Classification scheme for medical complications of stroke

Prospective studies suggest that direct effects of ischemic stroke, such as hemorrhagic conversion or cerebral edema, account for the majority of deaths within the first week, but medical complications account for at least 50% of mortality thereafter (153; 65).

The Stroke Unit Trialist Collaboration study demonstrated that stroke units significantly reduced the complications of neurologic deficits including immobility and reduced mortality within the first 4 weeks of the index stroke (04). The beneficial interventions consisted of speech and swallow evaluations to minimize aspiration, avoidance of urinary catheter use, and anticoagulation to prevent deep venous thrombosis. In the later months after stroke, the most frequent complications, significant in terms of mortality, are: cardiac arrhythmias, myocardial infarction, pneumonia, urosepsis, and venous thromboembolism. The less morbid complications are psychiatric disorders, central post-stroke pain, falls, and pressure sores (153).

Medical complications of stroke affect survival not only during the acute period, but up to several years after discharge (06). The Copenhagen Stroke study showed that atrial fibrillation, diabetes, smoking, and previous stroke significantly affect survival at 5 years from stroke. Smoking and daily alcohol consumption were associated with improved survival in the univariate analyses, but with adjustment for other factors, especially age, the lethality of smoking was exposed, and the positive effect of alcohol disappeared. This suggests that secondary preventive measures such as anticoagulation for atrial fibrillation, smoking cessation, and proper treatment of diabetes may significantly improve long-term survival (69).

A reasonable grouping of post-stroke medical complications, which includes the neurologic sequelae (recurrent stroke, post-stroke seizures), is provided in Table 1 (92). Several of these topics (sleep apnea, vascular dementia, depression, dysphagia, normal pressure hydrocephalus) are discussed in other clinical summaries. The topics discussed in this article are listed in Table 2.

Table 1. Medical Complications of Stroke: A Classification Scheme

Table 2. Medical Complications of Stroke

Deep venous thrombosis and pulmonary embolism

Epidemiology. Venous thromboembolism (VTE) is a major cause of morbidity and mortality after acute ischemic stroke. In absence of prophylaxis, within 2 weeks after a stroke, approximately 50% of patients with stroke developed deep venous thrombosis, the majority of which were below the knee. Deep venous thrombosis may occur as early as the second day after stroke and reach a peak incidence between days 2 and 7 (16). The risk of deep venous thrombosis correlates with the degree of paralysis (91). Before anticoagulation with heparin became routine, clinically apparent deep venous thrombosis was associated with mortality from pulmonary embolism in 37% of cases (20). Pulmonary embolism is responsible for about 5% to 10% of the deaths in the acute period, and 25% after the acute period (71). In a series from Mayo clinic, over 2 decades, sudden death occurred in 50% of patients with pulmonary embolism (184).

Among patients with ischemic stroke discharged between 1979 to 2003 (U.S. Department of Health and Human Services 2005), 1.17% had venous thromboembolism, 0.74% had deep venous thrombosis, and 0.51% had pulmonary embolism; in those with hemorrhagic stroke, the rates were higher, 1.93%, 1.37%, and 0.68%, respectively (154).

Venous thromboembolism is multifactorial and mainly involves 3 factors referred to as Virchow's triad: damage to the vessel wall, venous stasis, and hypercoagulability (145; 76).

Damage to the vessel wall prevents the endothelium from inhibiting coagulation and initiating local fibrinolysis.

The risk factors for arterial stroke and venous thromboembolism overlap significantly. Obesity, cigarette smoking, and hypertension are independent risk factors for pulmonary embolism (50), whereas hypercholesterolemia and diabetes mellitus are not. Venous stasis due to immobilization or venous obstruction inhibits the clearance and dilution of activated coagulation factors. In stroke, there is a predilection for the paretic leg to a likely combination of repeated minor trauma and loss of the calf muscle pump (80). Additionally, atrial fibrillation, oral contraceptives, hormone-replacement therapy, and several inherited thrombophilias (such as hyperhomocysteinemia and activated protein C resistance) predispose to both venous thromboembolism and ischemic strokes (120; 49).

Other risk factors include severity of the illness, age, dehydration, increasing time between stroke onset and the introduction of preventive measures, hemorrhagic stroke, cryptogenic ischemic stroke, previous venous thromboembolism, morbid obesity, and known prothrombotic conditions including contraceptive use (143; 08).

Pulmonary embolism can be asymptomatic, or it can massive, leading to sudden death. Almost 40% of asymptomatic patients with deep venous thrombosis have evidence of pulmonary embolism on lung scans (116). Although 90% of emboli originate in the lower extremities, ultrasonography of the leg veins was positive in only 29% of patients with pulmonary embolism (167). The remainder emboli arose mostly from pelvic deep venous thrombosis (71).

