Introduction and Historical Context
Central post-stroke pain (CPSP) syndrome is uncommon after stroke and occurs in only about 8% of patients. However, because of the common occurrence of stroke, CPSP is a major central neuropathic pain. The pain originates from the stroke lesion itself, which induces neuroplastic changes that result in disordered central nervous system (CNS) processing within the distributed sensory network. The first note of CPSP is attributed to Adolf Wallenberg in 1895 when he described a case of lateral medullary stroke, or Wallenberg’s syndrome . His case involved a 38-year-old man who suffered “vertigo without loss of consciousness.” Wallenberg reported that the man “developed pain and hyperesthesia of the left side of his face and body, hypoesthesiae of the right half of the face, and loss of pain and temperature sensitivity in the right extremities and right half of the torso.” In 1906, Dejerine and Roussy described a case of intractable pain following a thalamic stroke, which was then named the thalamic syndrome . Symptoms included persistent hemianesthesia, mild hemiataxia, severe persistent often intolerable pain unresponsive to treatment, and choreoathetoid movements, all found on the hemiplegic side of the body. In 1911, Head and Holmes, by using controlled stimuli in patients with spontaneous pain following stroke, determined that cortical lesions could not cause such pain without involvement of the thalamus.
Davison and Schick published 11 clinical-pathologic cases of spontaneous pain in 1935 that were associated with lesions in the thalamus, spinal cord, peripheral nerves, and cerebral cortex. It became clear from this review and other case studies that spontaneous pain may follow various lesions in the CNS. Riddoch wrote a summary of these findings and defined central pain as being spontaneous and associated with an over-reaction to stimulation as a result of lesions within the CNS. In 1969, Cassinari and Pagni determined that CPSP can result from a lesion anywhere along the spinothalamic and thalamocortical pathways and that involvement of these pathways is necessary for the development of CPSP. However, it must be recognized that pain does not always result from these lesions. Currently, it is recognized that cortical, subcortical, thalamic, and lateral brainstem strokes can all cause CPSP, in addition to sensory changes and impaired motor control and weakness, but pain is not always a necessary outcome.
Clinical Diagnosis
Pain from any cause is common after stroke and occurs at an incidence of 14% to 43% in the acute and subacute stages of recovery. Among the many causes of post-stroke pain, CPSP is a less common etiology. More frequently, pain after stroke is a result of musculoskeletal processes, including hemiplegic shoulder pain, arthritis, myofascial disorders, and tendonitis. For this reason, the diagnosis of CPSP cannot be made without eliminating other possible causes of localized pain. In addition to the musculoskeletal causes, others include gout, deep vein thrombosis, complex regional pain syndrome, and painful spasms. Painful diabetic neuropathy is another form of neuropathic pain that can be seen in patients with stroke because of the close association between diabetes and cerebrovascular disease, but this pain is peripheral rather than central. Pain occurs in diabetic neuropathy with damage to Aδ and C fibers. Diabetic neuropathy is often accompanied by bilateral pain, whereas CPSP is almost always unilateral, and both conditions may occur simultaneously in patients with stroke. Although these two forms of neuropathic pain may respond to similar treatment, because of subtle differences in response to therapy, a careful diagnosis is critical.
In clinical practice, therefore, CPSP is a diagnosis of exclusion. The incidence of CPSP in patients with stroke is 8% in general and 9% after thalamic hemorrhage, but there is only a 5% incidence of moderate to severe pain. Onset of CPSP in the first days following the stroke is rare, but 63% of patients will have pain within the first month after stroke onset and nearly all the rest within a year.
