Transthyretin amyloidosis

Transthyretin amyloidosis

Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland 1).

An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis 2).

Results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value 3).

Godara et al. investigated consecutive patients undergoing surgery for spinal stenosis (SS) for ATTR deposition in the resected ligamentum flavum (LF) and concomitant risk of cardiac amyloidosis. Each surgical specimen (LF) was stained with Congo red, and if positive, the amyloid deposits were typed by mass spectrometry. Patients with positive specimens underwent standard of care evaluation with fat pad aspirates, serum and urine protein electrophoresis with immunofixation, free light-chain assay, TTR gene sequencing and technetium 99 m-pyrophosphate-scintigraphy. In 2018-2019, 324 patients underwent surgery for SS and 43 patients (13%) had ATTR in the LF with wild-type TTR gene sequences. Two cases of ATTRwt cardiac amyloidosis were diagnosed and received treatment. In this large series, ATTRwt was identified in 13% of the patients undergoing laminectomy for SS. Patients with amyloid in the ligamentum flavum were older and had a higher prevalence of CTS, suggesting a systemic form of ATTR amyloidosis involving connective tissue. Further prospective study of patients with SS at risk for systemic amyloidosis is warranted 4).


Carr et al. presented the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset.

Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used.

The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history 5).

Carret al., described a patient with genetically confirmed Transthyretin amyloidosis (ATTR), a family history of the disease and histological confirmation following carpal tunnel release surgery but no other manifestations. The first major neurological or systemic manifestation was cauda equina syndrome with ATTR deposits contributing to lumbar spinal stenosis. Recent gene therapy trials showed improvement in the neuropathy in TTR amyloidosis. This case highlights the need for awareness of the heterogeneous neurological phenotype seen in ATTR to aid earlier diagnosis especially now that disease modifying therapies are available 6).


Patel et al., reported a case of transthyretin amyloidosis with myopathy, neuropathy, and cardiomyopathy resulting from an exceedingly rare mutation transthyretin Ala120Ser (c.418G > T, p.Ala140Ser) 7).


Oculoleptomeningeal amyloidosis (OLMA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges along with ocular involvement. Of >100 TTR mutations identified, few have been associated with OLMA. Herein we describe the first report of leptomeningeal amyloidosis associated with the c.381T>G (p.Ile127Met) TTR mutation, linking this variant to the OLMA phenotype. CASE DESCRIPTION:

A 53 year-old man presented with a 2-year history of progressive symptoms including upper and lower limb weakness, ataxia, and peripheral and autonomic neuropathy. Neuroimaging, including gadolinium-enhanced magnetic resonance imaging of the brain and spinal axis, identified diffuse leptomeningeal enhancement along the brainstem and spinal cord plus evidence of hemosiderosis. Pathologic and genetic analyses of biopsy material from enhancing intradural extramedullary tissue at the thoracolumbar junction was diagnostic of amyloidosis of a transthyretin type secondary to a TTR c.381T>G (p.Ile127Met) mutation.

OLMA represents a rare subtype of heritable transthyretin amyloidosis that may present with progressive neurological decline secondary to central nervous system leptomeningeal amyloid deposition. This case identifies the c.381T>G (p.Ile127Met) TTR mutation variant as being implicated in the OLMA phenotype 8).


Cervicomedullary compression as the main manifestation of wild-type transthyretin amyloidosis 9).


present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment 10)


1) , 5)

Carr AS, Pelayo-Negro AL, Evans MR, Laurà M, Blake J, Stancanelli C, Iodice V, Wechalekar AD, Whelan CJ, Gillmore JD, Hawkins PN, Reilly MM. A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J Neurol Neurosurg Psychiatry. 2016 Jun;87(6):620-7. doi: 10.1136/jnnp-2015-310907. Epub 2015 Aug 4. PubMed PMID: 26243339.
2)

Kapoor M, Rossor AM, Jaunmuktane Z, Lunn MPT, Reilly MM. Diagnosis of amyloid neuropathy. Pract Neurol. 2018 Dec 30. pii: practneurol-2018-002098. doi: 10.1136/practneurol-2018-002098. [Epub ahead of print] PubMed PMID: 30598431.
3)

