As a leading provider of stroke research services, Ace Therapeutics assists clients in investigating the pathology of neuropathy after stroke and in developing potential therapeutics.

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• Pathogenic Mechanism Analysis Services for Stroke
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Can a Stroke Cause Neuropathy?

Stroke is a serious and life-threatening condition that can lead to a variety of side effects, such as neuropathy. Neuropathy, which also becomes neuralgia, can manifest itself in different forms, including peripheral neuropathy or central neuropathy.

Peripheral neuropathy

Peripheral neuropathy, a type of nerve disorder, arises from localized damage to nerves outside the brain and spinal cord. Unlike nerve pain caused by a stroke, this condition is unrelated to brain or spinal cord injuries.

It is characterized by pain, tingling, or numbness, most commonly in the hands and feet, though it can affect other areas of the body. Peripheral neuropathy results from damage to the peripheral nerves or their endings. Common causes include traumatic injuries, diabetes, or infections.

Central neuropathy

Central neuropathy, the second type of neuropathic pain, can result from a stroke. This occurs because central neuropathy is caused by damage to the central nervous system, which includes the brain.

The Symptoms of Central Neuropathy After Stroke

Central neuropathy arises from dysfunction within the central nervous system and is commonly known as central post-stroke pain (CPSP). In the past, CPSP was attributed to a thalamic lesion but is now also associated with extrathalamic lesions. CPSP can manifest as continuous or intermittent pain, often described as burning, throbbing, pressure-like, or freezing. Sensory abnormalities, such as hyperesthesia, hyperalgesia, hypoesthesia, paresthesia, dysesthesia, allodynia, or hyperpathy, are common and may involve temporal and spatial summation.

Studies indicate that burning sensations are the most frequently reported symptom, followed by electric shock sensations, with pain aggravated by extremity movement, temperature changes, or psychological stress. Common sensory deficits include tactile allodynia and hyperalgesia, along with impairments in needle prick, temperature, or touch perception.

Fig. 1 Pain symptoms in central post-stroke pain. (Kumar, et al., 2009)

Lesion Site Associated With Central Neuropathy After Stroke

Pain is typically localized to areas with somatosensory abnormalities and correlates with the lesion's location in the central nervous system.

• Capsule-lenticular lesions: Pain is more prevalent in the lower limbs.
• Thalamic lesions: Contralateral hemi-body symptoms are most common.
• Medullary lesions: Symptoms vary based on lesion location (lateral or medial), with lateral lesions causing facial pain (ipsilateral or contralateral) and medial lesions affecting the trunk and extremities with numbness or tingling.

Fig. 2 Lesion site associated with central post-stroke pain. (Betancur, et al., 2021)

The Physiopathology of CPSP

CPSP is caused by complex mechanisms, including a functional imbalance between excitatory and inhibitory systems in the pain pathway, which may be related to specific neural circuits associated with areas of neuroanatomical injury. However, the specific pathophysiology of CPSP is not well understood but several theories have been suggested.

• Central disinhibition: Injury to the lateral thalamus leads to thalamic overactivity due to loss of cortical control, which causes an excessive pain response.
• Thermosensory imbalance: CNS damage causes an imbalance between the output of the insula thermoreceptor area and the limbic network associated with thermoregulatory motivation. As a result, thermosensory integration is lost, manifesting as a burning sensation and an exacerbated response to temperatures previously thought to be harmless.
• Damage to the spinal thalamic pathway: structural damage or dysfunction of this pathway predicts CPSP. Abnormal thermosensory integration and deregulation of nociceptive inhibition can lead to burning sensations and hyperalgesia in response to nonpainful stimuli.
• Neuroplastic dysfunction: maladaptive cortical and thalamic hyperexcitability, associated with changes in calcium channels and imbalances in GABAergic and glutamatergic systems, can lead to CPSP.

Treatments for CPSP

There are a variety of pharmacologic and nonpharmacologic treatments for CPSP. Despite the shortcomings and limitations of current treatments for CPSP, the most effective approaches are those that target increased neuronal hyperexcitability.

• Anticonvulsants. Drugs commonly used to manage seizures can help alleviate CPSP by reducing the excitability of neurons that transmit pain signals.
• Anti-depressants. Amitriptyline was the first antidepressant to be shown to be significantly effective in CPSP. Selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRIs) are also potential candidates for central neuropathy after stroke.
• Corticosteroids. Drugs such as prednisone can relieve central post-stroke pain. Combining corticosteroids with anticonvulsants has shown enhanced pain relief effects.
• Deep-brain stimulation (DBS): An invasive procedure that involves implanting electrodes deep in the brain to stimulate the central nervous system. It is considered an excellent option for severe CPSP, typically as a last resort.
• Repetitive transcranial magnetic stimulation (rTMS): This non-invasive, advanced treatment targets specific cerebral areas with electromagnetic pulses to alleviate neuropathic pain, particularly when thalamic damage is the source of the pain.

Fig. 3 Epoxyeicosatrienoic acids are potential therapeutic agents for central post-stroke pain. (Wan, et al., 2020)

1. Kumar, B., et al. (2009). Central poststroke pain: a review of pathophysiology and treatment. Anesthesia & Analgesia, 108(5), 1645-1657.
2. Betancur, D. F. A., et al. (2021). Central post-stroke pain: an integrative review of somatotopic damage, clinical symptoms, and neurophysiological measures. Frontiers in Neurology, 12, 678198.
3. Wan, L., et al. (2020). Epoxyeicosatrienoic acids: Emerging therapeutic agents for central post-stroke pain. Pharmacological Research, 159, 104923.