Differential diagnosis. Edema caused by decreased venous return in the paretic limb may mimic deep venous thrombosis. Respiratory failure may be due to cerebral herniation or a brainstem lesion. The postthrombotic syndrome (PTS) attributed to venous hypertension and abnormal microcirculation (15) is characterized by edema and persistent (occasionally) incapacitating pain with or without venous ulceration (80).

Diagnostic workup. The clinical suspicion should guide the choice of further testing. Most patients with pulmonary embolism have at least 1 of these symptoms: sudden onset dyspnea, chest pain, syncope, and hemoptysis (111).

All patients should be assessed for pretest clinical probability of pulmonary embolism (Tables 3 and 4). Three scoring systems were developed: Wells (177), Geneva (179), and Pisa (112). Only after the clinical probability was determined should further studies be performed.

D-dimer level is elevated in patients with various systemic illnesses, like myocardial infarction, pneumonia, heart failure, cancer, recent surgery, and stroke (49). A negative test result combined with low pretest probability of disease by clinical criteria excludes thrombotic disease without the need to perform ultrasound.

In patients with high pretest probability, the result should not affect clinical decision (178). Venous duplex ultrasonography is highly sensitive for deep venous thrombosis, especially in symptomatic patients (96). Rarely, in patients with a high clinical concern for deep venous thrombosis but a normal ultrasound, venography may be considered (78). Unfortunately, in many patients with pulmonary embolism, the venous thrombus is not detectable.

Perfusion lung scanning or spiral CT of the chest are both sensitive screening tests; spiral CT may also sometimes identify small distal pulmonary emboli that may indicate the potential to develop a major pulmonary embolus (49). Conventional pulmonary angiography is the gold standard. Echocardiography may detect right ventricular failure due to pulmonary embolus (49).

Visualization of the thrombus by MRI has confirmed a high incidence of any venous thromboembolism (40%), proximal deep venous thrombosis (18%), and pulmonary embolism (12%) in unselected patients with acute cerebral infarcts (79).

In elderly patients with typical vascular risk factors, evaluation for systemic coagulopathy is low-yield (19). Immobilization from hemiparesis is the main risk factor for the development of deep venous thrombosis in this population. However, approximately 20% of patients younger than 45 years of age may have a hematologic disorder (85).

In patients with high clinical probability, a D-dimer level below cutoff does not exclude the diagnosis of thromboembolism. This needs to be confirmed with lower limbs ultrasonography or helical CT scan of the chest (144). However, CT alone may not be sensitive enough to exclude pulmonary embolism in these patients (140).

Table 3. Wells Prediction Rule for Diagnosing Deep Venous Thrombosis

Clinical probability of deep venous thrombosis:
Low = less than 0; intermediate = 1 to 2; high = 3 or higher

From: (177)

Table 4. Wells Prediction Rule for Diagnosing Pulmonary Embolism

Clinical probability of pulmonary embolism:
Low = 0 to 1; intermediate = 2 to 6; high = 7 or higher

From: (23)

Prevention of thromboembolism. Nonpharmacologic prevention of deep venous thrombosis includes early mobilization, graduated compression stockings, and pneumatic sequential compression devices.

The simplest preventive measure is early mobilization (03). There are only a few absolute indications for bed rest following stroke: increased intracranial pressure due to a large cerebellar or cerebral lesion, severe (ie, exercise-induced or unstable) angina and myocardial infarction, deep venous thrombosis (prior to anticoagulation), and postural ischemia due to large-vessel carotid or vertebrobasilar artery disease. When possible, intravenous lines should not be placed in a paretic arm, as this may increase the risk of deep venous thrombosis development in that area.

The thigh-length graduated compression stockings (GCS) did not reduce the incidence of proximal deep venous thrombosis after stroke and caused skin complications (29).

Intermittent compression stockings prevent deep venous thrombosis and increase survival in patients with acute stroke (CLOTS Trials Collaboration 2013). The American College of Chest Physicians recommends the use of intermittent pneumatic compression devices or elastic stockings for patients who have contraindications to anticoagulants (77).

UFH 5000 IU sc given 3 times daily reduced venous thromboembolism in patients with acute cerebral infarct from 73% to 22%. There was also a decrease in the combined rate for deep venous thrombosis, pulmonary embolism, and death (107).

Low molecular weight heparins are given once-daily and are associated with less risk for thrombocytopenia and osteoporosis than unfractionated heparin. A metaanalysis in patients with acute ischemic stroke showed that low-dose low molecular weight heparin had the best benefit-to-risk ratio (70; 152). The once daily administration of enoxaparin may also reduce the cost of care (Pineo and Lin 2012).

