Download basics and application of Neurophysiology in leprosy

The 19th International Leprosy Congress
ILC 2016 - Beijing, China
Basics and application of
Neurophysiology in leprosy
神经电生理学基础知识及其在麻风中的应用
Jose A Garbino, MD, PhD
Clinical Neurophysiology - ILSL
Instituto Lauro de Souza Lima – Bauru, Brasil 巴西ILSL
Contents - 大纲
• Introduction介绍
•
•
•
•
•
Leprosy neuropathy (LN) general picture and particularities
麻风神经病变全貌和细节
Mononeuropathy multiplex pattern
单神经病的多元模式
Evolutive periods of LN - 麻风神经病变的发展阶段
• Neurophysiologic method in routine 常规的神经电生理学方法
• Electroneuromyography - 神经肌电图
• Nerve conduction studies (NCS) - 神经传导研究
• Needle electromyography - 针极肌电图
• Advantages - 优点
• How to help the diagnosis in: 如何帮助诊断:
• Reactions - 反应
• Differentiation Entrapment ≠ Neuropathic Pain - 压迫综合症与神经病理
性疼痛的鉴别
• Primary Neural Leprosy (PNL) - 纯神经炎麻风
2
Neurologic picture: focal distribution
神经图片：灶状分布
Focal fasciculaire distribution
局灶状束状分布
In the skin: The first focal LN design
“Micromononeuropathy multiplex” 1
1.
2.
Nerve focal distribution =
Mononeuropathy multiplex 2
Garbino JA. Manejo Clínico das diferentes formas de comprometimento da Neuropatia Hanseniana. Hansen Int, v. Supl , 1998
Sabin TD et al. Leprosy – Neuropathy Associated with infections.In: Dyck & Thomas. Peripheral Neuropathy, 2005
Leprosy neuropathy (LN) clinical presentations:
mononeuropathy multiplex (MM) - 麻风神经病变临床展示
≠
inharmonious
Distal “in patches”: cutaneous nerves
multiplex
3. Dos Santos CBA. Estudo da distribuição da perda sensitiva na hanseníase. [dissertação].
Departmento de Neurociencias, FMRP-USP; 2010
True
polyneuropathy =
Worst in lower
limbs/ longer fibers
“length
dependent”
Confluent MM
similar to
polyneuropathy
In
Multibacillary
lepromatous
patients
MM must be distinguished
from Polyneuropathy
Hallmarks – LN peculiarities - 特征：麻风神经
病变的独特性
1. Mononeuropathy (paucibacillary)
and mononeuropathy multiplex
(multibacillary)4 单神经病变（少菌型）和单
神经病变的多发型（多菌型）
2. Mixed: demyelinating → axonal4
混合型：脱髓鞘--轴突的
Frequency: Tibial ► Facial5
3. Enlarged nerves and entrapments4
神经粗大和压迫
4. Garbino J A Marques W Jr, Barreto JA, Heise CO et al et al, Primary neural leprosy: systematic review. Arquivos de neuro-psiquiatria,
5. Garbino JA. Neuropatia Hanseniana. In: Opromolla DVA. Noções de Hansenologia. 2000
The chronic evolution of LN- 麻风神经病变的慢性进展：麻风神经病变也是多因素神经病变
Early periods
Subclinical
亚临床
The ML colonizes
the Schwann Cells
amyelinic and
myelinic
Around 5 years
Reactions -反应炎症阶
段
inflammatory period
lush symptoms (pain)
(nerves swelling)
neuritis recurrent
Around 5 years
Late periods
intraneural fibrosis
神经内纤维化
destroying every fibers in a
nerve branch
Extensive axonal loss
The Leprosy neuropathy is also a MULTICAUSAL neuropathy
Leprosy neuropathy is a
Chronic and subacute inflammatory demyelinating
Neuropathy6,7
麻风神经病变是一个慢性亚急性炎症脱髓鞘神经病变
(similar to the Chronic inflammatory demyelinating neuropathy:
CIDP8)
6. Garbino JA, Marques Jr W. Neuropatia da Hanseníase. In: Alves E D, Ferreira TL e Ferreira IN. Hanseníase: Avanços e Desafios. 1ed. Universidade de Brasília UnB, 2014
7. Neal JW, Gasque P. Schwann cells are vulnerable to primary infection by pathogens responsible for inflammatory peripheral nerve neuropathies; a brief review.
The Journal of Infection, 2016
8. Robles MM, Baldisserotto CM, Garbino JA. Neuropatia da hanseníase versus CIDP. Hansenologia Internationalis, 2012
Aggravating aspects - 加重表现
1.
Chronicity: long and oscillatory evolution:
late reaction X relapse X reinfection
慢性：长期反复进展：晚期反应，
复发，再感染
(Saunderson P. 2000)
2.
