Sickle Cell Information Center Guidelines

Edited by James Eckman, M.D. and Allan Platt, PA-C

Neurologic Symptoms and Strokes by Lewis Hsu, MD, PhD

Central nervous system involvement in sickle cell diseases is common with obstruction of small or medium-sized arteries causing ischemia and infarction, aneurysms and arteriovenous malformations causing subarachnoid hemorrhage, and infections causing meningitis. Infections require prompt treatment with antibiotics and other complications are usually treated with hypertransfusion to prevent recurrences.

Patients presenting with acute neurologic events should always be admitted. Meningitis should be excluded in patients with fever and headache or altered mental status. Exchange transfusion should be initiated immediately. Diagnostic studies should be performed promptly if any central nervous system event is suspected and exchange transfusion initiated for stroke or subarachnoid hemorrhage

Clinical Findings

Present Illness. Note onset of symptom, new or recurrent, fever/chills, headache, syncope, head trauma, exposure to toxic substances, altered mental status, poor behavioral or cognitive function, weakness, incoordination, sensory changes, visual changes, seizures, aura, or incontinence. Antecedent infections, URIs, earaches, pneumonia should be sought.

Past Medical History. History of previous neurologic events, hospitalizations, surgery, present medications, illicit drug use, drug allergies, and sleep apnea may be present.

Review of Symptoms. Do a general ROS. Family history of seizures, diabetes, or hypertension.

Objective Data

- General. Mental status, orientation, distress, pallor, jaundice, cyanosis, hydration, signs of trauma.

- Vital Signs. Temperature, blood pressure, pulse, respiratory rate.

- Head. Swelling, trauma, Battle’s sign, masses.

- Ears. Blood behind TM, otitis media, mastoiditis.

- Eyes. PERRLA, EOMs, careful ophthalmoscopic exam for papilledema, venous pulse, hemorrhage, exudates.

- Mouth. Tongue trauma, airway obstruction, pharyngitis.

- Neck. SUPPLE! lymphadenopathy, thyroid size.

- Chest. Signs of pneumonia.

- Heart. Heart murmur, friction rub.

- Abdominal. Bowel sounds, liver/spleen size, tenderness.

- Neurologic. Careful examination to document initial status.

Mental Status. Degree of coma, If alert document orientation, recent/remote memory, aphasia, agnosia, side preference, speech.

Cranial Nerves. Determine if CN II - XII intact.

Sensation. Light touch, temperature, pain, vibratory, position.

Muscle Strength. Strength, symmetry, drift, atrophy, fasciculations.

DTRs. Activity, symmetry, clonus, plantar reflexes.

Cerebellum. Gait, Rhomberg, finger/nose, heel/shin, asterixis, involuntary movements.

- Minimum Lab. CBC with differential, reticulocyte count, and platelets, Chem profile including electrolytes, AST, BUN, Creat, glucose, bilirubin, UA, ECG (in adults), chest x-ray, Type and Cross packed red blood cells (four units for adults). Glucose should be determined immediately by dip stick for altered mental status.

- Additional Lab. If febrile consider urine culture, throat culture, blood cultures, and lumbar puncture. A urine and serum drug screen should be sent if there is altered mental status without clear explanation. Skull x-ray and/or CT (non-contrast) is done first if focal findings or history of head trauma. Lumbar puncture should done if bleeding or infection is considered, even if CT is negative. CT or MRI should exclude mass lesions in patients with focal findings before lumbar puncture is attempted. Arteriography after exchange transfusion (See Transfusion Protocol) if CT or lumbar puncture is positive for blood. EEG to evaluate new onset seizure or persistent alteration in mental status after a seizure. MRI and MRA may be indicated.

- Drug Overdose. A drug overdose must always be considered in patients with altered mental status without focal findings. Screening should be done for opiates, aspirin, acetaminophen, alcohol and other drugs based on the history.