For acute stroke patients with restricted mobility, the clinical guidelines of the American College of Chest Physicians recommend the prophylactic use of either LMWH, low dose of UFH, or danaparoid (77). Heparin may be used after 24 hours from thrombolysis; the combination with aspirin may be safely used later.

In 1 observational study, the addition of sequential compression devices to UFH reduced the risk of deep vein thrombosis more than 40-fold (71).

In patients with intracerebral hemorrhage, early initiation of low-dose UFH (5000 U sc 3 times daily) significantly lowered the incidence of pulmonary embolism, compared with delayed (day 4 or day 10) therapy (11). Low-dose enoxaparin (40 mg sc daily) initiated after 48 hours from ictus was as effective and safe as the compression stockings (Orken at al 2009).

In patients at risk for heparin-induced thrombocytopenia (HIT), fondaparinux, an indirect factor Xa inhibitor, 2.5 mg sc is a safe alternative (56).

The new oral anticoagulation (NOAC) agents have not yet been tested in patients with ischemic stroke. Nevertheless, 4 systematic reviews, network meta-analyses (NMAs), and cost-effectiveness analyses of randomized controlled trials have not shown strong evidence that the new oral anticoagulants should replace postoperative LMWH in primary prevention of venous thromboembolism. For acute treatment and secondary prevention of venous thromboembolism, there is little evidence that new oral anticoagulants are more efficacious than warfarin. However, the risk of hemorrhagic complications was lower for some new oral anticoagulants than for warfarin (158).

Treatment of venous thromboembolism in stroke patients. Initiation of treatment in patients with suspected venous thromboembolism depends on the strength of the clinical suspicion, how rapidly the results of the confirmatory tests are available, and the location of the deep venous thrombosis or pulmonary embolism.

If the clinical suspicion is high, parenteral anticoagulant is indicated while waiting for the results of diagnostic tests. If the suspicion is intermediate, initiation of parenteral anticoagulation is indicated if the results of diagnostic tests are likely to be delayed for more than 4 hours. In patients with low suspicion, there is no need to initiate parenteral anticoagulation provided the results will be available within 24 hours.

If deep venous thrombosis is isolated to a distal segment of the leg, and there are no severe symptoms or risk for extension, serial imaging for 2 weeks is reasonable. However, if the distal deep venous thrombosis is accompanied by severe symptoms and there is risk of extension, initiation of anticoagulation over serial imaging is recommended. Extension of the distal thrombus on serial imaging warrants anticoagulation. In patients with venous thromboembolism, low molecular weight heparin or fondaparinux is preferred over intravenous unfractionated heparin or subcutaneous unfractionated heparin. If low molecular weight heparin is used, a once-daily dose is preferred over twice-daily dose, provided the once-daily injection contains double the twice-daily injection.

Some patients may prefer to avoid the postthrombotic syndrome (PTS) and accept a higher risk of bleeding. They may benefit from catheter-directed or systemic thrombolysis.

In patients with contraindications for anticoagulation, like intracerebral hemorrhage, a temporary inferior vena cava (IVC) filter is recommended. Anticoagulation should be resumed if the contraindication no longer exists. However, insertion of IVC filter is not recommended in addition to anticoagulation.

The duration of therapy for the first unprovoked venous thromboembolism is 3 months if the risk of bleeding is high, and extended if the risk of bleeding is low or moderate. At the end of 3 months, the risk-benefit ratio should be reassessed before further recommendations are made. If venous thromboembolism is provoked by either surgery or a transient nonsurgical factor, the duration of anticoagulation is 3 months. If cancer is present, extended anticoagulation is recommended regardless of the bleeding risk.

Compression stockings for 2 years or more are indicated in patients with symptomatic deep venous thrombosis of the leg or postthrombotic syndrome. If they fail to relieve the symptoms, a trial of intermittent compression devise is reasonable.

If acute pulmonary embolism is associated with hypotension (systolic BP < 90 mmHg) or the patient is at risk for developing hypotension, intravenous thrombolytic therapy through a peripheral vein is indicated provided there is no increased risk for hemorrhage. Analysis of a National Inpatient Sample (NIS) from 2009 to 2012 revealed that systemic thrombolysis is associated with increased risk of hemorrhagic stroke compared with catheter-directed intervention, although mortality was similar (99). In this situation, catheter assisted thrombectomy is appropriate. In critical situations in which thrombolysis or catheter assisted thrombectomy failed or the patient is in shock and likely to die within a few hours, surgical pulmonary thrombectomy may be beneficial (77).

