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Pain in Fabry Disease - 14 February 2014

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Information about Pain in Fabry Disease - 14 February 2014
Health & Medicine

Published on March 17, 2014

Author: FSIG_ORG

Source: slideshare.net

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FSIG Expert Fabry Conference 2014, San Diego - presentation by Dr Raphael Schiffmann on Pain in Fabry disease.
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Pain in Fabry Disease Raphael Schiffmann M.D., M.H.Sc. Institute of Metabolic Disease Baylor Research Institute Dallas, Texas

Yousef Z et al. Eur Heart J 2012;eurheartj.ehs166 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. Fabry disease: Is an X-linked lysosomal storage disorder caused by a deficiency of lysosomal enzyme α–galactosidase A, resulting in intracellular accumulation of terminal α-D- galactosyl sphingolipids, globotriaosylceramide (Gb3 or GL-3, CTH) Structure of globotriaosylceramide (Gb3)

Fabry Pain Characteristics Onset in the first 20 years Burning, deep ache, shooting pain Continuous or episodic Heat, exercise, infection, stress induce pain Poor heat tolerance Poor cold tolerance Hypohidrosis  Eventually – decreased cold and heat perception (increased threshold

Fabry Pain Characteristics  Paresthesia- spontaneous is a sensation of tingling, tickling, prickling, pricking, or burning of a person's skin  Dysesthesia – 1. Allodynia – a normally non-painful stimulus 2. Hyperalgesia – A normally painful stimulus  Hyperpathia  Heat, exercise, infection, stress induce pain  Poor heat tolerance  Poor cold tolerance  Hypohidrosis  Eventually – decreased cold and heat perception

Fabry Small Fiber Neuropathy - However Normal, light touch, pinprick and vibration perception Normal nerve conduction Therefore – may be initially ignored or hard to diagnose

What is actually happening?

Mechanisms of Pain

Copyright © 1999 American Academy of Neurology. Published by Lippincott Williams & Wilkins, Inc. 2 Figure 1 Quantitative analysis of epidermal innervation in Fabry disease. Scott, L; MD, PhD; Griffin, J; Luciano, C; Barton, N; MD, PhD; Banerjee, T; Crawford, T; McArthur, J; MBBS, MPH; Tournay, A; Schiffmann, R Neurology. 52(6):1249-1254, April 12, 1999. Figure 1 . Innervation of epidermis in normal control subjects. (a) A single, simple fiber can be seen to enter into and terminate within the epidermis. (b) A subepithelial nerve (arrow) sends off a small bundle of axons, which penetrate the basal lamina of the epidermis (arrowhead). Once within the epidermis, individual axons branch off the bundle to form a candelabra pattern of innervation, which we refer to as the complex form of innervation.

Copyright © 1999 American Academy of Neurology. Published by Lippincott Williams & Wilkins, Inc. 3 Table 1 Quantitative analysis of epidermal innervation in Fabry disease. Scott, L; MD, PhD; Griffin, J; Luciano, C; Barton, N; MD, PhD; Banerjee, T; Crawford, T; McArthur, J; MBBS, MPH; Tournay, A; Schiffmann, R Neurology. 52(6):1249-1254, April 12, 1999. Table 1 Creatinine clearance (CrCl), forced expiratory flow (FEF 50%), and epidermal innervation density in patients with Fabry disease and normal control subjects

Copyright © 1999 American Academy of Neurology. Published by Lippincott Williams & Wilkins, Inc. 4 Table 2 Quantitative analysis of epidermal innervation in Fabry disease. Scott, L; MD, PhD; Griffin, J; Luciano, C; Barton, N; MD, PhD; Banerjee, T; Crawford, T; McArthur, J; MBBS, MPH; Tournay, A; Schiffmann, R Neurology. 52(6):1249-1254, April 12, 1999. Table 2 Comparison of sural nerve quantitation with thigh innervation density

Copyright © 1999 American Academy of Neurology. Published by Lippincott Williams & Wilkins, Inc. 5 Figure 2 Quantitative analysis of epidermal innervation in Fabry disease. Scott, L; MD, PhD; Griffin, J; Luciano, C; Barton, N; MD, PhD; Banerjee, T; Crawford, T; McArthur, J; MBBS, MPH; Tournay, A; Schiffmann, R Neurology. 52(6):1249-1254, April 12, 1999. Figure 2 . Electron micrographs of sural nerve biopsy specimens from patients with Fabry disease. (a) Field of unmyelinated fibers with numerous denervated Schwann cells. A cluster of denervated Schwann cells appears at the left (arrowheads). (b) Several denervated Schwann cells at higher magnification, with two normal unmyelinated axons remaining. The perineurium of the nerves from the Fabry patients typically has prominent lipid inclusions (c, arrows), but no lipid inclusions are present within the endoneurium (not shown). Although there is no detectable loss of large myelinated fibers in patients with Fabry disease who have preserved renal function, rare degenerating large fibers were seen (d).