- Hypoglycemia. This diagnosis should always be considered and treated in patients presenting with altered mental status, especially if there is a history of diabetes.

- Trauma. Careful history and examination are indicated to exclude recent trauma as a causeof focal findings or altered mental status and a history of trauma. CT scan or MRI should be done in all cases where trauma is suspected.

- Meningitis/Encephalitis. Severe headache, fever, stiff neck, (+) Kernig’s, (+) Brudzinski’s, photophobia, seizures, altered mental status, coma, petechial rash, papilledema. Lumbar puncture will show increased opening pressure, cloudy, leukocytosis, increased protein, decreased glucose CSF/serum.

- Seizure. Loss of consciousness or awareness, aura, muscle movement, incontinence, post-ictal state. Differentiate grand mal, petit mal, focal motor, and temporal lobe seizures.

- Syncope. Sudden loss of consciousness without seizure. Must differentiate vasovagal from orthostatic hypotension or cardiac cause such as arrhythmia or aortic stenosis.

- Central Nervous System Infarction. Patient may present with altered mental status, coma, hemiplegia, hemihypoesthesia, hemianopsia, aphasia, apraxia, dyslexia, gaze paresis, ataxia, vertigo of sudden onset. Much less common, spinal cord involvement causes paraplegia, quadraplegia, or sensory level.

- Transient Ischemic Attacks. As above but symptoms and signs will wax and wane. These attacks in patients with sickle syndromes have the same implications for treatment as do completed CNS infarctions.

- Subarachnoid Hemorrhage. Severe headache, stiff neck, and neurologic deficits as in infarction (See Headache). Must be considered for any new onset of headache or significant change in character of headaches in the patient, because many patients present early with no neurologic findings and do not have the classic "worst headache I have ever had".

- Fat Embolization. The typical presentation is a very severe pain episode which is followed by marked arterial oxygen desaturation, coma, petechial rash, liver failure, renal insufficiency, rhabdomyolysis and pulmonary insufficiency. Urine may show lipid bodies, and Disseminated intravascular coagulation (D.I.C.) is common.

- Mononeuritis. Sensory loss, muscle atrophy, fasciculations in a radicular or nerve distribution which may be caused by ischemia of the nerve from sickling. May also be related to any of the multitude of causes found in children and adults without sickle syndromes.

- Brain Abscess. Patient may have headache, fever, focal neurologic findings often occurring after sinusitis, otitis, or mastoiditis (See Headache ).

- Brain Tumor. Symptoms include: headache, progressive focal neurologic findings, personality changes, seizures, papilledema as outlined in previous chapter.

- Subdural Hematoma. Patients present with headache, confusion, sleepiness, history of trauma, alcohol, or seizures. Papilledema, focal neurologic findings may be present, however, diagnosis is often made by CT scan before these late findings appear.

- Vaso-occlusion in the Calvarium.  Headache with tenderness and sometimes edema of the scalp. Sometimes intracranial periosteal edema can be confused with hematoma or abscess.

- Cognitive Deficits might indicate brain ischemia and infarction in the absence of motor or sensory deficits, or may be due to sociobehavioral factors. Brain imaging may be warranted.

Head CT or MRI are probably the test of choice in evaluating patients that present with acute focal neurologic findings, a new or changed headache, altered mental status, or seizures of resent onset. Metabolic causes such as hypo- or hyperglycemia, hypoxia, hypercalcemia need to be considered but are not seen in increased frequency in sickle syndromes. Drug screens must always be considered in patients with altered mental status. A subsequent lumbar puncture is needed to document or exclude meningitis or subarachnoid hemorrhage. MRA with short TE is approaching arteriography in reliability.

- Drug Overdose. All patients with sickle syndromes should receive a trial of naloxone if they present with altered mental status because they commonly have access to narcotic analgesics. Naloxone (0.01 mg/kg up to 0.2 mg) is given I.V. q. 2 - 3 minutes as needed. The adult concentration of 0.4 mg/ml is diluted at least 1:10 before use in children. This must be used with extreme caution in patients receiving regular narcotics. Other overdoses are managed by supporting respirations and blood pressure and following the specific recommendations of drug information centers and toxicology texts.