Typically, a patient with CPSP will complain of severe pain on the side of the body contralateral to the lesioned hemisphere associated with sensory changes in the painful region. In the case of a lateral medullary stroke, the pain can be located in areas of sensory loss, which include the ipsilateral face and contralateral body. The pain associated with CPSP can be spontaneous or evoked. Spontaneous pain in some cases is episodic, whereas in others it may be continuous. Spontaneous pain is most commonly described as burning (47% to 59%) or aching (30% to 41%), often deep within the painful body area. Less commonly, a patient may complain of lacerating pain (7% to 26%) or pricking pain (6% to 30%). When pain is evoked, it can be caused by a nociceptive source that induces pain out of proportion to the stimulus (hyperpathia). Bovie and colleagues found that 59% of patients with CPSP had hyperalgesia in the painful region on pinprick testing, 37% had hypoalgesia, and only 4% had a normal pinprick sensation. Patients with stroke lesions in the thalamus are more likely to report that pinprick sensation is hyperalgesic.
Pain can also be evoked by non-nociceptive sources (allodynia), but the actual clinical response to different nonpainful stimuli can vary. Most patients will have some allodynia on examination, but as many as a third will have none. Of those with allodynia, the majority will experience pain with limb movement (70%), although some find that movement relieves the pain (19%). Thermal and tactile stimulation can evoke pain or reduce it as well. Nearly half of patients will have pain with cold stimuli (48%), but a few find that cold reduces their discomfort (7%). A warm stimulus was found to increase pain in 22% and reduce it in another 30%. Frequently, patients will find that emotions increase pain (19%), and 37% achieve relief of pain with rest.
Just over half (52%) of patients with CPSP have no hemiplegia, and only 37% have moderate hemiplegia. Severe hemiplegia is less commonly associated (11%). On the other hand, ataxia is present in 62%, but choreoathetosis is found in only about 4%.
Establishing a definitive diagnosis of CPSP is difficult and requires a thorough clinical assessment, elimination of other causes of the pain, and cranial imaging to confirm the presence of an appropriate brain lesion. Klit and associates recommended that definitive criteria for CPSP require that the patient have a history of stroke with an associated lesion on imaging and that the pain have a plausible anatomic distribution both by history and physical examination. Before confirming the diagnosis of CPSP, other possible causes of the pain must be excluded ( Box 27.1 ).
Exclusion of other probable causes of the pain
Pain with a distinct neuroanatomically plausible distribution
A history suggestive of stroke
Indication of a distinct neuroanatomic distribution by clinical examination
Indication of a relevant vascular lesion by imaging
Clinical Diagnosis
Pain from any cause is common after stroke and occurs at an incidence of 14% to 43% in the acute and subacute stages of recovery. Among the many causes of post-stroke pain, CPSP is a less common etiology. More frequently, pain after stroke is a result of musculoskeletal processes, including hemiplegic shoulder pain, arthritis, myofascial disorders, and tendonitis. For this reason, the diagnosis of CPSP cannot be made without eliminating other possible causes of localized pain. In addition to the musculoskeletal causes, others include gout, deep vein thrombosis, complex regional pain syndrome, and painful spasms. Painful diabetic neuropathy is another form of neuropathic pain that can be seen in patients with stroke because of the close association between diabetes and cerebrovascular disease, but this pain is peripheral rather than central. Pain occurs in diabetic neuropathy with damage to Aδ and C fibers. Diabetic neuropathy is often accompanied by bilateral pain, whereas CPSP is almost always unilateral, and both conditions may occur simultaneously in patients with stroke. Although these two forms of neuropathic pain may respond to similar treatment, because of subtle differences in response to therapy, a careful diagnosis is critical.
In clinical practice, therefore, CPSP is a diagnosis of exclusion. The incidence of CPSP in patients with stroke is 8% in general and 9% after thalamic hemorrhage, but there is only a 5% incidence of moderate to severe pain. Onset of CPSP in the first days following the stroke is rare, but 63% of patients will have pain within the first month after stroke onset and nearly all the rest within a year.
