physical exhaustion
• Exhaustion due to adaptation requirements / masking
  • Increased cognitive / emotional resources to adapt to social norms and expectations
    • Consequences: specific adaptation requirement exhaustion

3.32. Congenital myopathy and neuropathy¶

One person with ADHD reported that his suspected ADHD was mistaken and that he had congenital myopathy and neuropathy instead.

3.33. Mild Cognitive Impairment (MCI)¶

Mild Cognitive Impairment is a mild cognitive impairment that goes beyond the normal mental decline in old age, but does not yet constitute dementia.
A small study of n = 36 MCI persons with ADHD with an average age of 72 years found ADHD in 25 %.¹³³

3.34. Cerebrotendinous xanthomatosis (CTX)¶

Cerebrotendinous xanthomatosis is a rare genetic disorder (prevalence 1:70,000) of the CYP27A1 gene that is inherited in an autosomal recessive manner. CTX is often only diagnosed in early adulthood due to the neurological symptoms that then become apparent.¹³⁴
CTX includes:¹³⁵

• Lipid storage impaired
• Bile acid biosynthesis pathways altered
• Cholesterol metabolites (e.g. cholestanol) increased in
  • Fabric
  • Brain
  • Eye lens
  • Tendons

Symptoms:¹³⁵

• progressive neurological problems (64-92%)
  • Spasticity
  • Pyramidal signs
• neuropsychiatric symptoms
  • cognitive impairments (87 %)
  • Behavioral disorders
• juvenile cataracts (82 %)
• Xanthomas (yellowish / orange fat deposits)
  • Tendon xanthomas (76 %)
• Osteoporosis (65 %)
• chronic diarrhea (31 %)
• psychiatric disorders (11.4%)
• Cardiovascular diseases