Intravenous unfractionated initially followed by warfarin therapy has been the standard initial treatment of venous thromboembolism. Warfarin should be started the same day as the parenteral anticoagulation. Intravenous anticoagulation should be continued for a minimum of 5 days or at least 24 hours of INR 2 or above. The ideal INR target is 2 to 3. To ensure rapid and reliable systemic anticoagulation to therapeutic levels, warfarin should begin with 5 mg (and not higher) doses (58; 32). When available, outpatient anticoagulation clinics are preferred in terms of anticoagulation control, patient outcomes, and health care costs (25).

If warfarin is contraindicated, such as for a pregnant woman, alternatives include UFH or a LMWH such as enoxaparin. Secondary interventions such as early mobilization and stopping agents that promote coagulation (eg, hormone-replacement therapy or oral contraceptives) are both advisable.

In patients with cancer, LMWH is preferred to warfarin. Additionally, if the patient is unreliable, long-term subcutaneous injections of a LMWH is an alternative.

The American College of Chest Physicians recommends LMWH or vitamin K antagonists to the newer oral agents (77). However, more information regarding the efficacy of the newer anticoagulants is needed.

Patients with acute venous thromboembolism taking dabigatran, a direct thrombin inhibitor, 150 mg po bid were compared with warfarin after intravenous heparin. Dabigatran was non-inferior and was associated with fewer bleedings than warfarin (150).

Rivaroxaban was also proven effective for deep venous thrombosis and pulmonary embolism treatment. A dose of 15 mg po twice daily for 3 weeks followed by 20 mg daily was noninferior to enoxaparin followed by warfarin (39; 40).

Apixaban, another direct oral factor Xa inhibitor, was not inferior to enoxaparin followed by warfarin, yet caused fewer clinically relevant bleeding. The dose of apixaban was 10 mg po bid for 7 days, followed by 5 mg po bid for 6 months (01).

Bone disease: osteoporosis and fractures

Osteoporosis, caused by bone loss due to hypomobility, doubles the risk of fractures in the affected extremities in stroke patients, especially in women, compared to the normal population (143). Fractures are both early and late complications; Scottish hospitals’ data of 130,000 acute stroke patients discharged revealed that 2.0% suffered fractures by 1 year and 10.6% by 10 years (36).

Epidemiology. In the U.S., osteoporotic fractures are responsible for approximately 500,000 hospitalizations and 180,000 nursing home placements each year. Clinical risk factors that contribute to fracture risk independently of bone mineral density include age, previous fragility fracture, premature menopause, a family history of hip fracture, and the use of oral corticosteroids (73).

Table 5. Risk Factors for Osteoporotic Fractures in Women

Adapted from (73)

Pathophysiology. Bone strength is a composite of bone density and bone quality, with the latter thought to include bone architecture, bone damage (eg, microfractures), and mineralization (146).

Disuse from hemiparesis probably plays a major role, although 1 study found only weak associations between bone loss and motor function, activities of daily living, or ambulation (143). Vitamin D deficiency results from immobilization, advanced age, malnutrition, and sunlight deprivation (149). Additionally, medications such as warfarin, anticonvulsants, and proton pump inhibitors can decrease its serum level (147; 149; 101). Hypovitaminosis D increases the risk of hip fracture in elderly patients with disabling stroke symptoms (146).

Dabigatran, a direct oral thrombin inhibitor, was associated with lower risk of osteoporotic fractures compared to warfarin in a population-wide retrospective cohort study from Hong Kong (93).

In addition to weakness and imbalance, stroke patients often have a diminished level of awareness, either from neglect or hemisensory loss (visual or primary sensory modalities), which predisposes them to trauma (138).

Conversely, a Danish nationwide cohort study found an increased risk of stroke in patients with hip fracture (131).

Clinical features. Hip and vertebral fractures are the most important types of fracture. There is a 4-fold increased risk of a hip fracture following hospitalization for stroke versus the general population (72). The majority of these fractures occur late after stroke onset, on the hemiplegic side (143). Hip fractures are associated with increased risk of institutionalization and death (42).

Vertebral fractures are associated with chronic back pain, spinal deformity, functional limitations, and increased risk of hospitalization and mortality (68; 43). In strokes, 30% of fractures also occur in the upper extremity (128).

Osteoporosis is defined as bone mineral density of 2.5 SD or more below the average value for premenopausal women (T score, less than -2.5 SD). In the presence of 1 or more fragility fractures, osteoporosis is considered severe (73).

Table 6. World Health Organization (WHO) Definition of Osteoporosis

The major goals in the treatment of osteoporosis are: prevention of fractures, increased bone mass, treatment of fracture and skeletal deformity, and improvement of physical function (121). The U.S. Surgeon General has recommended a pyramidal approach to treatment (122). The base of the pyramid consists of lifestyle changes, including adequate calcium and vitamin D intake, physical activity, and fall prevention. Physical activity is needed for bone formation and maintenance.