Typically, a patient with CPSP will complain of severe pain on the side of the body contralateral to the lesioned hemisphere associated with sensory changes in the painful region. In the case of a lateral medullary stroke, the pain can be located in areas of sensory loss, which include the ipsilateral face and contralateral body. The pain associated with CPSP can be spontaneous or evoked. Spontaneous pain in some cases is episodic, whereas in others it may be continuous. Spontaneous pain is most commonly described as burning (47% to 59%) or aching (30% to 41%), often deep within the painful body area. Less commonly, a patient may complain of lacerating pain (7% to 26%) or pricking pain (6% to 30%). When pain is evoked, it can be caused by a nociceptive source that induces pain out of proportion to the stimulus (hyperpathia). Bovie and colleagues found that 59% of patients with CPSP had hyperalgesia in the painful region on pinprick testing, 37% had hypoalgesia, and only 4% had a normal pinprick sensation. Patients with stroke lesions in the thalamus are more likely to report that pinprick sensation is hyperalgesic.
Pain can also be evoked by non-nociceptive sources (allodynia), but the actual clinical response to different nonpainful stimuli can vary. Most patients will have some allodynia on examination, but as many as a third will have none. Of those with allodynia, the majority will experience pain with limb movement (70%), although some find that movement relieves the pain (19%). Thermal and tactile stimulation can evoke pain or reduce it as well. Nearly half of patients will have pain with cold stimuli (48%), but a few find that cold reduces their discomfort (7%). A warm stimulus was found to increase pain in 22% and reduce it in another 30%. Frequently, patients will find that emotions increase pain (19%), and 37% achieve relief of pain with rest.
Just over half (52%) of patients with CPSP have no hemiplegia, and only 37% have moderate hemiplegia. Severe hemiplegia is less commonly associated (11%). On the other hand, ataxia is present in 62%, but choreoathetosis is found in only about 4%.
Establishing a definitive diagnosis of CPSP is difficult and requires a thorough clinical assessment, elimination of other causes of the pain, and cranial imaging to confirm the presence of an appropriate brain lesion. Klit and associates recommended that definitive criteria for CPSP require that the patient have a history of stroke with an associated lesion on imaging and that the pain have a plausible anatomic distribution both by history and physical examination. Before confirming the diagnosis of CPSP, other possible causes of the pain must be excluded ( Box 27.1 ).
Exclusion of other probable causes of the pain
Pain with a distinct neuroanatomically plausible distribution
A history suggestive of stroke
Indication of a distinct neuroanatomic distribution by clinical examination
Indication of a relevant vascular lesion by imaging
Pathophysiology
In lecture II of a series of lectures published in 1906 under the title “The Integrative Action of the Nervous System,” C.S. Sherrington introduced the division of sensory systems into an exteroceptive pathway and an interoceptive pathway . The exteroceptive pathway begins with receptors in the skin and muscle that transmit stimuli external to the body. This pathway can transmit both nociceptive and non-nociceptive stimuli, with the nociceptive stimuli traveling along the spinothalamocortical tracts. Fibers in this conventional pathway ascend along the lateral spinothalmic tract through brainstem and terminate in the ventrolateral (VL) thalamus. Fibers from the VL thalamus terminate in both the primary (SI) and secondary (SII) somatosensory cortices in the anterior parietal region. Additional fibers ascend from the VL thalamus to the motor cortex (M1) in the precentral gyrus.
The interoceptive pathway, in contrast, responds to signals originating within the body, such as the viscera, and travels along a distinct pathway called the lamina I spinothalmocortical tract ( Fig. 27.1 ). This pathway manages afferent signals that transmit information about the physiologic condition of the entire body and thereby modulates homeostasis, visceral pain, and thermoregulatory activity. Fibers along this tract ascend to the ventromedial thalamus, which then provides a rich supply of afferent input to the insular cortex. The lamina I system also has input to the periaqueductal gray and parabrachial nucleus, which send signals to the anterior cingulate cortex via the medial thalamus. This input influences the emotional state of the individual. The insular cortex modulates this by providing inhibitory feedback to the periaqueductal gray and parabrachial nucleus (see Fig. 27.1 ). Lesions along either the exteroceptive or interoceptive pathway can result in reduced or altered sensation.
