GB syndrome and other

immune mediated neuropathies

Moderator :Dr Madhusudan c
(Associate professor department of medicine)

Presenter :Dr Teena Chandran

CASE 1
• 28yrs old female presented with history of numbness in b/l lower limb
since 6 days and gait instability since 3 days.
• Initially numbness was present over the sole of the foot which
gradually progressed to above knee over a period of 6 days.After 3
days of onset of symptoms she started having gait instability
described by the patient as “losing her balance” requiring her to use a
cane to walk.
• 15 days prior to episode she had acute gastroentroentritis for 3 days
which was treated conservatively
• No bowel and bladder symptoms were present
•General examination
•Vitals :-PR -120bpm
•Bp :130/90 mmhg(sitting posture)
•Bp:110/70mmhg (3min after standing)

Neurological examination :-
Higher mental function -normal
Reduced pressure sensation and proprioception in b/l lower limb below knee
Hypotonia of all four limbs
b/l foot drop was present
Power -3/5 b/l upperlimbs 2/5 across b/l hip joint and 0/5 b/l knee joint
B/l ankle and knee reflexes was absent
b/l plantar mute
Gait- high stepping gait
Romberg sign :-positive
 To summarise

Symmetrical ascending
Autonomic neuropathy
paralysis

Loss of DTR Prior history of

gastroenteritis
Follow up
• 4 days after admission she started having difficulty in lifting her hand
combing her hair .
• Her mother noticed her having change in voice and she started having
difficulty in swallowing after few days liquid more than solid.

• MRI brain and MRI spine done showed normal study

• NCS showed demyelination distal motor neuropathy
• CSF analysis showed :- Elevated or serial elevation of CSF protein.
CSF cell counts were <10 mononuclear cell/mm3.
GUILLIAN BARRE syndrome
• Guillain-Barré syndrome (GBS) is an acute, frequently severe, and
fulminant polyradiculoneuropathy that is autoimmune in nature.
Immunopathogenisis
• In AIDP, an early step in the induction of tissue damage appears to be
complement deposition along the outer surface of the Schwann cell.
• Activation of complement initiates a characteristic vesicular
disintegration of the myelin sheath, and also leads to recruitment of
activated macrophages, which participate in damage to myelin and
axons.
In AMAN, the pattern is different in that complement is
deposited along with IgG at the nodes of Ranvier along
large motor axons. Interestingly, in cases of AMAN
antibodies against GD1a appear to have a fine
specificity that favors binding to motor rather than
sensory nerve roots, even though this ganglioside is
expressed on both fiber types.
Pathophysiology
• In the demyelinating forms of GBS, the basis for flaccid paralysis and
sensory disturbance is conduction block.
• This finding, demonstrable electrophysiologically, implies that the
axonal connections remain intact.
• Hence, recovery can take place rapidly as remyelination occurs. In
severe cases of demyelinating GBS, secondary axonal degeneration
usually occurs; its extent can be estimated electrophysiologically.
• More secondary axonal degeneration correlates with a slower rate of
recovery and a greater degree of residual disability.
 Compliment
Anti GM1
mediated Disrupts the
GM1 on antibody as a
injury at cluster of Conduction Flaccid
nerves,node part of
paranodal sodium block paralysis
s of ranvier molecular
axon-glial channel
mimicry
junction
• When a severe primary axonal pattern is encountered
electrophysiologically, the implication is that axons have degenerated
and become disconnected from their targets, specifically the
neuromuscular junctions, and must therefore regenerate for recovery
to take place.
• In motor axonal cases in which recovery is rapid, the lesion is thought
to be localized to preterminal motor branches, allowing regeneration
and reinnervation to take place quickly
• Alternatively, in mild cases, collateral sprouting and reinnervation
from surviving motor axons near the neuromuscular junction may
begin to reestablish physiologic continuity with muscle cells over a
period of several months.
Clinical manifestation
• GBS manifests as a rapidly evolving areflexic motor paralysis with or
without sensory disturbance. The usual pattern is an ascending paralysis
that may be first noticed as rubbery legs.
• Weakness typically evolves over hours to a few days and is frequently
accompanied by tingling dysesthesias in the extremities. The legs are
usually more affected than the arms, and facial disparesis is present in
50% of affected individuals.
• The lower cranial nerves are also frequently involved, causing bulbar
weakness with difficulty handling secretions and maintaining an airway;
the diagnosis in these patients may initially be mistaken for brainstem
ischemia
• Fever and constitutional symptoms are absent at the onset and, if
present, cast doubt on the diagnosis.
• Deep tendon reflexes attenuate or disappear within the first few days
of onset.
• Sensory deficits (e.g., loss of pain and temperature sensation) are
usually relatively mild, but functions subserved by large sensory fi
bers, such as deep tendon reflexes and proprioception, are more
severely affected.
• Bladder dysfunction may occur in severe cases but is usually transient.
If bladder dysfunction is a prominent feature and comes early in the
course, diagnostic possibilities other than GBS should be considered,
particularly spinal cord disease
• Once clinical worsening stops and the patient reaches a plateau
(almost always within 4 weeks of onset), further progression is
unlikely. )
• Autonomic involvement is common and may occur even in patients
whose GBS is otherwise mild. The usual manifestations are loss of
vasomotor control with wide fluctuation in blood pressure, postural
hypotension, and cardiac dysrhythmias.
• Atypical presentations are very common indeed and include bilateral facial
weakness ,which is easily missed unless eye closure ,cheek blowing and lip
pouting are routinely tested.
• A descending version of the disorder,starting with facial weakness and then
involving the upperlimb.

