Iatrogenic neurological disorders

Vorokhta Y., MD, PhD

 Causes
• Pharmactotherapy
• Interventional therapy
• Surgical interventions
• Physiotherapy
• Physical therapy
• Diagnostic procedures
• Psychogenic
 Drug-induced neurological disorders
[DIND]
Drugs may directly induce neurological damage (through primary
neurotoxicity, such as damage to the blood-brain barrier [BBB], disturbances
of brain energy metabolism, ion channels/neurotransmitters disturbances,
mitochondrial dysfunction, metabolite mediated toxins, drug-induced
selective cell death) or do so indirectly (cardiovascular, hematological or
renal effects).
Identification of DIND is important because early recognition and drug
withdrawal can prevent irreversible damage. The numerous intrinsic risk
factors for DIND should be well known by medical practitioners.
Drug-induced neurological disorders (DIND) can mimic neurological disorders
due to other causes. However, when there is a reasonable suspicion of
association with a drug or a known or plausible pathomechanism for DIND,
the drug should be considered in the differential diagnosis
 Some definitions
• Adverse Event/Adverse Experience (AE): This is any untoward
medical occurrence that may present during treatment with a
pharmaceutical product but which does not necessarily have a
causal relationship with this treatment.
• Adverse Drug Reaction (ADR): This is an event which is related or
suspected to be related to the trial medicine. An ADR is a
response to a drug which is noxious and unintended, and which
occurs at doses normally used in man for prophylaxis, diagnosis,
or therapy of disease, or for modification of physiological
function.
• Side Effect: This is any unintended effect of a pharmaceutical
occurring at doses normally used in humans which is related to
the pharmacological properties of the drug
 Direct neurotoxicity
• Disturbances of brain energy metabolism
– ATP synthetase inhibition
– Uncoupling Disturbances of oxygen consumption
– Enzymatic dysfunction
– Selective vulnerability of the central nervous system
• Sequelae of disturbances of brain energy metabolism:
– Ca2+ ion entry in the cell
– free radical formation
– Excitatory amino acids Ion channel disturbances
• Mitochondrial dysfunction, e.g, zidovudine-induced mitochondrial myopathy
• Neurotransmitter disturbances, e.g, atropine produces memory impairment by
reducing acetylcholine
• Metabolite-mediated toxins, e.g, MPTP neurotoxicity to dopamine cell in the
substantia nigra
• Drug-induced selective cell death Unknown mechanisms
• Disturbance of the proteome
• Alterations of individual protein structure by drugs leading to loss of neuronal function
Kajih R. et al. 2015
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Amin H., Greer D. 2015
Shen J. et al., 2018