THE ROLE OF PLASMAPHERESIS

IN NEUROLOGICAL DISORDERS
DR Dr Retnaningsih SpS(K) KIC
Bag/KSM Neurologi FK Universitas Diponegoro/RS Dr Kariadi
Semarang
Plasmapheresis adalah prosedur yang melibatkan pemisahan plasma dari
darah menggunakan membran untuk filtrasi dan menggantinya dengan
solusi albumin isovolumetrik ataupun fresh frozen plasma.

Costantini, Nicoletta, MD, Antonella Mameli, MD,

Francesco Marongiu, MD. Plasmapheresis for
Preventing Complication of Hypertriglyceridemia: A
Case Report and Review of Literature. 2016.(23)288-91
 INDICATIONS FOR PLASMA EXCHANGE IN NEUROLOGY
KATEGORI
KATEGORI I Lambert-Eaton
Guillain-Barre II myasthenic
syndrome syndrome

Myasthenia Multiple
Gravis Sclerosis

CIDP

• Acute Inflammatory Demyelinating Polyneuropathy (Guillain-Barr!e Syndrome): Category I

• Myasthenia Gravis: Category I
• Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Category I
• Paraproteinemic Polyneuropathies with IgG/IgA (Category I) or IgM (Category II)
• Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and
Sydenham's Chorea. Both Category I
• ASFA Category I indications for therapeutic plasma exchange
• AIDP/Guillain–Barrésyndrome
• Chronicinflammatorydemyelinating polyneuropathy
• Myastheniagravis
• Polyneuropathyassociatedwith paraproteinaemias
• N-methylD-aspartatereceptorantibody encephalitis(2016)

• ASFA Category II indications for therapeutic plasma exchange

• ADEM
Lambert–Eatonmyasthenicsyndrome
Multiplesclerosis(Acuteexacerbation) Acute Central Nervous System
Inflammatory Demyelinating Disease
Neuromyelitisoptica(acute)
PANDAS
Hashimoto’s encephalopathy: SREAT(2016)
• Rasmussen's Encephalitis: Category II
• ASFA Category III indications for therapeutic plasma exchange
• – Paraneoplasticneurologicalsyndromes
• – Chronic progressive Multiple sclerosis
• – NMOSD-maintainance

• ASFA Category IV indications for therapeutic plasma exchange

• – Amyotrophic lateral sclerosis
• – Inclusionbodymyositis
– POEMSsyndrome
Guidelines on the Use of Therapeutic Apheresisin Clinical
Practice—Evidence-Based Approach fromthe Writing
Committee of the American Societyfor Apheresis: The
Seventh Special Issue

Joseph Schwartz, Anand Padmanabhan, Nicole Aqui, Rasheed A. Balogun, Laura

Connelly-Smith, Meghan Delaney, Nancy M. Dunbar, Volker Witt, Yanyun Wu, and
Beth H. Shaz

*Journal of Clinical Apheresis 31:149–338 (2016)

Spectrum of Autoimmune Central and Peripheral Neurological
Disorders in Southeast Asia

Shanthi Viswanathan, Metha Apiwattanakul, Seinn Mya, Riwanti Estiasari. Second

regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the
immunomodulatory role of plasma exchange in central and peripheral nervous
system disorders. 2018:10
I. Cortese, MD V. Chaudhry, MD Y.T. So, MD, PhD F.
Cantor, MD D.R. Cornblath, MD A. Rae-Grant, MD.
Evidence-based guideline update: Plasmapheresis
in neurologic disorder. 2011. 294-301
Update: Plasmapheresis in Neurologic Disorders-
AAN 2011
Plasma Exchange Therapy for inflammatory of
Central Nervous System
• The transient effects of plasma exchange
and the possibility of a rebound
phenomenon would call for the
combination of short-term active plasma
exchange with long-term
immunosuppression.
• The sudden abolition of feedback
inhibition of B cells may synchronize their
activity and render them particularly
sensitive to a pulse of
immunosuppression
• Complete removal of pathogenic
antibodies is impossible to achieve.
Because of a slow equilibration of large
macromolecules between the vascular
space and the interstitium,
GUILLAIN BARRE SYNDROME
Description GBS • Consists of a group of neurologic
conditions characterized by progressive
weakness and diminished/ absent
myotactic reflexes.
• up to 90% of cases of GBS, is an acute
progressive paralyzing illness affecting both
motor and sensory peripheral nerves.
• begins with symmetrical muscleweakness
and paresthesias that spread proximally.
• Weakness progresses over a period of 12 h
to 28 days before the nadir is reached and
may involve respiratory and oropharyngeal
muscles in more severe cases.
• Autonomic dysfunction can cause variability in blood pressure and
heart rate.
• may require intensive care, mechanical ventilation, is required
for 25% of patients.
• and assistance through paralysis and necessary rehabilitation
over several months to a year or more.
• Spontaneous recovery may occur, neurologic complications persist in
up to 20% of patients, with about half of them severely disabled.