3.
Entrapments in the anatomic tunnels, during inflammatory periods
炎症阶段解剖管道的压迫
Neuropathic pain: can remain after
neuritis treatment9
神经病理性疼痛：神经炎治疗后可以持续
9. Stump PR, Baccarelli R, Marciano LHSC et al. Neuropathic pain in leprosy patients. Int J Lepr Other Mycobact Dis. 2004
Neurophysiologic method in routine - 常规神经电生理学方法
Nerve conduction studies (NCS) motor and sensory:
two directions pathways - 神经传导研究：运动和感觉：两个方向
But several conductor types and
sizes of nerve fibers
神经纤维大小与两三种传导体类型
• Heavily myelinated – Aβ motor and
sensory
• Thinly myelinated - Aδ
– Thermal and autonomic
• Non myelinated – C Fibers
– Nociceptive (pain) and autonomic
LN has an universal fiber involvement, but Aβ is a sufficient sample to
understand the nerve environment abnormalities10
10. Sabin TD et al. Leprosy – Neuropathy Associated with infections.In: Dyck & Thomas. Peripheral Neuropathy, 2005
Motor conduction study (A β fibers): CMAP and CV
运动传导研究：复合动作电位与传导速度
Record
Compound motor action potential
(CMAP) 复合动作电位
Motor conduction velocity (CV) = Distance
/L2-L1 (m/s) and D/L3-L2 ...
CMAP decomposition - 复合动作电位分解
sparse demyelination = temporal dispersion
时间离散
Segmental demyelination
(sparse) = subacute or chronic
inflammatory demyelination
CMAP decomposition
Sensory nerve conduction (A β fibers) - 感觉神经传导
stimulus
Recording areas: nerve or skin
Ortho or antidromic conduction and
Sensory Action Potential (SAP)
SAP and sensory velocity
CV = Distance / latency
ILSL
Wide sensory conduction of the digital nerve branches in the hand11
mononeuropathy multiplex (MM) of sensory branches
手部手指神经分支的神经传导
Normal
NCS
Since the 1990s in
Brazil, Carlos Roberto de
Faria coined the term
“mosaic distribution”
for this distal MM 11.
Both
mosaicked
MM
11. De Faria CR, Silva IM. Electromyographic diagnosis of leprosy. Arq. NeuroPsiquiatr, 1990
complete
axonal loss
Motor NC asymmetry in Mononeuro Multiplex
运动神经传导的不对称性
Normal NCS
Distal
Latency
DL ↑
CV ↓↓
TD ↑ ↑
Normal
DL
CV ↓
TD ↑
Conduction block CB
acute demyelination
Advantages - 优势
nerve conduction studies (NCS) -神经传导研究
• NCS > specificity and sensibility12
• definition of underline pathology (myelin or axonal)
•Prognosis indications13 (myelinic better than axonal)
• Can tell if the anti-inflammatory treatment is already useful13
• > objectivity12
• Semmes-Weinstein abnormal and normal NCS = simulation is suspected
• needle electromyography less specificity12
“Gold standard” since 1993, Dyck PJ14
12. Garbino J A et al, Primary neural leprosy: systematic review. Arquivos de neuro-psiquiatria, 2013
13. Garbino J A et al. Neurophysiological patterns of ulnar nerve neuropathy in leprosy reactions. Leprosy Review, 2010
14. Dyck PJ. Quantitation Severity of Neuropathy.In: Dyck PJ & Thomas PK. Peripheral Neuropathy, 3 ed. 1993
Reactions neurophysiological patterns - 反应阶段神经电生理学模式
neuritis: periods of huge inflammation and demyelination神经炎：广泛炎症和脱髓
鞘
ULNAR : temporal dispersion at the
elbow tunnel and above ↑↑↑13
Tibial PLANTAR MEDIAL e LATERAL:
temporal dispersion ↑↑ across the Tarsal tunnel and
VC ↓↓↓15
13. Garbino JA et al. Neurophysiological patterns of ulnar nerve neuropathy in leprosy reactions. Leprosy Review , 2010
15. Robinson RGG, Alexandre PL, Kirchner DR, Garbino JA. Nerve conduction studies of the tibial nerve across the tarsal tunnel in leprosy patients. Hansen
Int. 2015
Response under treatment 16,17 - 治疗反应
(steroid or immunosuppressant) - 激素和免疫抑制剂
Ulnar T1R Neuritis treated with ciclosporina VO
before 03/june/14
after 07/august/14
CMAP recomposition
16. Marques JrW, Garbino J A. Neurites da Hanseníase. In: Sebastião Eurico de Melo-Souza et al (Org.). Tratamento das Doenças Neurológicas. 3ed. 2013
17. Garbino J A. Tratamento clínico da reações da hanseníase com repercussão neurológica - Revisão Histórica. Hansenologia Internationalis, 2012
Reduction of cellularity in type 1 reaction (T1R) in the skin18 - 皮肤1型麻风反应
时细胞结构的减少
accompanied by reduction of demyelination in nerve - 伴随神经脱髓鞘的减少19
120
Figure 4
100
Temporal Dispersion =
segmental demyelination
%
80
60
40
RT1
media
RT2
media
20
0
0
1
2
3
4
5
6
7
8
first to eigth assessments
Inflammatory Infiltration
Inflammation around Schwann Cels
18. Little et al. Cellularity,γ-INF, IL-12, iNOS in
T1R under oral steroids, 2001
19. Garbino JA, Virmond M et al. A randomized clinical
trial of oral steroids for ulnar neuropathy in type 1 and
type 2 eactions. Arq. Neuro-psiquiatr. 2008
压迫 - Entrapment: can show more focal lesion at
beginning20
Mechanical ► vascular21
Findings are focal: CMAP
amplitude focal ↓ and focal ↓
of CV
20. Garbino JA, Heise CO, Marques WJr. Assessing nerves in leprosy. Clinics in Dermatology, 2015
21. Burns TM, Neuropathy caused by compression, entrapment or physical injury, Part D. Mechanisms of acute and chronic compression neuropathy.