Walking does not increase bone mineral density or reduce fracture risk. Exercises that reduce the risk of falling by means of improvements in mobility, muscle function, and balance could reduce fracture risk (44). Weight training has variable effects at different skeletal sites (47). To reverse osteoporosis after hemiplegia, daily weight training for minimum 60 and 90 minutes was needed for males and females, respectively (57).

Calcium and vitamin D reduce the risk of fracture (35). The recommended dietary intake of calcium is 1000 mg/day for men and women aged 50 years or younger and 1200 mg/day for those older than 50 years of age (NIH Dietary Supplement Fact Sheet--Calcium). The recommended dose of vitamin D is 400 IU/day for men and women aged 51 to 70 years and 600 IU/day for those 71 years or older (NIH Dietary Supplement Fact Sheet—Vitamin D). The second level includes addressing and treating secondary causes of osteoporosis. The third level includes pharmacotherapeutic interventions to improve bone density and reduce the risk of fracture.

Bisphosphonates inhibit the osteoclastic activity and reduce bone resorption. Etidronate disodium was studied in patients with stroke in a dose of 400 mg/day for a 2-week period followed by 13 weeks off therapy. After 2 years there was a nonsignificant reduction in fractures (148). Other potentially useful bisphosphonates include: alendronate, used at a preventive dose of 35 mg/week and therapeutic dose of 70 mg/day, ibandronate (150 mg/month), and risedronate (35 mg/week).

Although nitrogen containing bisphosphonates (alendronate and zoledronate) are more potent than the non-nitrogenous ones, they have been found to increase the risk of heart failure and atrial fibrillation (175).

Other drugs available are raloxifene, teriparatide, calcitonin, and certain estrogens. Raloxifene and strontium ranelate may increase the risk of venous thromboembolism and fatal stroke and should be avoided in patients at risk for stroke (173).

Complications of stroke

Falls. Traumatic brain injury is 1 of the most devastating and feared complications of falls, making up 78% of fall-related deaths and 79% of the cost (159).

Patients with a history of stroke have a risk of falling twice as high as the control subjects (66). Those who fall accidentally in the hospital are twice as likely to fall after discharge home (46).

Balance problems while dressing was the strongest risk factor for falls after stroke, whereas residual motor symptoms are not associated with increased risk of falling (90). In another study, most falls occurred during transfers to and from a wheelchair or bed (133).

Depression following stroke and TIA has been associated with accidental falls (160). Independent predictors of depression and anxiety were female sex, younger age, and higher socioeconomic deprivation score (17). Impaired executive-controlled processes, frequent in stroke patients, negatively affect the balance and mobility and contribute to falls (104). These factors compounded by comorbidities, polypharmacy, decreased vision, and often decreased cognition in stroke patients pose a greater risk of falling.

More criteria are needed to identify individuals at risk for fall. Detailed cognitive testing and formal gait and balance testing are used by stroke rehabilitation centers. Screening tests such as the Postural Assessment Scale for Stroke patients (PASS) and the Postural Control and Balance for Stroke test (PCBS) are valuable clinical measurements of postural control in stroke patients (07; 139) and can play a role in assessing the risk of fall.

Fall prevention programs provide education about supervision of high-risk patients, proper seating and wheelchair transfers, and regular toileting.

Pressure sores. Pressure sores are a prevalent medical complication of bedridden stroke patients (21). They result from decreased blood supply to dermal tissue caused by sustained pressure on the weight-bearing points, usually over bony prominences. Most often they occur in the lower body, with the sacrum being most frequently affected at 22.1% (54). They can develop and progress quickly, and if infected, they can cause great morbidity and mortality.

A Swedish retrospective study of 161 patients with stroke recorded 116 pressure ulcers, 30 patients having more than 1 ulcer (59).

Greatest risk factors to developing pressure sores are immobility and reduced tissue perfusion. Other risk factors include diabetes, peripheral vascular disease, urinary incontinence, and low body mass index (Berlowitz et al 2001).

Pressure sores are classified according to stages (118).

Stage I is nonblanchable erythema on intact skin.

Stage II is a partial thickness skin loss of the dermis presenting as a shallow open ulcer with a red pink wound bed, without slough.

Stage III is a full thickness tissue loss involving the subcutaneous tissue or fascia. Bone, tendon, and muscle are not exposed.

Stage IV is a full thickness tissue loss with exposed bone, tendon, or muscle.

The Braden Scale developed in the 1980s remains a useful tool in the early identification of patients at risk for developing pressure sores. The scale uses 6 measures as follows: sensory perception, skin moisture, activity, mobility, friction and shear, and nutritional status (09; 14). The total score ranges from 6 to 23, with higher risk associated with lower scores.