• Mortality is estimated at 3%.

Pathogenesis
• GBS is autoimmune antibody-
mediated damage to the peripheral
nerve myelin.

• Preceding infectious illness, such as

Campylobacter, suggest cross-
reactive antibodies may be a
component in disease pathogenesis
 Pathogenesis
• Acute motor axonal neuropathy
(AMAN), Acute motor-sensory
axonalneuropathy (AMSAN),
• Miller Fisher syndrome,
• acute autonomic neuropathy.
• Pathogenesis : due to the presence of
autoantibodies against various
gangliosides including GM1,
GD1a,GalNAc-GD1a, GD1b, GQ1b,
GD3, and GT1a, particularly in AMAN
and Miller Fisher syndrome subtypes.
 Rationale for therapeutic apheresis in GBS

• TPE was the first therapeutic modality

• TPE can accelerate motor recovery, decrease time on the
ventilator, and speed attainment of other clinical milestones.
• TPE significantly increased proportion of patients able to walk
after four weeks. While recovery with TPE is improved, the
duration of disability from AIDP remains significant.
• Other therapeutic modalities studied include
immunoadsorption apheresis, CSF filtration, and double
filtration plasmapheresis.
• Some trials usingTPE and/or IVIG in GBS have included AIDP
and other variants
Plasma Exchange in Neuroimmunological Disorders
Plasma Exchange Pada Pasien Dengan Gangguan Pada
Sistem Saraf Tepi

Pada
Guillain-
Barre
Syndrome

Helmar C. Lehmann, MD;

Hans-Peter Hartung, MD;
Gerd R. Hetzel, MD; Olaf Stu ̈
ve, MD; Bernd C. Kieseier,
MD. Plasma Exchange in
Neuroimmunological
Disorders.2006(63):1066-71
 ACUTE INFLAMMATORY DEMYELINATING
POLYRADICULONEUROPATHY/GUILLAIN–BARRESYNDROME
Rationale for therapeutic apheresis in GBS
• There were no differences in the three treatment groups in mean
disability improvement at 4 weeks nor the time to be able to walk
without assistance(TPE group 49 days, IVIG group 51 days, and
TPE/IVIG group 40 days).
• French Cooperative Study: median time to wean from mechanical
ventilation was 18 days versus 31 days for TPE compared to
conventional treatment
• In the North American Trial, the median time to walk without
assistance was 53 days versus 85 days in the TPE and conventional
treatment arms
• The Cochrane Neuromuscular Disease Group review of TPE in AIDP
performed in 2012 found that TPE is most effective when initiated
within 7 days of disease onset.