Piekarski E, Chequer R, Algalarrondo V, Eliahou L, Mahida B, Vigne J, Adams D, Slama MS, Le Guludec D, Rouzet F. Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers. Eur J Nucl Med Mol Imaging. 2018 Jul;45(7):1108-1118. doi: 10.1007/s00259-018-3963-x. Epub 2018 Mar 6. PubMed PMID: 29511839.
4)

Godara A, Riesenburger RI, Zhang DX, Varga C, Fogaren T, Siddiqui NS, Yu A, Wang A, Mastroianni M, Dowd R, Nail TJ, McPhail ED, Kurtin PJ, Theis JD, Toskic D, Arkun K, Pilichowska M, Kryzanski J, Patel AR, Comenzo R. Association between spinal stenosis and wild-type ATTR amyloidosis. Amyloid. 2021 Jul 15:1-8. doi: 10.1080/13506129.2021.1950681. Epub ahead of print. PMID: 34263670.
6)

Carr AS, Shah S, Choi D, Blake J, Phadke R, Gilbertson J, Whelan CJ, Wechalekar AD, Gillmore JD, Hawkins PN, Reilly MM. Spinal Stenosis in Familial Transthyretin Amyloidosis. J Neuromuscul Dis. 2019 Mar 7. doi: 10.3233/JND-180348. [Epub ahead of print] PubMed PMID: 30856118.
7)

Patel K, Tagoe C, Bieri P, Weidenheim K, Tauras JM. A case of transthyretin amyloidosis with myopathy, neuropathy, and cardiomyopathy resulting from an exceedingly rare mutation transthyretin Ala120Ser (c.418G > T, p.Ala140Ser). Amyloid. 2018 Sep;25(3):211-212. doi: 10.1080/13506129.2018.1491398. Epub 2018 Jul 24. PubMed PMID: 30039724.
8)

Mathieu F, Morgan E, So J, Munoz DG, Mason W, Kongkham P. Oculoleptomeningeal Amyloidosis Secondary to the Rare Transthyretin c.381T>G (p.Ile127Met) Mutation. World Neurosurg. 2018 Mar;111:190-193. doi: 10.1016/j.wneu.2017.12.096. Epub 2017 Dec 23. PubMed PMID: 29277593.
9)

Rezania K, Pytel P, Highsmith WE, Gabikian P. Cervicomedullary compression as the main manifestation of wild-type transthyretin amyloidosis. Amyloid. 2017 Jun;24(2):133-134. doi: 10.1080/13506129.2017.1331907. Epub 2017 May 23. PubMed PMID: 28532173.
10)

Carr AS, Pelayo-Negro AL, Jaunmuktane Z, Scalco RS, Hutt D, Evans MR, Heally E, Brandner S, Holton J, Blake J, Whelan CJ, Wechalekar AD, Gillmore JD, Hawkins PN, Reilly MM. Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy. Neuromuscul Disord. 2015 Jun;25(6):511-5. doi: 10.1016/j.nmd.2015.02.001. Epub 2015 Feb 14. PubMed PMID: 25819286.

Electrical stimulation for peripheral nerve injury treatment

Electrical stimulation for peripheral nerve injury treatment

Peripheral nerve injury afflicts individuals from all walks of life. Despite the peripheral nervous system’s intrinsic ability to regenerate, many patients experience incomplete functional recovery. Surgical repair aims to expedite this recovery process in the most thorough manner possible. However, full recovery is still rarely seen especially when nerve injury is compounded with polytrauma where surgical repair is delayed. Pharmaceutical strategies supplementary to nerve microsurgery have been investigated but surgery remains the only viable option 1).


Electrical stimulation is regarded pivotal to promote repair of nerve injury, however, failed to get extensive application in vivo due to the challenges in noninvasive electrical loading accompanying with construction of biomimetic cell niche.

Building on decades of experimental evidence in animal models, several recent, prospective, randomized clinical trials have affirmed electrical stimulation as a clinically translatable technique to enhance functional recovery in patients with peripheral nerve injuries requiring surgical treatment 2).


Implantable wireless stimulators can deliver therapeutic electrical stimulation to injured peripheral nerve tissue. Implantable wireless nerve stimulators might represent a novel means of facilitating therapeutic electrical stimulation in both intraoperative and postoperative settings 3).