- Hypoglycemia. Administration of D50W after obtaining a sample for glucose level will establish the diagnosis and initiate therapy.

- Trauma. Neurosurgery should be involved with the evaluation and planning of therapy where altered mental status or focal findings are thought to result from trauma.

- Meningitis. Admit for treatment with appropriate antibiotics based on the gram smear of the cerebral spinal fluid. Empiric therapy should cover S. pneumoniae and H. influenzae organisms

- Seizure. Patient should be admitted for evaluation of first time seizure. The seizures thought to be secondary to ischemic damage are usually treated by hypertransfusion. Use seizure precautions. If chronic, check dilantin/phenobarb levels and consult a neurologist for advice.

- Syncope. If vasovagal, observe patient and discharge when improved. Admit patients with orthostatic hypotension, cardiac arrhythmias, or significant murmurs.

- Central Nervous System Infarction. Admit for emergency exchange transfusion and initiate a chronic transfusion program with a goal of Hb S below 30%, hemoglobin level no more than 11 gm/dL, with transfusion every 3 to 5 weeks (See transfusion chapter).  Functional recovery can be aided by multidisciplinary rehabilitation therapy. Most programs are finding that strokes recur in children if transfusions are discontinued, so many are suggesting the need for life-long transfusion and iron chelation therapyor erythrocytophoresis. Transfusions are also used in adults, however, indications and guidelines are not well established. Antiplatelet drugs may provide additional protection from recurrences.

- TIA. Admit for exchange and hypertransfusion. Most centers will transfuse these patients as if they have had a stroke. Others advocate doing arteriography and only transfusing patients that have arterial wall abnormalities.

- Subarachnoid Hemorrhage. All patients with subarachnoid hemorrhage who are not in stage 3 or 4 coma should have an exchange transfusion followed by arteriography to determine if surgically correctable lesions are present. Preoperative management and timing of surgery is coordinated by the neurosurgery service.

- Fat Embolization. Treatment consists of rapid complete exchange transfusion with fresh red cells and plasma if D.I.C. is severe. Hypoxia must be corrected with ventilator support. The prognosis is guarded.

- Mononeuritis. Consult Neurology. If thought to be secondary to the hemoglobinopathy, consider exchange and hypertransfusion.

- Brain Abscess/Tumor. Admit to neurosurgery for evaluation and therapy.

- Subdural Hematoma. Admit to neurosurgery for surgical drainage.

- Vaso-occlusion in the Calvarium.  Observe,and manage pain.  Consider drainage if intracranial periosteal edema becomes symptomatic.

Reinforce the doctors explanation of medical management.

Explain all test and procedures.

Teach essential aspects of care.

Prepare patient and significant other for possible long term speech and physical rehabilitation.

Stress importance of ongoing outpatient care and follow up visits.

Transfusions and Chelation therapy should be explained to patient and family.

Stress importance of verbalization of feelings to patient and significant other.

Provide consultations with social worker, financial counselor, and psychologist as necessary.

Preventing Recurrent Ischemic Stroke - Transfusion therapy has been shown to reduce the recurrence of ischemic neurologic events in patients with sickle cell disease. Transfusions should be continued for at least 3 years. Many believe that transfusions will be life-long if recurrences are to be eliminated. Iron overload will require chelation therapy after two to three years.(See Transfusions and chelation). Erythrocytophoresis is considered an alternitive therapy. For children with an HLA-matched sibling, a consortium has demonstrated that risk of recurrent stroke can be greatly reduced by allogeneic bone marrow transplantation, as alternative to long-term transfusion and iron chelation. Link to STARS Clinic at Grady - a special clinic for those who have had a stroke.