Raphaël JC1, Chevret S, Jars-Guincestre MC, Chastang

C, Gajdos P.
Myasthenia Gravis
• an autoimmune disease characterized
by weakness and fatigability with
repetitive physical activity,
usuallyimproving with rest.
• Common presentation includes ptosis
and diplopia with more severe cases
having facial, bulbar, and limb
muscleinvolvement.
• Most commonly in 20–40 years
women
• Most common causative antibody is
directed against acetylcholine
receptor (anti-AChR) on the post-
synaptic surface of the motor end
plate.
Pathofisiology MG • motor nerves release neurotransmitter
acetylcholine (ACh) at neuromuscular junction.
• ACh crosses synaptic space to muscle surface
binding to AChR and stimulates an action
potential and muscle contraction.
• Anti-AChRreduces the number of available AChR,
decreasing the action potential achieved.
• Anti-AChR level does not correlate with disease
severity;severe disease can occur without
detection of this antibody.
• Antibodies to muscle specific receptor tyrosine
kinase (MuSK) are detected in 50% of anti-AChR
seronegative disease.
• MuSK mediates formation of the neuromuscular
junction and induction of AChR.
• Antibodyagainst low-density lipoprotein receptor-
related protein 4 (LRP4) has also been described.
• LRP4 is an agrin receptor, which is essential
for agrin-induced activation of MuSK and AChR
clustering and neuromuscular junction formation.
• Other antibodies include anti-titin, and anti-agrin.
 Description of MG
• Myasthenic crisis is characterized by acute respiratory failure
requiring intubation, prolonged intubation following thymectomy,
or bulbar weakness causing dysphasia and high risk of aspiration.
• Thymic abnormalities (hyperplasia or thymoma) are commonly
associatedwith MG.
Pattern & Spreading
of Weakness
 Current management/treatment
• Modern treatment regimens have decreased MG mortality from 30% to 5%.
• Four major treatment approaches include cholinesterase inhib-itors, thymectomy,
immunosuppression, and either TPE or IVIG.
• Cholinesterase inhibitors (pyridostigmine bromide) delay breakdown andincrease
availability of ACh at motor end plate and lead to variable strength improvement.
• Cholinergic side effects, including diarrhea,abdominal cramping, increased
salivation, sweating, and bradycardia, are dose limiting and lead to non-
compliance.
• Thymectomy leads to clinical improvement in many patients 65 years but may take
years for benefits.
• Immunosuppressive drugs (corticosteroids, azathioprine,cyclosporine, tacrolimus)
have delayed effect and are important for long-term rather than short-term
management.
• Rituximab demonstrated effectiveness in many cases, particularly in MuSK-MG.
Other promising monoclonal antibodies include belimumab, eculizumab
Indications for plasmapheresis in myasthenia gravis
• The treatment of myasthenia gravis includes thymectomy, acetylcholine
esterase inhibitors, corticosteroids, immunosuppressive agents,
plasmapheresis, and IVIG.
• It is presumed that by eliminating circulating nicotinic AChR antibodies and
other humoral factors, plasmapheresis accounts for the observed beneficial
effects.
• Indications for plasmapheresis include situations that necessitate rapid
clinical improvement, such as myasthenic crisis, impending crisis, and
preoperative stabilization; patients in whom long-term control of
symptoms is suboptimal with other forms of therapy also benefit from
plasmapheresis.
• On occasion, patients require long-term outpatient exchange in order to
achieve adequate control of myasthenia gravis symptoms.
Indications for plasmapheresis
• RecommendationCategory
Moderate–severe TPE –Cat. I
• Pre-thymectomyTPE–Cat.I
• Myasthenic crisis
• Perioperatively for thymectomy,
• As an adjunct to other therapies to maintain optimal clinical status
• – Number and frequency of procedures depends upon clinical scenario.
• – Some patients may require long-term maintenance TPE.

• – Myasthenic crisis is characterized by acute respiratory failure requiring intubation

prolonged intubation following thymectomy, or bulbar weakness causing dysphasia
and high risk of aspiration
 Rationale for therapeutic apheresis in MG
• TPE is used to remove circulating autoantibodies, particularly in myasthenic crisis,
perioperatively for thymectomy, or as an adjunct to other therapies to maintain
optimal clinical status.
• TPE works rapidly; clinical effect can be apparent within 24 h but may take a
weeks
• The benefits will likely subside after 2–4 weeks, if immunosuppressive therapies
are not initiated to keep antibody levels low.
• TPE may be more effective than IVIG in patients with MuSK-MG.
• TPE may be more effective if initiated earlier in the disease’s course.In one RCT
87 patients with major exacerbations underwent three every other day 1.5 TPV
TPE, 0.4g/kg/day x 3 days of IVIG, or 0.4g/ kg/day x 5 days of IVIG.

• RCT that included 12 stable patients with moderate–severe dis-ease found TPE to
be better at 1 week, equivalent improvement at 4 weeks, and neither to show
improvement at 16 weeks.
• RCT included 84 worsening moderate–severe patients treated with IVIG (1
EFFECTIVENESS OF THERAPEUTIC PLASMA EXCHANGE IN
MYASTHENIA GRAVIS
MYASTHENIA GRAVIS
• Improvement at Day 14 was equivalent (69% IVIG and 65% TPE, and 18%
worsened IVIG and 2% TPE).
• Notably in this study patients who received TPE versus IVIG were more likely to
be intubated and have respiratory failure prior to initiatingtreatment.
• RCT showed daily to be equivalent to every-other-day small volume exchanges
(20–25 mL/kg).
• Clinical trials have reportedon the use of TPE prior to thymectomy: most
studies have shown improved patient outcome with routine use of TPE but
other studies have shown equivalent outcomes with selective
• TPE use in patients at high-risk for post-procedure prolonged intubation.
• DFPP has been shown to be beneficial as well.
• newer technology using specific adsorbents for MG autoantibodies is being
developed
EFFECTIVENESS OF THERAPEUTIC PLASMA EXCHANGE IN
MYASTHENIA GRAVIS