Zhang et al. demonstrated a new concept of magneto responsive electric 3D matrix for remote and wireless electrical stimulation. By the preparation of magnetoelectric core/shell structured Fe3 O4 @BaTiO3 NPs-loaded hyaluronan/collagen hydrogels, which recapitulate considerable magneto-electricity and vital features of native neural extracellular matrix, the enhancement of neurogenesis both in cellular level and spinal cord injury in vivo with external pulsed magnetic field applied is proved. The findings pave the way for a novel class of remote controlling and delivering electricity through extracellular niches-mimicked hydrogel network, arising prospects not only in neurogenesis but also in human-computer interaction with higher resolution 4).


The frequency of stimulation is an important factor in the success of both quality and quantity of axon regeneration as well as growth of the surrounding myelin and blood vessels that support the axon. Histological analysis and measurement of regeneration showed that low frequency stimulation had a more successful outcome than high frequency stimulation on regeneration of damaged sciatic nerves.

The use of autologous nerve grafting procedures that involve redirection of regenerative donor nerve fibers into the graft conduit has been successful in restoring target muscle function. Localized delivery of soluble neurotrophic factors may help promote the rate of axon regeneration observed within these graft conduits.

An expanding area of nerve regeneration research deals with the development of scaffolding and bio-conduits. Scaffolding developed from biomaterial would be useful in nerve regeneration if they successfully exhibit essentially the same role as the endoneurial tubes and Schwann cell do in guiding regrowing axons.

The surgeon, who treats nerve injuries, should have knowledge about how peripheral nerves react to trauma, particularly an understanding about the extensive pathophysiological alterations that occur both in the peripheral and in the central nervous system. A large number of factors influence the functional outcome, where the surgeon only can affect a few of them. In view of the new knowledge about the delicate intracellular signaling pathways that are rapidly initiated in neurons and in nonneuronal cells with the purpose to induce nerve regeneration, the timing of nerve repair and reconstruction after injury has gained more interest. It is crucial to understand and to utilize the inborn mechanisms for survival and regeneration of neurons and for activation, survival, and proliferation of the Schwann cells and other cells that are acting after a nerve injury. Thus, experimental and clinical data clearly point toward the advantage of early nerve repair and reconstruction of injuries. Following an appropriate diagnosis of a nerve injury, the nerve should be promptly repaired or reconstructed, and new rehabilitation strategies should early be initiated. Considering nerve transfers in the treatment arsenal can shorten the time of nerve reinnervation of muscle targets. Timing of nerve repair and reconstruction is crucial after nerve injury 5).


1)

Willand MP, Nguyen MA, Borschel GH, Gordon T. Electrical Stimulation to Promote Peripheral Nerve Regeneration. Neurorehabil Neural Repair. 2016 Jun;30(5):490-6. doi: 10.1177/1545968315604399. Epub 2015 Sep 10. PMID: 26359343.
2)

Zuo KJ, Gordon T, Chan KM, Borschel GH. Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation. Exp Neurol. 2020 Oct;332:113397. doi: 10.1016/j.expneurol.2020.113397. Epub 2020 Jul 3. PMID: 32628968.
3)

MacEwan MR, Gamble P, Stephen M, Ray WZ. Therapeutic electrical stimulation of injured peripheral nerve tissue using implantable thin-film wireless nerve stimulators. J Neurosurg. 2018 Feb 9:1-10. doi: 10.3171/2017.8.JNS163020. Epub ahead of print. PMID: 29424647.
4)

Zhang Y, Chen S, Xiao Z, Liu X, Wu C, Wu K, Liu A, Wei D, Sun J, Zhou L, Fan H. Magnetoelectric Nanoparticles Incorporated Biomimetic Matrix for Wireless Electrical Stimulation and Nerve Regeneration. Adv Healthc Mater. 2021 Jun 27:e2100695. doi: 10.1002/adhm.202100695. Epub ahead of print. PMID: 34176235.
5)

Dahlin LB. The role of timing in nerve reconstruction. Int Rev Neurobiol. 2013;109:151-64. doi: 10.1016/B978-0-12-420045-6.00007-9. Review. PubMed PMID: 24093611.