The pathophysiology of CPSP has not been clarified but probably results from maladaptive neuroplastic changes within the CNS that result in aberrant sensory perception. CPSP can be considered a kind of “deafferentation phenomenon” because lesions are located within the spinothalamocortical pathway and probably resulting in maladaptive alterations in synaptic facilitation and inhibition. Less likely would be a type of “release phenomenon” in which lesions of the lemniscal pathway carrying nonpainful sensation leave the pain pathways and unbalanced pain signals are transmitted to the cortical centers. Because lemniscal injury is neither critical nor necessary for the development of CPSP, this later theory lacks much scientific support. Theories on the cause of CPSP are dependent on several concepts: first is that injury to the spinothalamocortical tracts is necessary; second, that the pain is a result of late neuroplastic changes within CNS; and third, that pain perception is linked closely to the emotional state of the individual and the behavioral drive that signals a homeostatic imbalance. For example, disruption of the negative feedback loop to the midbrain homeostatic structures (see Fig. 27.1 ) might lead to unopposed afferent input to the anterior cingulate gyrus. Activity in the cingulate gyrus is associated with emotional distress. The current theories for CPSP follow.
Central disinhibition : This theory suggests that CPSP is a result of a reduction in inhibitory neural activity at the cortical or thalamic level. In addition, pain may derive from reduced γ-aminobutyric acid (GABA) concentrations within the spinal cord or cerebral levels.
Central excitation : This theory proposes that pain is due to abnormal burst activity within the lateral and medial thalamic nuclei.
Thermosensory inhibition : In this theory, CPSP is proposed to be due to loss of descending inhibitory control from the interoceptive cortical structures, including the dorsal posterior insula on brainstem homeostatic sites such as the periaqueductal gray and parabrachial nucleus, which in turn will result in unabated thermoregulatory drive to the medial thalamus and the anterior cingulate cortex (see Fig. 27.1 ).
Abnormal central modulation : This theory suggests that there is a loss of central non-noxious temperature fibers along the lamina I spinothalamocortical pathway above the motor decussation. Loss of fibers in this tract would disrupt the capability of the CNS to modulate temperature perception, which could cause symptoms of allodynia.
Loss of aminergic modulation : If there is a general reduction in adrenergic and serotonergic modulation within the CNS, the function of the afferent pathways may be altered and result in greater perception of pain.
Alteration of the N -methyl-d-aspartate (NMDA)-glutamate system : Thalamocortical excitability might be enhanced by increased glutaminergic NMDA stimulation and result in changes consistent with long-term potentiation that enhance the perception of pain.
These different proposed mechanisms may all be involved in the development of CPSP, or different mechanisms may be involved. For example, some of the theories listed were formulated by considering the pharmacology of medications that have shown efficacy in treating CPSP, including their inhibitory, excitatory, or modulating effects on CNS activity. It is important to note that because there are a number of medications with different pharmacologic mechanisms and no single medication is completely effective, it is likely that CPSP has multiple physiologic causes associated with neuropharmacologic changes at multiple locations. In any one patient, multiple pain-inducing mechanisms may also be at play. This not only complicates our understanding of the etiology of CPSP but also complicates management as well.
Pharmacologic Management
Use of medication for the treatment of CPSP is part of the overall comprehensive approach to pain management, which also includes physical conditioning, modification of functional task performance, supportive counseling, and behavior modification. Thus, pharmacology is not used in isolation, especially since the clinical response to treatment with medications is literally “fifty-fifty.” That is, at best only about half the patients will derive any benefit from the medications prescribed, and those who do will have only about 50% relief of their symptoms. Medications useful in managing CPSP fall into five categories: membrane stabilizers, aminergic agents, glutamate antagonists, GABA agonists, and N-type calcium channel blockers ( Box 27.2 ). When medications are used, it is recommended that one class be tried at a time and if one class fails, a medication from a different class be used for the next trial.
Membrane stabilizers: carbamazepine, intravenous lidocaine
Aminergic agents: amitriptyline, fluvoxamine, duloxetine (a study showed a trend toward improved pain scores )
Antiglutaminergic agents: ketamine, lamotrigine (a study showed a reduction in pain scores but no clear effect on evoked pain )
γ-Aminobutyric acid agonists: oral baclofen may be efficacious
N-type calcium channel blockers: pregabalin, possibly gabapentin
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