In: DYCK P J, THOMAS, P K. Peripheral Neuropathy. 4th ed., Elsevier, 2005
Differentiation between normal response and Entrapment or Neuropathic Pain
(NP) during immunossupression treatment – follow up
免疫抑制治疗阶段压迫或神经病理性疼痛与正常反应的鉴别诊断20
Normal response ↓ in
TD = OK
70
60
50
40
30
20
10
Treatment curve
Left
Median
Left
Ulnar
Right
Median
Right
Ulnar
Prednis
one
0
20. Garbino JA, Heise CO, Marques WJr. Assessing nerves in leprosy. Clinics in Dermatology, 2015
Normal response ↓ in
TD, but the symptoms
persist = Neuropathic
Pain
No response with ↓ in
TD, despite sufficient
immunossuppression =
entrapment must be
suspected
Primary Neural Leprosy22,12
(PNL) - 纯神经炎
primarily neuritic leprosy and pure neuritic leprosy Indian Classification in 1955,
and accepted by Job e Chacko in 1981 (Hastings, 1985; Kaur et al, 1991)
22. Garbino J A, Jardim M MR, Marques Jr W et al. Hanseníase neural primária, revisão sistemática. In: Associação Médica Brasileira e
Conselho Federal de Medicina. (Org.). Projeto Diretrizes. 1ed.Brasilia: 2011.
12. Garbino J A, Marques W Jr, Barreto JA et al. Primary neural leprosy, systematic review. Arquivos de Neuro-psiquiatria, 2013
,
21
Primary Neural Leprosy - 发生率
Frequency in series of leprosy patients with neuritis :
• Van Brakel W in Asia (1994): 8.6% (n: 703)
• Grimaud et al (1994) in Africa: 3.9% (n: 228)
• Garbino JA (1998) in Brazil:
4% (n:256)
• Garbino JA et al in Brazil(2004) < 1/1000 (between all leprosy out patients seen during 2004 at
ILSL)
• Garbino JA (2007) in 162 nerve biopsies (1985-2005) in the ILSL: 1,7/50 new cases of leprosy / year:
3,4% among the new cases of leprosy in Bauru
• Rao and Suneetha in India (2016): 4% - 18%
Varies from 3,4 to 18% (18% seems to be too much)
Was the skin sufficiently evaluated? Was other causes of neuropathy withdrawn?
22
Lets take a glimpse to the scope of Neuropathies more
commonly misdiagnosed as leprosy
经常被误诊的神经病变
• Mononeuropathies - 单神经病变
• Mononeuropathies
• Mononeuropathies multiplex
• Polineuropathies - 多神经病变
• Sensory and motor
• Sensory polineuropathies
• Sensory and/ or autonomic polineuropathies
23
Mononeuropathies: common differential diagnosis
单神经病变鉴别诊断
Mononeuropathies:
•
Ulnar (elbow tunnel, Garbino et al, 2004) and fibular (retro-fibular tunnel)
•
Cheiralgia (superficial radial) and meralgia (lateral cutaneous femoralis)
paresthetica (Theuvenet et al,1993)
•
A case of isolated tuberculoid leprosy of brachial cutaneous nerve.