Iatrogenic peripheral nerve injury

Iatrogenic peripheral nerve injury

Treatment

Iatrogenic peripheral nerve injury is a considerable social and economic concern and the majority of cases are preventable. Complications should be referred to and dealt with promptly by experienced surgeons, to ensure the best chances for optimal functional recovery. Their prevention should be emphasized. Their management should include ensuring early diagnosis, administering an appropriate treatment with rehabilitation, rendering psychological support, and providing control of pain 1).


The combination of morphological assessment (neurosonography) with functional assessment (nerve conduction studies) is of paramount importance in the management of traumatic peripheral nerve injuries. If on sonography, the nerve appears intact, then intraoperative nerve conduction studies the functionality of the nerve. If conduction is impaired (signifying the presence of a neuroma-in-continuity), then nerve grafting is done. If the conduction is somewhat preserved, neurolysis is performed 2).


If it is noted during an operation that a nerve has been severed, it should be repaired immediately during the same operation (primary repair) or within 2–3 weeks (early secondary repair) 3).

The same is true when the nerve is torn or damaged but not cleanly cut. The same operative approach is used as for any other nerve injury. The repair ideally is done with microsurgical tools and magnifying devices, insuring maximal visualization for the repair.

Once again, this ideal situation with the immediate repair is seldom achieved. Usually, the cause of the damage is unknown. In our experience, the operative report rarely provides useful information. When the mechanism for the damage is unknown but there is reason to think that the nerve may regenerate itself, we prefer to wait 3 months with monthly neurological examinations. If at this time, the deficit has not changed or only minimally improved, the nerve should be surgically explored in the next month. If the neurosonographic examination after exposure of the nerve identifies a neuroma, one should not delay. The operation should ideally occur within 3 weeks 4).

A severed nerve should be reconstructed, if possible. Usually, this requires nerve grafting. The sural nerve on the lateral calf is usually used as a source. Other cutaneous nerves such as the saphenous nerve and the medial antebrachial cutaneous nerve can also be used 5). If the nerve appears to be intact, then intraoperative nerve conduction studies help assess how functional it is in the area of damage. If conductivity is impaired, then the affected segment of the nerve surrounded by scar tissue—usually thickened and diagnosed as a neuroma in continuity—is excised and replaced by a transplant. In other cases, when conductivity studies are more promising, it suffices to free the nerve up from the surrounding reactive tissues (neurolysis). In recent years intraoperative neuro sonography has been employed, facilitating the evaluation of individual nerve fascicles, helping distinguish between a complete neuroma in continuity without any residual fascicles and a partial lesion still containing functioning fascicles 6).

The combination of the functional evaluation (nerve conduction studies) and the morphologic assessment (neuro sonography) is very helpful in the surgical management of traumatic injuries in peripheral nerve surgery. The exact approach is documented in the interdisciplinary guidelines of the AWMF “Versorgung peripherer Nervenverletzungen” 7).

A key factor in improving the prognosis is physical therapy, both after the deficit is identified and then post-operatively until re-innervation of the affected muscles has occurred. Electric stimulation therapy is also worthwhile in our option. In this way, the muscle structures can be better maintained until nerve regeneration has occurred.

Case series

Dubuisson et al. analyzed the management of iatrogenic peripheral nerve injury (iNI) in 42 patients.

The iNI occurred mostly during a surgical procedure (n = 39), either on a nerve or plexus (n = 13), on bone, joint, vessel, or soft tissue (n = 24) or because of malpositioning (n = 2). The most commonly injured nerves were the brachial plexusradial nervesciatic nervefemoral nerve, or peroneal nerves. 42.9% of the patients were referred to later than 6 months. A neurological deficit was present in 37 patients and neuropathic pain in 17. Two patients were lost to follow-up. Conservative treatment was applied in 23 patients because of good spontaneous recovery or compensation or because of expected bad prognosis whatever the treatment. Surgical treatment was performed in 17 patients because of known nerve section (n = 2), persistent neurological deficit (n = 12) or invalidating neuropathic pain (n = 3); nerve reconstruction with grafts (n = 8) and neurolysis (n = 8) were the most common procedures. The outcome was satisfactory in 50%. Potential reasons for poor outcomes were a very proximal injury, placement of very long grafts, delayed referral, and predominance of neuropathic pain. According to the literature, delayed referral of iNI for treatment is frequent. They provides an illustrative case of a young girl operated on at 6.5 months for femoral nerve reconstruction with grafts while the nerve section was obvious from the operative note and pathological tissue analysis. Litigation claims (n = 10) resulted in malpractice (n = 2) or therapeutic area (n = 5) (3 unavailable conclusions).