• Ascending paralysis may be associated with cord inflammation ,producing a

coincidental transverse myelitis and this may mimic spinal cord compression.

• In some patients profound loss of posture sense may produce such severe
deafferentation of limbs that static tremor and ataxia may occur .This is
particularly likely in those cases with cranial nerve involvement and this has
been subclassified as fisher syndrome
Course of the disease
 Diagnosis
• Asbury Criteria for GBS
• Diagnostic criteria
(Assessment of current diagnostic criteria for Guillain-Barre syndrome)
Required features
• Progressive weakness in both arms and legs
• Areflexia (or hyporeflexia).
Features supportive of diagnosis
• Progression of symptoms over days to 4 weeks
• Relative symmetry
• Mild sensory signs or symptoms
• Cranial nerve involvement, especially bilateral facial weakness
• Recovery beginning 2 to 4 weeks after progression ceases
• Autonomic dysfunction
• Absence of fever at onset
• Typical CSF (albuminocytologic dissociation)
• EMG/nerve conduction studies (characteristic signs of a
demyelinating process in the peripheral nerves)
Features casting doubt on the diagnosis
• Asymmetrical weakness
• Persistent bladder and bowel dysfunction
• Bladder or bowel dysfunction at onset
• >50 mononuclear leukocytes/mm3 or presence of
polymorphonuclear leukocytes in CSF
• Distinct sensory level.
Features that rule out the diagnosis
• Hexacarbon abuse
• Abnormal porphyrin metabolism
• Recent diphtheria infection
• Lead intoxication
• Other similar conditions: poliomyelitis, botulism, hysterical
paralysis, toxic neuropathy.
Laboratory investigations
Treatment
• Either high-dose intravenous immune globulin (IVIg) or
plasmapheresis can be initiated, as they are equally effective for
typical GBS.
• Each day counts; ∼2 weeks after the first motor symptoms, it is not
known whether immunotherapy is still effective.
• Anecdotal data has also suggested that IVIg may be preferable to PE
for the AMAN and MFS variants of GBS.
• IVIg is administered as five daily infusions for a total dose of 2 g/kg
body weight. There is some evidence that GBS autoantibodies are
neutralized by anti-idiotypic antibodies present in IVIg preparations,
perhaps accounting for the therapeutic effect.