R N Makroo, V Raina, A Kohli, V Suri,P

Kumar. EFFECTIVENESS OF THERAPEUTIC
PLASMA EXCHANGE IN MYASTHENIA
GRAVIS .2008(5)
INDIKASI
KATEGORI I

CIDP
Immunopathogenesis of chronic inflammatory
demyelinating polyneuropathy.
• The putative antigen is
presented by antigen
presenting cells to
autoreactive T cells in the
peripheral immune
compartment. T cells become
activated, undergo clonal
expansion, release
inflammatory mediators and
cross the blood-nerve barrier
(BNB)
Plasma Exchange in Neuroimmunological Disorders

Plasma Exchange Pada Pasien Dengan Gangguan Pada

Sistem Saraf Tepi
Pada
CIDP

Helmar C. Lehmann, MD;

Hans-Peter Hartung, MD;
Gerd R. Hetzel, MD; Olaf Stu ̈
ve, MD; Bernd C. Kieseier,
MD. Plasma Exchange in
Neuroimmunological
Disorders.2006(63):1066-71
CIDP

• RecommendationCategory-I
• Volumetreated:1–1.5TPV
• Frequency:23/week until
improvement, then taper as
tolerated
• Replacement fluid:Albumin
• TPE provides shortterm benefit but
rapid
• deterioration may occur afterwards
• The frequency of maintenance TPE
may range from weekly to monthly .
Multiple Sclerosis
 MULTIPLE SCLEROSIS

• AcuteCNSinflammatorydemyelinating–Cat.II
• Chronic progressive MS , TPE – Cat. III
• Standard treatment for MS exacerbation –
High dose IV MPS.
• If unresponsive, a second steroid pulse is
given after an interval of 10–14 days.
• In acute, severe attacks of MS in patients
who fail initial treatment with high-dose
steroids, TPE may be beneficial
(Gwathmey,2014).
• TPE has also been used for drug removal in
MS patients treated with Natalizumab who
developed PML.
 Description Multiple Sclerosis
• a relapsing and often progressive disorder of central nervous system (CNS) white
matter demyelination.
• 80% of MS is the relapsing-remitting MS (RRMS)form where signs and symptoms
evolve over days, stabilize, and then improve within weeks.
• Corticosteroids speed recovery, but the response decreases over time.
• Persistent symptoms may develop and the disease may progress between
relapses, referred to as secondary progressive MS.
• Alternatively, 20% of MS patients have a primary progressive form with
continuous progression without improvement.
• Clinical symptoms include sensory disturbances, unilateral optic neuritis,
diplopia, limbweakness, gait ataxia, neurogenic bladder, and bowel symptoms.
• MRI shows multiple lesions of different ages involving the white matter of the
cerebrum, brain stem, cerebellum, and spinal cord.
• The characteristics of demyelination for each pattern are:
Type I, T-cell/macro-phage-associated;
Type II, antibody/complement-associated;
Type III, distal oligodendrogliopathy;
Type IV, oligodendrocyte degeneration.
• A more severe clinical course can be predicted by frequent relapses in the first 2
years, primary progressive form, male sex, and early permanent symptoms.
• Acute CNS inflammatory demyelinating disease is usually secondary to MS but
includes cases of acute transverse myelitis and neuromyelitis optica (NMO or
Devic’s syndrome
 Rationale for therapeutic apheresis
• severe attacks of MS in patients who fail initial treatment with high-dose
steroids, TPE may be beneficial (Gwathmey,2014).
• A study of patients with fulminant CNS inflammatory demyelinating disease
demonstrated that all 10 patients withType II but none of the 3 with Type I or 6
with Type III had substantial improvement with TPE (Keegan, 2005).
• A recent case series retrospectively evaluated 60 patients and observed an 88%
response rate (Heigl, 2013).
• Several controlled clinical trials demonstrate minimal to no benefit of TPE in
chronic progressive MS (Klingel, 2013).
• TPE has also been used for drug removal in MS patients treated with
natalizumab who developed progressive multi focal leukoencephalopathy
Plasmapheresis Improves the Suppressive Function of Regulatory T Cells
in Patients with Fast-Progressing Amyotrophic Lateral Sclerosis (P3.183)
Jason Thonhoff, David Beers, Weihua Zhao, Shixiang Wen, JinghongWang, L
uis Lay, Lisa Thompson, Christopher Leveque, Stanley Appel
Neurology Apr 2016, 86 (16 Supplement) P3.183;
MECHANISMS OF ACTION AND PROCEDURE
OF PLASMA EXCHANGE
• Therapeutic plasma exchange constitutes an extracorporeal blood
purification tech- nique designed to remove large molecular weight
particles from plasma.
• The re- moval of circulating autoantibodies, im- mune complexes,
cytokines, and other in- flammatory mediators is thought to be the
principal mechanism of action.
• Antibodies against self have been identified in various neurological
disorders, including antibod- ies against nicotinic acetylcholine
receptor in myasthenia gravis,5 antibodies against
MECHANISMS OF ACTION AND PROCEDURE
OF PLASMA EXCHANGE
• Therapeutic plasma exchange involves the selective removal of
plasma from a patient and replacement with another appropriate
fluid.
• The cellular components of the blood are returned with the
replacement fluid to restore normal volume.
• Albumin, crystalloids or both are generally used to replace the
plasma, the removal:return ratio being 1:1.
• Previously, fresh frozen plasma was frequently used as the
replacement fluid
MECHANISMS OF ACTION AND PROCEDURE
OF PLASMA EXCHANGE A. Pengeluaran
dari antibodi
MEKANISME
patologis