NI can result in considerable disability, pain, and litigation. Optimal management is required 8).


Rasulić et al. describe and analyze iatrogenic nerve injuries in a total of 122 consecutive patients who received surgical treatment at there institution during a period of 10 years, from January 1, 2003, to December 31, 2013. The final outcome evaluation was performed 2 years after surgical treatment.

The most common causes of iatrogenic nerve injuries among patients in the study were the operations of bone fractures (23.9%), lymph node biopsy (19.7%), and carpal tunnel release (18%). The most affected nerves were median nerve (21.3%), accessory nerve (18%), radial nerve (15.6%), and peroneal nerve (11.5%). In 74 (60.7%) patients, surgery was performed 6 months after the injury, and in 48 (39.3%) surgery was performed within 6 months after the injury. In 80 (65.6%) patients, we found lesion in discontinuity, and in 42 (34.4%) patients lesion in continuity. The distribution of surgical procedures performed was as follows: autotransplantation (51.6%), neurolysis (23.8%), nerve transfer (13.9%), direct suture (8.2%), and resection of neuroma (2.5%). In total, we achieved satisfactory recovery in 91 (74.6%), whereas the result was dissatisfactory in 31 (25.4%) patients.

Patients with iatrogenic nerve injuries should be examined as soon as possible by experts with experience in traumatic nerve injuries so that the correct diagnosis can be reached and the appropriate therapy planned. The timing of reconstructive surgery and the technique used are the crucial factors for functional recover 9).


340 patients underwent surgery for iatrogenic nerve injuries over a 23-year period in the District Hospital of Günzburg (Neurosurgical Department of the University of Ulm). In a study published by the authors in 2001, 17.4% of the traumatic nerve lesions treated were iatrogenic. 94% of iatrogenic nerve injuries occurred during surgical procedures 10).

References

1)

Kumar A, Shukla D, Bhat DI, Devi BI. Iatrogenic peripheral nerve injuries. Neurol India. 2019;67(Supplement):S135-S139. doi:10.4103/0028-3886.250700
2)

Sinha S. Management protocol in the case of iatrogenic peripheral nerve injuries. Neurol India. 2019;67(Supplement):S140-S141. doi:10.4103/0028-3886.250696
3) , 4) , 5) , 7)

Deutsche Gesellschaft für Handchirurgie (DGH), Deutsche Gesellschaft für Neurologie (DGN), Deutsche Gesellschaft für Neurochirurgie (DGNC), Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie (DGOOC), Deutsche Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC), Deutsche Gesellschaft für Unfallchirurgie (DGU) Leitlinen: Versorgung peripherer Nervenverletzungen. http://www.awmf.org/leitlinien/detail/ll/005-010.html Stand 30.06.2013
6)

Koenig RW, Schmidt TE, Heinen CPG, et al. Intraoperative high-resolution ultrasound: a new technique in the management of peripheral nerve disorders. Clinical article Journal of Neurosurgery. 2011;114:514–521
8)

Dubuisson A, Kaschten B, Steinmetz M, et al. Iatrogenic nerve injuries: a potentially serious medical and medicolegal problem. About a series of 42 patients and review of the literature [published online ahead of print, 2020 Jul 11]. Acta Neurol Belg. 2020;10.1007/s13760-020-01424-0. doi:10.1007/s13760-020-01424-0
9)

Rasulić L, Savić A, Vitošević F, et al. Iatrogenic Peripheral Nerve Injuries-Surgical Treatment and Outcome: 10 Years’ Experience. World Neurosurg. 2017;103:841-851.e6. doi:10.1016/j.wneu.2017.04.099
10)

Antoniadis G, Kretschmer T, Pedro MT, König RW, Heinen CP, Richter HP. Iatrogenic nerve injuries: prevalence, diagnosis and treatment. Dtsch Arztebl Int. 2014;111(16):273-279. doi:10.3238/arztebl.2014.0273
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