In high-risk patients, the goal is to alleviate pressure, friction, and sheer forces. Ideally, the objective is to keep tissue pressure below capillary closing pressure of 32 mmHg to maintain tissue perfusion. The 2-hour turning schedule, different pressure-reducing devices, good skin care (especially in those with fecal incontinence), daily checks, and high protein nutritional intake have been suggested (166).

Pressure-sore treatment starts with creating a moist healing environment using proper wound dressing. In addition, necrotic debris is removed to prevent bacterial growth and infection, which can complicate the healing process (52).

Peripheral nerve injury. Compression peripheral nerve injury in stroke patients results from limb malposition and may cause additional disability or pain. The risk of injury increases with sensory loss, weakness, neglect, and limb edema. In addition, use of manual wheelchairs increase the likelihood of an upper limb nerve injury like the median and ulnar nerves (12). Hematoma, a complication of anticoagulation, may result in brachial plexus injury or femoral nerve entrapment (41).

Electrodiagnostic studies can aid in confirming nerve injury site and assessing the degree of injury, and they can often dictate the need for surgical intervention. In most cases, splinting and other supportive devices as well as pain management may be sufficient.

Pain syndromes

A prospective study of 443 patients with stroke showed that 29.56% suffered from pain (14.06% in acute, 42.73% in the subacute, and 31.90% in the chronic stroke stage). Headache manifested acutely, musculoskeletal and central post-stroke pain was seen more often in the subacute and chronic stage, and spasticity-related pain was prevalent in the chronic stage (129).

Central post-stroke pain. Central post-stroke pain is caused by a lesion in the central nervous system and impairs the quality of life. In a systematic review of 69 papers, central post-stroke pain was reported in 11% of strokes in any locations and in 50% of patients with medulla and thalamus strokes. Central post-stroke pain coincided with acute stroke in 26% of patients (98).

Lesions of the spinothalamocortical pathway, including the brainstem and cerebral cortex, lead to post-stroke pain (119). The ventroposterolateral thalamic region was involved in 61% of patients with central post-stroke pain (13). The trigemino- and spinothalamic pathways end in the ventral medial nucleus and medial dorsal nucleus (31). A rare location for pure central post-stroke pain is the postero-lateral region of the mesencephalon involving the spinothalamic tracts and it may be demonstrated by suppressed laser-evoked potentials. Because of paucity of associated symptoms, it may be mistaken for malingering or psychogenic pain (30).

The medial lemniscus pathway is thought to have a modulatory effect. One woman with well controlled central post-stroke pain due to lateral medullary stroke redeveloped central post-stroke pain after a second infarct involving the ipsilateral medial medullary region (82). Lesions of the ventral caudal nucleus suggest involvement of other pathways in central pain development (113; 81).

Central pain is described as a burning, aching, throbbing, cramp-like sensations, or a combination of different types of pain, and is often provoked by a non-noxious stimulus. Patients older than 70 years of age tend to experience non-burning pain. The type of pain does not correlate with the site of the lesion (13). Pain sites can range from the entire half of the body to a restricted limb or part of a limb. Characteristic to central pain is the sensory loss to pinprick or temperature in the same region; however, preservation of the spinothalamic sensation is still possible in many patients (88). Injury to the spinothalamic strokes may be achieved with diffusion tensor tractography (62).

Central post-stroke pain is a diagnosis of exclusion, and other causes for pain must be considered.

Central post-stroke pain can be resistant to standard use of analgesics and opioids. There is lack of high-quality clinical trials.

Amitriptyline has been effective in a small, randomized controlled study (95); however, there is a need for more data (114).

Pregabalin is effective at escalating doses of 150, 300, and 600 mg/day (174). In addition, it may improve pain-related anxiety and sleep disturbances (84).

Carbamazepine is probably effective for chronic neuropathic pain, but there is a lack of information beyond 4 weeks (182).

The effect of gabapentin on neuropathic pain is probably not superior to carbamazepine (180).

Lamotrigine in dose of 200 mg daily was moderately effective in a small randomized, double-blind, placebo-controlled, cross-over study (172). However, a Cochrane review provided no convincing evidence of benefit at doses of 200 to 400 mg/day. In addition, its titration is difficult because of risk for rash (181). Levetiracetam is not effective for post-stroke pain treatment (67; 183).

Intravenous lidocaine and morphine improve central pain; however, their delivery method is limited to short-term use and carries a large side-effect profile (05). Intrathecal baclofen may improve central post-stroke pain (161). Fluvoxamine and mexiletine may also be used as adjuvants for pain treatment (83).