• A course of plasmapheresis usually consists of ∼40–50 mL/kg plasma

exchange (PE) four to five times over a week
• In the worsening phase of GBS, most patients require monitoring in a
critical care setting, with particular attention to vital capacity, heart
rhythm, blood pressure, nutrition, deep vein thrombosis prophylaxis,
cardiovascular status, early consideration (after 2 weeks of intubation)
of tracheotomy, and chest physiotherapy.
AIDP
Most common variant :85% of
cases
Primarily motor
Generally preceded by
bacterial or viral infection
Lymphocytic infiltration and
macrophage mediated
demyelination of nerves is
present
Symptoms usually improve
with remyelination
Maximum time of progression
4 weeks
GM1antibodies are positive in
80%
AMSAN
Patients are commonly adults
Motor sensory involvement
with severe course
Respiratory and bulbar
involvement
Primary axonal degeneration
Marked muscle wasting will be Hyperreflexia can be present
present
Poor recovery
AMAN
Patients are typically of
pediatric age group
Motor only
Early respiratory involvement
Primary axonal degeneration
Rapidly progressive,ensuing
respiratory failure,good
recovery
75% will be positive for
c.jejuni serology
Anti –GM1 antibody and Anti
GD1A antibody positive
Miller Fischer variant
Triad :ophthalmoplegia
,sensory ataxia,areflexia
Patient may have mild limb
weakness ,ptosis,,facial palsy
or bulbar palsy
Demyelination
Ataxia tends to be out of
proportion to sensory loss
Generally recovery within 1-
3months
96% positive for GQ1b
positive
Case 2
• Female 62 years of age presents with a progressive loss of sensation
that began in her toes and is progressively moving upwards. She first
noticed the symptoms when she suffered from multiple broken toes in
a short period of 2 years. Patient described the symptom as ‘not
feeling where her feet ended’ and as a consequence kept walking into
things and suffering from injuries to the toes on multiple occasions.
• The following is an excerpt of her symptoms in her own words:
• “My feet are completely numb. I can wiggle my toes by telling my brain
but I cannot feel them doing so. I can see that they are responding but I
have lost the sensation of this. My feet feel warm to touch but I am
mindful that I wear warm socks because I am worried that because I
cannot tell if my feet are cold or not. I first started noticing this about 2
years ago when I was in bed. Then I broke toe after toe (on both feet,
multiple toes). It was definitely worse on the left side to begin with but
now I would say that both feet are just as bad as the other. I have to be
very careful to check the bath water with my hands before I step into it
otherwise, I would scald my feet.”
• Past history :-she is known case of T2DM since past 10yrs on OHAs
• No relevant personal of family history was present.

• General examination was normal.

Neurological examination
Higher mental function -normal
Reduced pressure sensation and proprioception in b/l lower limb below
knee
Temperature sensation was also lost
b/l foot drop was present
Power -5/5 in b/l UL and LL
B/l ankle and knee reflexes was absent
b/l plantar mute
Gait- high stepping gait
Investigation
• CBC-WNL
• ESR-120
• LFT-reversed albumin globulin ratio
• RFT-slightly deranged Case 3
• Urine RE-showed proteinuria

• MRI spine was normal

• Nerve conduction study showed slow nerve conduction with f wave
latencies was present in 2 nerve
• Csf examination showed albuminocytogenic dissociation

• Peripheral nerve biopsy done showed perivascular and interstial

infiltration of endoneurium
• Evidence of segmental demyelination and remyelination with onion
bulb formation was present.
Onion bulb formation in chronic
demyelination
Diagnosis ??
CHRONIC INFLAMMATORY
DEMYELINATING POLYNEUROPATHY
• CIDP is distinguished from GBS by its chronic course. In other
respects, this neuropathy shares many features with the common
demyelinating form of GBS, including elevated CSF protein levels.
Pathogenesis
• Although there is evidence of immune activation in CIDP, the precise
mechanisms of pathogenesis are unknown.
• Biopsy typically reveals little inflammation and onion-bulb changes
(imbricated layers of attenuated Schwann cell processes surrounding
an axon) that result from recurrent demyelination and remyelination.
• The response to therapy suggests that CIDP is immune-mediated;
CIDP responds to glucocorticoids, whereas GBS does not. Passive
transfer of demyelination into experimental animals has been
accomplished using IgG purified from the serum of some patients
with CIDP, lending support for a humoral autoimmune pathogenesis.
Clinical manifestations
• Onset is usually gradual over a few months or longer, but in a few
cases the initial attack is indistinguishable from that of GBS.
• An acute-onset form of CIDP should be considered when GBS
deteriorates >9 weeks after onset or relapses at least three times.
• Symptoms are both motor and sensory in most cases.
• some patients experience a chronic progressive course, whereas
others, usually younger patients, have a relapsing and remitting
course.
• Some have only motor findings, and a small proportion present with a
relatively pure syndrome of sensory ataxia.
• Tremor occurs in ∼10% and may become more prominent during
periods of subacute worsening or improvement.
• A small proportion have cranial nerve findings, including external
ophthalmoplegia.
Diagnosis
• The CSF is usually acellular with an elevated protein level, sometimes
several times normal.
• NCS findings reveal variable degrees of conduction slowing, prolonged
distal latencies and conduction block as the principal feature.
• Evidence of axonal loss, presumably secondary to demyelination, is
present in >50% of patients
• Serum protein electrophoresis with immunofixation is indicated to
search for monoclonal gammopathy and associated conditions
• If the disorder is mild, management can be expectant, awaiting
spontaneous remission.
• Initial therapy is usually with IVIg, administered as 2.0 g/kg body weight
given in divided doses over 2–5 days; three monthly courses are
generally recommended before concluding a patient is a treatment
failure
• If the patient responds, the infusion intervals can be gradually increased
or the dosage decreased (e.g., 1 g/kg per month). PE, which appears to
be as effective as IVIg, is initiated at two to three treatments per week
for 6 weeks; periodic re-treatment may also be required
• Treatment with glucocorticoids is another option (60–80 mg
prednisone PO daily for 1–2 months, followed by a gradual dose
reduction of 10 mg per month as tolerated), but long-term adverse
effects including bone demineralization, gastrointestinal bleeding, and
cushingoid changes are problematic.
Lewis summner Syndrome

