In an individual with sickle cell disease , from birth their blood cells form into an abnormal c-shape, causing blockage and restriction of oxygen and blood flow to the body. Long-term health risks associated with sickle cell disease include infection, acute chest syndrome, stroke, and chronic pain. There is no one specific cause for these pain episodes. It can be anything from colder weather, stress, infection, or even age — but the pain is often debilitating because of how much of the body is affected and often requires intravenous medication to ease it during an episode.
Neurological examination at the time of admission revealed power of all muscle groups of the affected limb. Tone was reduced and deep tendon reflexes were absent even after reenforcement, suggesting peripheral nerve pathology.
Gait could not be assessed as the patient could not stand. Save for lower spinal and left hip tenderness on palpation in keeping with VOC, the rest of the neurological and general physical examination was unremarkable. Results of baseline diagnostic tests are summarized in Table 1. CT of the brain was unremarkable with no evidence of intracranial hemorrhage and subacute or any established territorial infarct. MRI of the brain showed no evidence of acute ischemia and there were no vascular abnormalities on MRA.
MRI of the spine showed normal cord caliber and signal, with no evidence of intramedullary infarcts. There was no evidence of hemorrhage or compression. Conservative therapy with fluids and parenteral opiate analgesia led to improvement of pain. In the absence of any anatomical abnormalities, it was felt that the most likely cause for her acute peripheral nerve injury was ischemia due to vasoocclusion and the patient underwent emergency automated red cell exchange transfusion ARCET 24 hours after her initial presentation.
Pre- and posttransfusion haematological values are summarized in Table 2. ARCET led to immediate clinical improvement with almost complete resolution of the neurological deficit by the end of the procedure and, shortly afterwards, the patient was able to walk independently. She was reviewed again by the neurologists who confirmed complete resolution of the deficit. Even though the patient was scheduled to have nerve conduction studies and a diagnostic lumbar puncture, these were now considered unnecessary and cancelled.
She was discharged home, 48 hours after admission, without any neurological deficit. These deformed and rigid erythrocytes lead to the two cardinal manifestations of SCD: a vasoocclusion due to impaired rheology and infarction of the microvasculature and b haemolysis and chronic anaemia due to red cell deformability and increased destruction both intra- and extravascularly [ 9 ].
Intravascular sickling and haemolysis lead to a cascade of events including endothelial damage, ischemia re-perfusion injury, alteration of adhesion molecules, activation of coagulation, and nitric oxide NO depletion, that result in the systemic vasculopathy and chronic inflammatory state that characterize SCD [ 9 ].
Neurological complications involve principally the brain, while the spinal cord or the PNS are rarely involved [ 10 ]. Nerve distribution varies and some nerves are more sensitive to ischemia than others [ 11 — 13 ]. Size and number of nutrient vessels that supply the different peripheral nerves are different among individuals and among nerves in the same individual.
These variations make certain individuals and certain nerve regions even in the same individual more susceptible when exposed to ischemia [ 14 ]. Animal studies have found the proximal tibial and peroneal nerves, distal sciatic nerve, and distal foot nerves to be most vulnerable to ischemia [ 14 ].
In humans, the peroneal, sural, tibial, ulnar, median, and radial nerves are most frequently affected by ischemia [ 11 — 13 ].
The extensive peripheral nerve vascular supply and the widespread network of large capillaries of the peripheral nerves could possibly explain the reason why ischemic neuropathy is rare in SCD [ 14 ]. There are limited reports in the literature of acute peripheral neuropathies presenting in patients with SCD. One such reports a mononeuropathy affecting the median nerve presenting as a painful VO [ 6 ].
They conclude that the neurophysiology confirmed an ischemic injury to the median nerve with the only identifiable cause being that of a vasoocclusive insult. The main objective was a primary stroke-prevention trial for children with SCA who had received at least 12 months of blood transfusion therapy for TCD velocities above cm per second.
Treatment was scheduled to last for 24 months after random allocation, at which point the primary outcome, TCD velocities, between the 2 arms was compared. After the first interim analysis, the trial was ended early because the noninferiority was demonstrated margin of 15 cm per second.
Pooled analysis of the 7 studies documenting TCD measurement before and after hydroxyurea therapy. The pooled analysis is based on the random-effect model demonstrating the average drop in TCD measurement after starting hydroxyurea therapy of 25 cm per second. The black diamond represents the results of random-effect models.
Regardless of vasculopathy status of children with elevated TCD measurements, the event rate of strokes is very low, 0. Given the success of hydroxyurea therapy for primary prevention of strokes and the relative low risk-to-benefit ratio when compared with hematopoietic stem cell transplant HSCT , we would recommend continuing blood transfusion therapy or switching to hydroxyurea therapy, after at least one year of blood transfusion therapy over HSCT for the perceived high-risk group of children with MRA-defined vasculopathy and elevated TCD measurements.