A potentially useful noninvasive method is repetitive transcranial magnetic stimulation—rTMS (97). Fiber tracking with diffusion tensor imaging may predict response to rTMS (51). However, analysis of the Repository of Registered Analgesic Device Studies database revealed that only 45% of chronic regional pain syndromes and central post-stroke pain trials had available results, suggesting a publication bias (37). A systematic review of Transcranial Direct Current Stimulation (tDCS) on neuropathic pain in patients with stroke shows promise, but the heterogeneity of the studies does not allow a definitive conclusion regarding its efficacy (34; 142).

There is evidence that graded motor imagery (like limb laterality recognition, imagined movements, and mirror movements) and mirror therapy provide clinically meaningful improvements in pain and function (115; 164). For multimodal physiotherapy, electrotherapy, and manual lymphatic drainage, the evidence is either absent of very low quality (155).

Botulinum toxin, BTX-A, has been used with some success for neuropathic pain; however, large clinical trials are needed to confirm the initial results (61).

An interesting effect of cold caloric stimulation is rapid relief of thalamic pain (141; 108; 109). Refractory thalamic pain was successfully treated by stellate ganglion block (100). In 1 case report, ultrasound guided block of the stellate ganglion with lidocaine had lasting effect at 9 months (103).

Motor cortex stimulation is the preferred neurosurgical method to control intractable central pain. The motor prefrontal cortex seems to be the optimal site of stimulation because the procedure is less invasive, achieves better pain control (48% vs. 25% for deep brain stimulation vs. 7% for spinal cord stimulation), and is less likely to trigger painful sensations (75). For nonthalamic lesion, spinal cord stimulation achieved relief for more than 12 months in 44.4% of patients (163). Motor cortex stimulation is also useful for painful brainstem and spinal cord lesions (162).

Pain relief from motor cortex stimulation can persist at 12-month follow-up (157; 171). The long-term results were excellent (over 80% reduction in pain) in 31% of patients, satisfactory (50% to 80% reduction) in 23% of patients, and no improvement in 15% of patients (156). Epidural hematoma and subdural effusion are potential complications of this procedure.

The mechanism of action of motor cortex stimulation is thought to be increasing of regional cerebral blood flow to the ipsilateral corticothalamic connections (18) or anti-inflammatory effects of stimulation (151).

Other useful locations for electrical stimulation include peri-ventricular grey matter (117; 136) and the centromedian thalamic nucleus (02).

Unfortunately, the data on neurosurgical management of central post-stroke pain are limited, and further studies are needed to confirm these findings (33; 45).

Shoulder pain. Shoulder pain was reported by 22% of patients within the first 4 months of the first stroke. Seventy-nine percent of these patients had moderate to severe pain. Loss of arm motor function and a high NIHSS score correlate with development of shoulder pain. This symptom limits daily functioning and the rehabilitation process (102). A retrospective study of 786 patients with stroke shows a decrease of shoulder pain frequency over the last 15 years, suggesting an improvement of both stroke and rehabilitation therapies (110).

There are multiple causes of shoulder pain after stroke: shoulder subluxation, proximal arm spasticity, local traumatic injury, shoulder-hand syndrome, and complex regional pain syndrome. The severity of paralysis and its stage (flaccid or spastic) alter the anatomy of the shoulder joint differently and determine the type of shoulder pain (168). It is unclear why pain resolves spontaneously in some patients but not in others. A study of 16 patients with shoulder pain revealed decreased adaptation to pain compared to a group of 14 patients with similar functional status but without shoulder pain (74).

Shoulder subluxation. Shoulder subluxation may result from the inferior displacement of the paretic arm (168). Glenohumeral subluxation was present in nearly 50% of patients in a case-control study of 107 hemiplegic adults with stroke within 30 days (126). Subluxation can be detected by palpation, plain radiographs of the shoulder, or ultrasonography (130).

Positioning and special attention to the hemiparetic limb is important in preventing subluxation, especially in those dependent on transfers for mobility (176).

Multiple support slings have been used to reduce shoulder subluxation with mixed results (125). One study showed that the level of subluxation decreased in patients who did not use a sling and that wearing of an arm sling may impair this correction (170).

Electrical stimulation of the shoulder successfully prevented and treated subluxation by maintaining muscle bulk and tone and by enhancing functional recovery through cortical feedback. Long-term follow-up was limited, however (168). A small randomized pilot study failed to demonstrate additional benefit of kinesio-tape or neuromuscular electric stimulation (NEMS) to conventional therapy alone, which consisted of careful shoulder handling and daily mobilization (60).

Intramuscular electrical stimulation in 61 chronic stroke survivors with shoulder pain and subluxation significantly reduced pain levels. The effect was maintained at 12-month follow-up (22). A small single-blinded randomized trial showed better pain control with EMG-triggered neuromuscular electric stimulation compared to transcutaneous electrical nerve stimulation (TENS), both immediately and at 1-month follow-up (27). A fully implantable peripheral nerve stimulator was found safe and significantly reduced shoulder pain at 12-month follow-up (185).