B. Inisiasi
H. Koreksi dari
proliferasi dari sel
tipe sel T-helper
B dan plasma

C. Pemindahan
G. Peingkatan
dari kompleks
aktivitas sel T
imun

D. Penggantian
F. Perubahan
komponen plasma Hollie M. Reeves,Jeffrey L. Winters. The
jumlah limfosit mechanisms of action of plasma
yang hilang
exchange. British Journal of
Haematology, 2014, 164, 342–351
E. Pengeluaran
dari sitokin
MECHANISMS OF ACTION AND PROCEDURE
OF PLASMA EXCHANGE

• The beneficial effects of plasma exchange de- pend on one or both oft
wo postulated mechanisms:
(a) the removal of some abnormal plasma constituent
(b) the replenishment of a normal plasma constituent in which the
patient is deficient.
• The procedure can be compared to renal dialysis, but only small
molecules and substances are removed from the blood during dialysis.
• New techniques involving specific absorbent and immuno- affinity
columns permit direct removal of toxic compounds such as antibodies
and low-density lipo- proteins (LDLs).
TPE Contraindication

tidak dapat mentolerir

Sepsis/hemodinamika
penempatan jalur Alergi FFP/Albumin
tidak stabil
sentral

Rutin mengkonsumsi
Alergi heparin Hipokalsemia
ACE inhibitor
Pregnancy and Plasmapheresis

• Plasmapheresis can be performed safely during pregnancy, and

introduction of plasmapheresis during pregnancy for diseases necessitating
that procedure has improved maternal and fetal survival rates.
• Plasmapheresis has been safely carried out in patients with myasthenic
crisis, Guillain-Barré syndrome, anti-GBM disease, acute fatty liver of
pregnancy, and TTP. Until the effectiveness of plasmapheresis was
recognized, the rate of mortality from TTP was 95%; in cases of pregnancy-
related TTP, maternal survival was rare, and the fetal mortality rate
approached 80%. Since 1990, numerous reports have revealed the efficacy
of plasma exchange, and TTP has become a curable disease, with a
response rate of about 80%, with minimal or no sequelae
RISK

• 􏰄 Plasmapheresis can result in premature delivery because

hormones crucial in maintaining pregnancy are removed.
• Other complications can result from hypovolemic reaction, allergy,
transitory cardiac arrhythmias, nausea, and impaired vision.
• During the exchanges, hypotension must be carefully monitored and
corrected, and in the second or third trimester
Membrane versus centrifuge‐based therapeutic plasma
exchange: a randomized prospective crossover study

TREATMENT TIME
(min)

P = 0,0076

PLASMA REMOVAL
RATE (mL/min)

P = 0,0057
Carsten Hafer, Paulina Golla, Marion Gericke, Gabriele Eden,
Gernot Beutel, Julius J. Schmidt . Membrane versus
centrifuge‐based therapeutic plasma exchange: a randomized
prospective crossover study. (2016) 48:133–138
TPE Complications

Wojciech Szczeklik, Katarzyna Wawrzycka , Anna

Włudarczyk, Aurelia Sega , Ilona Nowak , Bożena
Seczyńska. Complications in patients treated with
plasmapheresis in the intensive care unit. 2013, (45)7–13
TPE Complications
Conclusion
Plasmapheresis in Neurologic Disorders
•– Removal of immunoglobulins
•– Centrifugation and Plasma filtration
•– Albumin MC used
•– 5 cycles alt. days
•– Good response in GBS,Myasthenia crisis, Autoimmune encephalitis.
•– Good for acute management
TERIMAKASIH