Preventing First Ischemic Stroke - Trans-Cranial Doppler Ultrasound (TCD)Link to Patient Information Sheet about TCD screening is a useful tool to identify children at high risk for stroke, before they have suffered a clinical stroke. Children with Hb SS or HbS beta ⁰ thal between the ages of 2 and 16 should be considered candidates for TCD screening  every 12 months.  A clinical trial demonstrated that children with abnormal TCD blood flow patterns may be offered transfusion therapy to decrease the risk of stroke. Link to STOP Study

Patient and Parent Education

Parents should be taught to seek medical attention for signs of neurologic dysfunction. Parents and patients must understand the importance of regular transfusion once they are initiated. Compliance with anticonvulsant medications, transfusions, and chelation therapy requires ongoing education and reinforcement.

References

Wertham F, Mitchell N, Angrist A. The brain in sickle cell anemia. Arch. Neuro. Psych. 47:752-767, 1942.

Greer M and Schotland D. Abnormal hemoglobin as a cause of neurologic disease. Neurology 12:114-123, 1962.

Portnoy BA and Heroin JC. Neurologic manifestations in sickle-cell disease. Ann. Intern. Med. 76:643-652, 1972.

Russell MO, Goldberg HI, Reis L, et al. Transfusion therapy for cerebrovascular abnormalities in sickle cell disease. J. Pediatr. 88:382-387, 1976.

Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The natural history of stroke in sickle cell disease. Amer. J. Med. 65:461-471, 1978.

Wilimas J, Goff JR, Anderson HR, et al. Efficacy of transfusion therapy for one or two years in patients with sickle cell disease and cerebrovascular accidents. J. Pediatr. 96:205-208, 1980.

Sarnaik SA, Lusher JM. Neurological complications of sickle cell anemia Amer. J. Pediatr. Hematol./Oncol. 4:386-394, 1982.

Russell MO, Goldberg HI, Hodson A, et al. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood 63:162-169, 1984.

El Gammal T, Adams RJ, Nichols FT, et al MR and CT investigation of cerebrovascular disease in sickle cell patients. Amer. J. Neuro. Radiol. 7:1043-1049, 1986.

Prohovnik I, Pavlaskis SG, Piomelli S, et al. Cerebral hyperemia, stroke, and transfusion in sickle cell disease. Neurology 39:344-348, 1989.

Powars D, Adams RJ, Nichols FT, et al. Delayed intracranial hemorrhage following cerebral infarction in sickle cell disease. J. Assoc. Acad. Minor. Phys. 1:79-82, 1990.

Oyesiku NM, Eckman JR, Barrow DL et al. Intercranial aneurysms in sickle cell anemia: Clinical features and pathogenesis. J. Neuro. Surg. in press.

Walters MC, Patience M, Leisenring W, et al for the Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease.: Bone marrow transplantation for sickle cell disease.  New Engl.J.Med. 1996;335:369-376.

Walters MC, Storb R, Patience M, et al., for the Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease.  Impact of Bone Marrow Transplantation for Symptomatic Sickle Cell Disease: An Interim Report. Blood (in press).

Ohene-Frempong K, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors.  Blood. 1998 Jan 1; 91(1): 288-294.

Adams RJ, McKie VC, Hsu LL, et al for the Multicenter STOP study group. Transfusion Prevents First Stroke in Children with Sickle Cell Anemia and Abnormal Transcranial Doppler: The STOP Trial. N Engl J Med. 1998 339:5-11.

Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia
(STOP) study. J Child Neurol. 2000 May;15(5):344-9.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10830201&dopt=Abstract 

Gebreyohanns M, Adams RJ. Sickle cell disease: primary stroke prevention.CNS Spectr. 2004 Jun;9(6):445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15162093

Send mail to aplatt@emory.edu with questions or comments about this web site.
Copyright © 1997 Sickle Cell Information Center
Last modified: June 11, 2004