• It is a clinical asymmetrical variant of chronic immune demyelinating

polyneuropathy (CIDP).
• LSS is five times less frequent than CIDP whose prevalence is between
2 and 7/ 100,000.
• Patients with LSS usually present with an asymmetrical involvement of
the upper limb with distal sensorimotor deficit in median or ulnar
territories.
• A purely sensory onset with numbness and paresthesia or pain in
median or ulnar territory is observed 30% of cases. A lower limb
onset is present in 30% of patients with a distal and asymmetrical
sensorimotor deficit.
• Amyotrophy and cranial nerve involvement may be observed in 50%
and 20% of patients, respectively. LSS could mimick a nerve
entrapment or a vasculitis.
• Contrarily to CIDP, other conduction anomalies (reduction of truncal
motor nerve velocities, prolonged distal latencies or prolonged F
waves) occur rarely outside the blocked nerve territory.

• The course is progressive or remitting. Electrophysiological pattern

associates a multifocal motor demyelination with conduction blocks
mostly situated in the forearm.
• Sensory conduction shows a multifocal sensory involvement. Sural
nerve biopsy in LSS show elements consistent with a primary
demyelination, indistinguishable from that seen in typical CIDP.

• However nerve biopsy is not necessary to establish the diagnosis.

Serum anti-GM1 antibodies are negative and CSF protein content is
usually normal or mildly elevated with a mean value of 0.7 g/l.
• LSS is characterized by a responsiveness to IVIg and steroids. For LSS
patients, a treatment similar to that of CIDP, with a first line treatment
with intravenous Ig (IVIg) (2g/kg/course), is recommended.

• Patients who do not respond after 2 or 3 courses should be switched

to prednisone; a dose of 1mg/kg/day should be maintained for 4-6
weeks, then slowly tapered.
Variants of CIDP
MULTIFOCAL MOTOR NEUROPATHY
• Multifocal motor neuropathy (MMN) is a distinctive but uncommon
neuropathy that presents as slowly progressive motor weakness and atrophy
evolving over years in the distribution of selected nerve trunks, associated
with sites of persistent focal motor conduction block in the same nerve trunk

• Sensory fibers are relatively spared. The arms are affected more frequently
than the legs, and >75% of all patients are male.

• Some cases have been confused with lower motor neuron forms of
amyotrophic lateral sclerosis
• Less than 50% of patients present with high titers of polyclonal IgM
antibody to the ganglioside GM1.
• Pathology reveals demyelination and mild inflammatory changes at
the sites of conduction block.
• Most patients with MMN respond to high-dose IVIg (dosages as for
CIDP, discussed earlier); periodic re-treatment is required (usually at
least monthly) to maintain the benefit.
• Some refractory patients have responded to rituximab or
cyclophosphamide. Glucocorticoids and PE are not effective.
Case 2? 3
• A 45-year-old man with epilepsy and immunoglobulin G (IgG) κ multiple
myeloma (MM) diagnosed a year ago presented to the neurology clinic
with right hand weakness and paresthesias, painless proximal left arm
weakness, and paresthesias in the right foot.

• Symptoms began acutely over a 2-week period in the setting of a

diffuse nonpruritic rash.
• The patient had undergone an allogenic hematopoietic stem cell
transplant (HSCT) a month prior due to suboptimal response to
bortezomib, cyclophosphamide, etoposide, cisplatin, carfilzomib, and
autologous stem cell transplant.

• He denied headaches, neck pain, radicular symptoms, bladder or

bowel dysfunction, or gait imbalance.
• Examination revealed normal vital signs, mental status, and cranial
nerves. A maculopapular rash was seen over the trunk and
extremities, without a dermatomal pattern.
• Motor examination revealed normal tone and strength except for
profound weakness (2/5) in the muscles innervated by the left C5-6
myotomes and weakness ( 4/5) in the muscles innervated by the right
ulnar nerve.
• Reflexes were 1+ throughout except for absent left biceps and
brachioradialis. Plantar reflexes were flexor.