A systematic review of neuromuscular electric stimulation showed reduction of shoulder subluxation in the acute and subacute phase but not in the chronic stroke or reduction of shoulder pain (94).

Spasticity. Spasticity of the shoulder muscles following stroke is often painful and limits the range of motion. There is adduction and medial rotation of the arm associated with flexion at the elbow, wrist, and fingers. Different treatments have been employed, including medication for pain and spasticity, treatment of capsulitis, surgical release with transaction of the subscapularis tendon, and local botulinum toxin A injections.

Botulinum toxin type A injection in the pectoralis major reduced pain in the first week after stroke in a double-blind, randomized clinical trial of 31 patients (106). Subscapularis muscle is another useful site for injection (186). However, botulinum toxin has not been efficacious against nonspastic causes for shoulder pain (87).

Other promising therapeutic modalities include repetitive transcranial magnetic stimulation (26), suprascapular nerve block (135), modified wheelchair arm support (127), and extracorporeal shock wave therapy (63).

Frozen shoulder. Frozen shoulder, or adhesive capsulitis, caused by recurrent local injuries, is characterized by shoulder pain and limited motion in all directions. It is diagnosed by contrast enhanced arthrograms in 50% of hemiplegic patients with shoulder pain. In addition, rotator cuff tear was seen in 22% of patients (105).

Shoulder-hand syndrome. Shoulder-hand syndrome, a form of complex regional pain syndrome in the arm after stroke, is characterized by severe shoulder pain, metacarpophalangeal joint tenderness, hand edema, changes in skin color and temperature, dysautonomia with excessive sweating, and hyperesthesia. Atrophy of skin and muscles of the shoulder and hand with sparring of the elbow often follows.

The mechanism is probably central and peripheral sensitization due to stroke (134). Although it was known as reflex sympathetic dystrophy, involvement of the sympathetic system has not been demonstrated. Furthermore, shoulder subluxation and peripheral nerve damage increase the likelihood of developing complex regional pain syndrome (48).

The diagnosis of complex regional pain syndrome is primarily based on the clinical presentation. Diagnostic studies are used to exclude other processes. Bone scintigraphy is somewhat useful for showing increased periarticular uptake, particularly at the shoulder and wrist (53), and decreased bone mineral density in the paretic limb when compared to matched healthy controls (89).

Preventative measures consist of avoidance of shoulder trauma. Treatment is a combination of physical therapy and pain management. Patients with signs and symptoms of severe sympathetic dysfunction are candidates for regional block despite the lack of strong evidence. Investigations into neuromodulation through spinal cord stimulation and administration of intrathecal analgesia have been undertaken in patients with complex regional pain syndrome (89).

Two systematic reviews of the benefits of acupuncture found several heavily biased studies, suggesting the need for further randomized clinical studies (24; 132).

Heterotopic ossification. Heterotopic ossification is a rare cause of poststroke pain that leads to functional limitations and deposition of bony tissue in the soft tissue of the paretic limb (124). The calcification may also occur in the nonparetic limb (86; 55).

Urinary incontinence. Urinary incontinence within the first 7 days of stroke was noted in 53% of patients. One third of these patients remained incontinent at 12-month follow-up. Furthermore, those who were incontinent in the acute phase were 4 times more likely to be institutionalized after 1 year and a predictor of death (64).

Post-stroke urinary incontinence can be described based on etiology (159):

(1) Urge urinary incontinence: urgency followed by involuntary leakage that can result from a lesion of the central micturition pathways.

(2) Functional urinary incontinence: inability to achieve self-toileting due to impaired mobility from stroke.

(3) Stress urinary incontinence: involuntary leakage on effort such as coughing. This is usually present prior to stroke onset, but is exacerbated by coughing associated with dysphagia and aspiration.

A Cochrane review showed there are insufficient data from clinical trials to guide continence care in patients with stroke (165). Management of urinary incontinence in stroke patients does not differ from that of the general population with diagnostic studies and includes urine analysis and urodynamic studies. The rehabilitation professionals receive little training in dealing with urinary incontinence and should be encouraged to evaluate the patients systematically for it. The least invasive procedure should be tried first. Treatment begins with behavioral interventions if possible with timed voiding, prompted voiding, bladder retraining with urge suppression, and pelvic floor muscle retraining and compensatory rehabilitation approaches (38). A Cochrane review showed there are insufficient data from clinical trials to guide continence care in patients with stroke. However, a structured assessment and management of care in early rehabilitation and specialist continence nursing care may reduce urinary incontinence symptoms after stroke (166). Pharmacological treatment and urologic consultation with surgical intervention may be necessary.