eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Fabry Disease: Treatment & Medication

Author: Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Coauthor(s): Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Dec 11, 2008

Treatment

Medical Care

  • Antiplatelet agents have been used for secondary stroke prevention in Fabry disease, but their effectiveness in this setting has not been proved.
  • Anticoagulants may be necessary if embolic events that stem from cardiac causes are a concern.
  • Painful neuropathies may be treated with a variety of medications. Carbamazepine and phenytoin have been used anecdotally in Fabry disease.
  • Two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), reportedly help in normalizing renal function, cardiac function, and cerebrovascular flow.
    • Whether therapy with these enzymes changes the natural history of strokes attributable to Fabry disease is unclear.
    • Medical regulatory requirements are different in various parts of the world, and the appropriate authorities should be consulted regarding the approval status of these enzymes.
    • Research to replenish deficient enzymes by means of gene transfer via adenovirus is in its early stages.

Surgical Care

  • Renal failure is a clear indication for renal transplantation. However, renal transplantation may not alter the course of disease progression in other organ systems.
  • Fetal liver transplantation has been tried in a small number of patients.
    • In the limited group of patients tested, no changes in serum or leukocyte alpha-galactosidase A levels were reported.
    • Clinical use of this experimental procedure should be undertaken with caution, since published literature on this topic is sparse.

Consultations

  • Consultation with a neurologist is recommended if Fabry disease is suspected as a cause of stroke or if the usual causes of stroke are not present. A neurologist also better handles painful neuropathies not amenable to treatment in the primary care setting.
  • If an embolic event is thought to have caused a stroke, a cardiologist's expertise can be sought for both diagnostic and therapeutic options.
  • A nephrologist should be consulted if a patient has renal failure.
  • Sessions with a physical therapist and an occupational therapist can be helpful in rehabilitative efforts.

Medication

Antiplatelet agents are used for secondary stroke prevention. Anticoagulation with warfarin is prescribed when a cardioembolic stroke is suspected. Painful neuropathies can be treated with a variety of medications, including carbamazepine or phenytoin.

Two enzymes, agalsidase-alpha (Replagal) and agalsidase-beta (Fabrazyme), reportedly help in normalizing renal function, cardiac function, and cerebrovascular flow. Whether therapy with these enzymes changes the natural history of strokes attributable to Fabry disease is unclear.

Antiplatelet agents

These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator.


Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Adult

50-325 mg PO qd; may use in combination with dipyridamole 200 mg PO bid

Pediatric

Not established

Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease salicylate serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; because of association with Reye syndrome, do not use in children (<16 y) with flu

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic renal disease; avoid use in patients with severe anemia, or history of blood coagulation defects or those taking anticoagulants


Ticlopidine (Ticlid)

Second-line antiplatelet therapy for patients who cannot tolerate or do not respond to aspirin therapy.

Adult

250 mg PO bid

Pediatric

Not established

Corticosteroids and antacids may decrease effects; theophylline, cimetidine, aspirin, and NSAIDS increase toxicity

Documented hypersensitivity; neutropenia or thrombocytopenia; liver damage; active bleeding disorders

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Life-threatening neutropenia and thrombotic thrombocytopenic purpura reported; manufacturer suggests close monitoring of CBC count, especially at start of therapy; discontinue if absolute neutrophil count <1200/mm3 or if platelet count <80,000/mm3


Clopidogrel (Plavix)

Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, inhibiting platelet aggregation.

Adult

75 mg PO qd

Pediatric

Not established

Naproxen associated with increased occult GI blood loss; safety of coadministration with warfarin not established

Documented hypersensitivity; active pathological bleeding, such as peptic ulcer or intracranial hemorrhage

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

TTP reported in 1 person per 15,000-100,000; prolongs bleeding time; caution in patients at increased risk of bleeding from trauma, surgery, or pathologic conditions; caution in patients with lesions with propensity to bleed (eg, ulcers)


Aspirin 25 mg/dipirydamole 200 mg (Aggrenox)

To complement usual warfarin or aspirin therapy. Platelet adhesion inhibitor, possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. May inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-AMP in platelets and formation of potent platelet activator thromboxane A2.

Adult

200 mg dipirydamole PO bid; used in combination with 25 mg aspirin bid

Pediatric

Not established

Theophylline may decrease hypotensive effects; antiplatelet activity may increase heparin toxicity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hypotension; has peripheral vasodilating effects

Anticoagulants

These agents are used in the treatment of clinically evident intravascular thrombosis.


Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. For prophylaxis and treatment of deep venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Adult

5-10 mg/d PO qd for 2-5 d; adjust dose according to desired INR of 2-3

Pediatric

Not established

Griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate may decrease effects; oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac may increase effects

Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Patients with suspected protein C or S deficiency may have skin necrosis and should receive heparin first; increased risk of intracerebral and systemic hemorrhage; many toxic effects possible

Enzyme replacement agents

These agents are the recombinant form of the enzyme alpha-galactosidase and beta-galactosidase-A.


Agalsidase alfa (Replagal)

Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.

Adult

0.2 mg/kg IV infused over 40 min q2wk

Pediatric

Not established; appropriate time to initiate treatment in children has not been determined

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause IgG antibody production in 55% of treated patients; may cause allergic reactions in 10% of treated patients (prevented by premedication with hydrocortisone and/or antihistamines before IV infusion); infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment


Agalsidase beta (Fabrazyme)

Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.
Manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells.

Adult

1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk

Pediatric

Not established; appropriate time to initiate treatment in children has not been determined

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause IgG antibody production in 83% of patients treated with Fabrazyme; may cause allergic reactions (which are prevented by premedication with hydrocortisone and/or antihistamines [standard] before IV infusion) in 59% of patients treated with Fabrazyme; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

More on Metabolic Disease and Stroke - Fabry Disease

Overview: Metabolic Disease and Stroke - Fabry Disease
Differential Diagnoses & Workup: Metabolic Disease and Stroke - Fabry Disease
Treatment & Medication: Metabolic Disease and Stroke - Fabry Disease
Follow-up: Metabolic Disease and Stroke - Fabry Disease
References
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References

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Further Reading

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Keywords

Fabry's disease, angiokeratoma corporis diffusum, glycolipid lipidosis, metabolic disease and stroke, Fabry disease, lysosomal disorder, glycosphingolipids

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Contributor Information and Disclosures

Author

Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences, Royal Society of Medicine, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey L Saver, MD, Director, Stroke Center, Professor, Department of Neurology, University of California at Los Angeles Medical Center
Jeffrey L Saver, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Neurological Association, and National Stroke Association
Disclosure: Boehringer-Ingelheim - Secondary Prevention Consulting fee Consulting; Talacris Consulting fee Consulting; ImaRx Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

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