• Pinprick was diminished in the right fourth and fifth digits, and lateral
aspect of the right foot. The rest of his neurologic examination was
unremarkable.
Neuropathies with monoclonal
gammopathies
• Clinically overt polyneuropathy occurs in ∼5% of patients with the commonly
encountered type of multiple myeloma, which exhibits either lytic or diffuse
osteoporotic bone lesions

• These neuropathies are sensorimotor, are usually mild and slowly progressive
but may be severe, and generally do not reverse with successful suppression
of the myeloma

• In contrast, myeloma with osteosclerotic features, although representing only

3% of all myelomas, is associated with polyneuropathy in one-half of case
• These neuropathies, which may also occur with solitary
plasmacytoma, are distinct because they:

• (1) are usually demyelinating in nature and resemble CIDP

• (2) often respond to radiation therapy or removal of the primary lesion

• (3) are associated with different monoclonal proteins and light chains
(almost always lambda as opposed to primarily kappa in the lytic type of
multiple myeloma)

• (4) are typically refractory to standard treatments of CIDP

• (5) may occur in association with other systemic findings including
thickening of the skin, hyperpigmentation, hypertrichosis,
organomegaly, endocrinopathy, anasarca, and clubbing of fingers.
These are features of the POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, M protein, and skin changes)
• Levels of vascular endothelial growth factor (VEGF) are increased in
the serum, and this factor is felt to somehow play a pathogenic role in
this syndrome.
• Treatment of the neuropathy is best directed at the osteosclerotic
myeloma using surgery, radiotherapy, chemotherapy, or autologous
peripheral blood stem cell transplantation.
VASCULITIC NEUROPATHY
• Peripheral nerve involvement is common in polyarteritis nodosa
(PAN), appearing in half of all cases clinically and in 100% of cases at
postmortem studies.
• The most common pattern is multifocal (asymmetric) motor-sensory
neuropathy (mononeuropathy multiplex)due to ischemic lesions .
• Symptoms of neuropathy are a common presenting complaint in
patients with PAN.
• The nerve biopsy findings are those of an axonal process. Small- to
medium-sized arteries of the vasa nervorum, particularly the
epineural vessels, are affected in PAN, resulting in a widespread
ischemic neuropathy.
• Systemic vasculitis should always be considered when a subacute or
chronically evolving mononeuropathy multiplex occurs in conjunction
with constitutional symptoms (fever, anorexia, weight loss, loss of
energy, malaise, and nonspecific pains).

• Diagnosis of suspected vasculitic neuropathy is made by a combined

nerve and muscle biopsy, with serial section or skip-serial techniques.
• Vasculitic neuropathy may also be seen as part of the vasculitis
syndrome occurring in the course of other connective tissue
disorders.
Management
• Treatment of the underlying condition as well as the aggressive use of
glucocorticoids and other immunosuppressant drugs.
• Use of these regimens has resulted in dramatic improvements in
outcome, with 5-year survival rates now greater than 80%.
• One reasonable starting regimen is daily prednisone (initial dose 1
mg/kg per day PO with a gradual taper after 1 month) plus IV pulse
(or daily oral) cyclophosphamide for 3–6 months.
ANTI-HU PARANEOPLASTIC
NEUROPATHY
• This uncommon immune-mediated disorder manifests as a sensory
neuronopathy (i.e., selective damage to sensory nerve bodies in
dorsal root ganglia).

• The onset is often asymmetric with dysesthesias and sensory loss in

the limbs that soon progress to affect all limbs, the torso, and face.
• Marked sensory ataxia, pseudoathetosis, and inability to walk, stand, or
even sit unsupported are frequent features and are secondary to the
extensive deafferentation.

• Subacute sensory neuronopathy may be idiopathic, but more than half

of cases are paraneoplastic, primarily related to lung cancer, and most
of those are small cell lung cancer (SCLC).

• The target antigens are a family of RNA-binding proteins (HuD, HuC,

and Hel-N1) that in normal tissues are only expressed by neurons.
• The same proteins are usually expressed by SCLC, triggering in some
patients an immune response characterized by antibodies and
cytotoxic T cells that cross-react with the Hu proteins of the dorsal
root ganglion neurons, resulting in immune-mediated neuronal
destruction.
• An encephalomyelitis may accompany the sensory neuronopathy and
presumably has the same pathogenesis.

• Neurologic symptoms usually precede, by ≤6 months, the identification of SCLC.

• The sensory neuronopathy runs its course in a few weeks or months and
stabilizes, leaving the patient disabled.

• Most cases are unresponsive to treatment with glucocorticoids, IVIg, PE, or

immunosuppressant drugs.
Some common paraneoplastic syndromes
with neurological manifestations
Thank you