In the only study to date, Valadi et al evaluated adults with SCA and controls, and did not find any values that were elevated. No definitive approach has been applied for primary stroke prevention in children with SCA living in Africa or India, where the majority of the children are born with SCA. The early results indicated that the families are willing to participate in a formal trial. The essential question for primary stroke prevention in low- and middle-income countries is what dose of hydroxyurea therapy maximizes the benefit and minimizes the toxicity and laboratory surveillance costs.
In a setting of high rates of life-threatening bacterial infections and malaria, treatment with hydroxyurea therapy, a myelosuppressive agent, may result in an increased rate of infections or other complications.
Thus, limiting the financial burden for complete blood count surveillance for hydroxyurea-related toxicity may decrease the financial barrier without potentially sacrificing safety.
Standard treatment of secondary stroke prevention is blood transfusion therapy. Figure 8 depicts the unsatisfactory results of the treatment options for secondary infarct recurrence prevention in children with SCA and overt strokes. A hypothetical cohort of children with SCA and strokes followed for 5 years receiving either no therapy, hydroxyurea therapy, or regular blood transfusion therapy.
The figure depicts the number of children in the cohort with stroke recurrence in the no-treatment group, hydroxyurea therapy group, and regular blood transfusion therapy group with expected incidence rates of Given the evidence that blood transfusion therapy is palliative for secondary stroke prevention, 66 we believe that, after an initial stroke, alternative treatment options should be considered.
Current evidence strongly suggests that HSCT decreases the rate of stroke recurrence 83 , 84 ; however, most children and adults do not have a viable donor.
A range of revascularization procedures has become an option for patients with internal carotid artery occlusion and moyamoya collaterals. Given the unknown risk-to-benefit ratio of alternative donor haploidentical or nonmyeloablative HSCT or revascularization procedures for secondary stroke prevention, we strongly recommend that single or preferably multi-institutional studies be registered with clinicaltrials.
Based on challenges of routine blood transfusion therapy in low- and middle-income countries, no definitive strategy has emerged for secondary stroke prevention. However, several investigators in these settings have elected to use hydroxyurea therapy as opposed to no therapy. Using pooled analysis comparing blood transfusion therapy to hydroxyurea therapy and no therapy, the expected stroke recurrence incidence rates were 1.
The completion of the trial is not expected to occur for an additional 4 years. In the meantime, we believe that the available data suggest that treatment with hydroxyurea therapy for secondary prevention of strokes is a reasonable alternative when compared with no therapy at all.
Based on the preponderance of evidence, the use of hydroxyurea therapy clearly decreases TCD measurements, which is the main modifiable risk factor for overt strokes. Further bolstering the evidence of the impact of hydroxyurea therapy on decreasing TCD measurements, the TWiTCH trial has demonstrated the noninferiority of hydroxyurea therapy to blood for primary stroke prevention in children with SCA with high TCD velocities without vasculopathy on MRA who have already been transfused for a year.
In low- and middle-income countries, where the majority of children with SCA are born and blood transfusion therapy is not routinely available, primary and secondary stroke-prevention RCTs are under way to determine the optimal hydroxyurea dose that maximizes benefits and limits toxicity, while potentially minimizing laboratory surveillance.
Correspondence: Michael R. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. Ischemic lesions of the brain may be temporary or evolve to infarcts. Acute and chronic headaches are challenging to manage in SCD. Hemorrhagic stroke and aneurysms are more common in adults. Extradural and subdural intracranial hemorrhage may occur without trauma. Seizures and epilepsy must be distinguished and managed appropriately. Article Navigation. DeBaun , Michael R.
This Site. Google Scholar. Fenella J. Kirkham Fenella J. Blood 7 : — Article history Submitted:. Connected Content. Central nervous system complications and management in sickle cell disease.
A related article has been published: Sickle cell disease: challenges and progress. A companion article has been published: Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. View more.
A companion article has been published: Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology.
A companion article has been published: Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. A companion article has been published: Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease.
View less. Cite Icon Cite. Figure 1. Abstract Background Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis.
Design and Methods Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics.
The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin were made on blood samples collected in steady-state conditions.
Results Results showed that: 1 patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2 patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age.
Conclusions Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.
Design and Methods Participants and protocol This study was designed to compare inflammatory, hemorheological, and ANS activity markers in: i 15 Jamaican SCA patients with at least three episodes of acute vaso-occlusive pain crises requiring day care 16 or hospital admission, and opioid analgesia within the previous year frequent crisis, FSCA group ; ii 20 Jamaican SCA patients who had not experienced any pain crises during the year prior to recruitment infrequent crisis, IFSCA group ; and iii 24 healthy Jamaican subjects without hemoglobinopathy controls, CONT group.
Hematology and blood viscosity Venepuncture was performed between a. Article Information Vol. Pubmed Central. Published By. Ferrata Storti Foundation, Pavia, Italy. Print ISSN. Online ISSN. Article Usage.
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