Pathogenesis Glycolipid accumulation in dorsal root ganglia and peripheral nerves Loss of small myelinated and nonmyelinated fibers Loss of dermal unmyelinated fibers But preservation of large myelinated fibers Scott LJ et al Neurology 1999

Quantitative Sensory Tessting

Fabry Disease: Quantitative Sensory Testing P=0.00 P=0.00 P=0.00 P=0.00 P=0.02 P=NS Luciano et al Muscle Nerve

Reduction in Cold Perception Threshold with ERT Schiffmann et al Muscle Nerve 2003

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 2 Table Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Table Vibratory detection thresholds at the first toe (VDT), cold detection thresholds (CDT), and heat-pain perception thresholds (HP) assessed on dorsum of feet in 25 healthy control and in 22 Fabry patients before, after 5-6, and after 18 or 23 months of enzyme replacement therapy (ERT)

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 2 Table Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Table Vibratory detection thresholds at the first toe (VDT), cold detection thresholds (CDT), and heat-pain perception thresholds (HP) assessed on dorsum of feet in 25 healthy control and in 22 Fabry patients before, after 5-6, and after 18 or 23 months of enzyme replacement therapy (ERT)

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 3 Figure 1 Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Figure 1 . Vibratory perception thresholds in 22 patients before and after 18 or 23 months of agalsidase beta (Fabrazyme) therapy. Before therapy, four Fabry patients had elevated vibratory detection threshold (VDT) values. After 5 to 6 months of enzyme replacement therapy (ERT) and after 18 or 23 months of ERT, only two patients had pathologic VDT values. Diamonds = patient with 23 months of agalsidase beta (Fabrazyme) treatment; triangles = patient with 18 months of agalsidase beta (Fabrazyme) treatment; circles = number of patients being insensitive to vibratory stimulation; JND = just noticeable difference.

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 4 Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Figure 2 . Cold detection thresholds (CDT in 22 Fabry patients before and after 18 or 23 months of enzyme replacement therapy (ERT). Before therapy, 12 Fabry patients had elevated CDT values, including 2 patients being insensitive to cold stimulation. After 5 to 6 months of ERT, 10 patients still had pathologic CDT values, including 1 insensitive patient. After 18 or 23 months of ERT, only seven patients had pathologic CDT values, including two insensitive patients. Diamonds = patient with 23 months of agalsidase beta (Fabrazyme) treatment; triangles = patient with 18 months of agalsidase beta (Fabrazyme) treatment; circles = number of patients being insensitive to cold stimulation; JND = just noticeable difference.

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 5 Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Figure 3 . Heat-pain (HP) 0.5 thresholds indicating perception of beginning discomfort in 22 patients before and after 18 or 23 months of agalsidase beta (Fabrazyme) therapy. Before enzyme replacement therapy (ERT), seven Fabry patients had elevated HP 0.5 values, including one patient being insensitive to low heat-pain stimulation. After 5 to 6 months of ERT, six Fabry patients still had pathologic HP 0.5 values, including three insensitive patients. After 18 or 23 months of ERT, all 22 patients had normal HP 0.5 perception thresholds. Diamonds = patient with 23 months of agalsidase beta (Fabrazyme) treatment; triangles = patient with 18 months of agalsidase beta (Fabrazyme) treatment; circles = number of patients being insensitive to HP 0.5 stimulation; JND = just noticeable difference.

©2004 American Academy of Neurology. Published by LWW_American Academy of Neurology. 6 Enzyme replacement therapy improves function of C-, A[delta]- , and A[beta]-nerve fibers in Fabry neuropathy. Hilz, MJ; MD, PhD; Brys, M; Marthol, H; Stemper, B; Dutsch, M Neurology. 62(7):1066-1072, April 13, 2004. DOI: 10.1212/01.WNL.0000118207.84514.40 Figure 4 . Heat-pain (HP) 5.0 thresholds indicating perception of intermediate pain severity in 22 patients before and after 18 or 23 months of agalsidase beta (Fabrazyme) therapy. Before therapy, 20 Fabry patients had elevated HP 5.0 values, including 1 patient being insensitive to intermediate heat-pain stimulation. After 5 to 6 months of enzyme replacement therapy (ERT), 18 Fabry patients still had pathologic HP 5.0 values, including 3 insensitive patients. After 18 or 23 months of ERT, only four Fabry patients still had elevated HP 5.0 thresholds. Diamonds = patient with 23 months of agalsidase beta (Fabrazyme) treatment; triangles = patient with 18 months of agalsidase beta (Fabrazyme) treatment; circles = number of patients being insensitive to HP 5.0 stimulation; JND = just noticeable difference.

Fabry Pain ‘Non-Specific’ Therapy • Avoid pain-inducing states (stress, heat exposure, etc.) • Antidepressants example amitriptyline, imipramine, and clomipramine – Note contraindications especially arrhythmia • Atypical antidepressants: Duloxetine, Bupropion, Venlafaxine • Anticonvulsants – Gabapentin (Neurontin), Lamotrigine (Lamictal), Topiramate (Topamax), Carbamazepine/Oxcarbazepine (Trileptal), Valproate, Pregabalin (Lyrica), Lacosamide (Vimpat) • Tramadol (Ultram, Rybix, Ryzolt) • Opiates – Controversial but may be effective in combination

Fabry Pain Therapy Cont. • Cannabis: smoking is probably effective • Capsaicin: topical; not effective for generalized disease • Botulinum toxin – one small RCT in diabetic neuropathy

Number-Needed-to-Treat Analyses (NNT) Trivedi et al 2013

Medications of Neuropathic Pain Trivedi et al 2013

Thank you!

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