(Nogueira L A,1990)
•
Nerve tumors – occur out of anatomical tunnels (Garbino et al, 2007)
Multiple Mononeuropathies:
•
inflammatory (collagenosis, vasculitic)
•
metabolic (diabetes, hypothyroidism 23,24)
•
Infections, AIDS 25, Lyme disease, HCV
•
Hereditary: hereditary neuropathy with liability to pressure palsy (HNPP)
(tomaculous neuropathy) - > demyelating than axonal involvement
(Marques et al, 2002)
•
Multifocal Motor neuropathy with conduction block – affect nerves in more
proximal sites and also out of anatomical tunnel26
23. Garbino JA . Avaliação Eletroneuromiográfica da Neuropatia Diabética. In. Khun P. O Pé Diabético. Atheneu. São Paulo, 2006
24. Pollard JD. Neuropathy in Disease of the Thyroid and Pituitary Glands. In: Dyck &Thomas. Peripheral Neuropathy, 4th ed. 2005
25. Höke A and Cornblath DR. Peripheral Neuropathies in Human Immunedeficency Virus Infection. In: Dyck &Thomas. Peripheral Neuropathy, 4th ed.
2005
26. Garbino JA, Galesso AP, Marques JrW. Neuropatia motora multifocal mimetizando mononeuropatia múltipla suspeita de hanseníase. In: V
Simpósio Nacional de Eletromiografia, Annals, São Paulo 2008
24
Polineuropathies: differential diagnosis
多神经病变鉴别诊断
• Sensory and motor27: (diabetes, hypothyroidism and
acromegaly, hereditary and inflammatory, AIDS) = more
probable to be leprosy
• Sensory28 : (diabetes, inflammatory – paraneoplastic, AIDS,
drugs, hereditary) = less probable to be leprosy
• Sensory and/ or autonomic29: (diabetes, inflammatory –
paraneoplastic - and hereditary) = less probable to be leprosy
27. Rosenberg & Lovelace. Arch Neurol, 1968 (sensory and motor)
28. Freitas & Nascimento e col. Arq neuropsiquiatr, 2003 ( > small fibres)
29. Gadoth N et al. Journal Neurol Sci, 1979 (sensory and autonomic)
25
Nerve biopsy directed by nerve conduction 12
Never choose a nerve with normal conduction
神经传导指导下的神经病理
Sural without response
Sural with reduction of amplitude > 50%
PREFERENCIAL NERVES: sural > ulnar dorsal branch > radial superficial > superficial
peroneus or motor branch of deep peroneus
12. Garbino J A et al, Primary neural leprosy: systematic review. Arquivos de neuro-psiquiatria 71 (6), 2013
Patients submitted to nerve biopsy in ILSL during 20 years (1985-2005)30
162 sural nerves
Suspicion of primarily neural leprosy
n=113
34 cases of primarily
neural leprosy
Excluded 49 persons
who were suspected of
neuropathy due to other
causes
79 cases of neuropathy
due to other causes
30. Garbino JA. O paciente com suspeita de hanseníase primariamente neural. Hansen Int, v. 32, p. 925-2720-1-PB, 2007
Findings in the 79 finals/113 (1985 – 2005)30
1.
2.
3.
4.
5.
6.
7.
Nutritional alcohol associated (polineuro): 营养酒精性 25%
Diabetic Neuropathy (polineuro): 糖尿病性
15%
Ulnar tunnel syndrome (mononeuro):
15%
Hereditary neuropathy (poli and MM): 遗传性
10%
Collagenosis and vasculitis (MM): 胶原病和血管炎
10%
Thoracic Outlet (plexo, MM like): 胸廓出口
1,5%
Without confirmed diagnosis: 未证实的
23,5%
30. Garbino JA. O paciente com suspeita de hanseníase primariamente neural. Hansen Int, v. 32, 2007
Algorithms for the PNL investigation
Dermatology
Infectology
Neurology
Anamnesis =
neuropathy +
skin negative
Bacilloscopy
and skin biopsy
Anamnesis
Mononeuropathy
multiplex →
Nerve biopsy
ENMG
positive
EXTENSIVELY
in
Reference
Centers
www.projetodiretrizes.org.br/.../hanseniase_neural_primaria
Prymary neural leprosy – systematic review – SciELO
The Leprosy
patients - XXI
Century Migrants:
21 - 世纪移民
Acrylic on canvas,
120X120 cm, 2012.
Reference to the
painting Migrants
by Portinari. In lieu
of the
malnourished
patients, typical
leprosy deformities
were used in an
apocalyptic
atmosphere of the
outskirts of large
Brazilian cities
Dedicated to Prof.
Diltor Vladimir Araujo
Opromolla, our
teacher, mentor and
friend, one of the
research institute ILSL
architects.
It belongs to the ILSL
collection and it is
permanentely
exposed in the “Luiza
Keffer” Library
The author José A
Garbino signs this
work as Seu Zé.