Inflammatory Neuropathies based on case questions

1. INFLAMMATORY NEUROPATHIES
Ezgi Deniz Arikan

2. INFLAMMATORY NEUROPATHIES
 A group of immune-mediated disorders affecting the
peripheral nervous system in which leukocytes actively
participate in axonal degeneration, demyelination or both,
with resultant motor and sensory deficits.
 Inflammatory neuropathies can be caused by
autoimmunity, infections or vasculitis.

3. INFLAMMATORY NEUROPATHIES
 Guillain-Barre syndrome (GBS)
 Chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP)
 Multifocal motor neuropathy (MMN)
 Paraneoplastic neuropathy
 Infections (leprosy, diphtheria, HIV, Lyme borreliosis,
poliomyelitis, herpes zoster)
 Vasculitis (CSS, PAN)

4. CASE 1.
A NEW YEAR’S EVE TO REMEMBER
 65-year-old librarian
 History of hypertension
 Conjunctivitis with ocular erythema and discharge
one week before New Year’s eve
 Symptoms resolved with antibiotic eye drops

5. CASE 1.
A NEW YEAR’S EVE TO REMEMBER
 Bilateral hand clumsiness resulting in difficulty typing - on
New Year’s eve
 Gait deteriorated significantly – one day
 Admitted to a community hospital
 Developed progressive dyspnea requiring intubation

6. CASE 1.
A NEW YEAR’S EVE TO REMEMBER
 Cerebrospinalfluid (CSF):
 protein, glucose, leukocyte counts, Gram stain,
culture normal
 1.5 g/kg of intravenous immune globulins (IVIg)
divided over 3 days for presumed GBS before
transfer to a tertiary care hospital.
 MRI of the spine  nerve root enhancement and
enlargement

7. CASE 1.
A NEW YEAR’S EVE TO REMEMBER

8. CASE 1.
A NEW YEAR’S EVE TO REMEMBER
 Nerve conduction studies: absent F responses
 This can be an isolated finding in early GBS, it
could also be explained by the sedation given in the
intensive care unit and the patient’s asleep state.
 Most aspects of this patient’s history and
presentation are consistent with GBS.

9. CLINICAL QUESTIONS
 What feature is atypical for GBS?
A. Upper respiratory and gastrointestinal infections
typically precede GBS rather than conjunctivitis.
B. The normal CSF protein level (ie, lack of
cytoalbuminologic dissociation).
C. Her rapid decline resulting in respiratory failure.

10. CLINICAL QUESTIONS
 In general, which of the following diagnostic studies
argues against a diagnosis of GBS?
A. Cytoalbuminologic dissociation on CSF analysis
B. Enlarged, enhancing nerve roots on MRI studies of the
spine
C. Positive CSF cytology
D. Prolonged or absent F waves and H reflexes on
electrodiagnostic studies

11. CLINICAL QUESTIONS
 All the following are appropriate next steps in
management except:
A. Admission to the intensive care unit for monitoring and
respiratory support
B. Close monitoring for development of dysautonomia
C. Administration of an additional 0.5 g/kg of IVIg
D. Initiation of plasma exchange

12. GBS
 autoimmune, acute-onset demyelinating polyradiculoneuropathy
 rapidly evolving symmetrical limb weakness,
 the loss of tendon reflexes,
 absent or mild sensory signs,
 variable autonomic dysfunction
 1-2 cases per 100.000

13. GBS
 The most frequent pattern in Europe
 acute inf. demyelinating polyradiculoneuropathy (AIDP).
 More common in other parts of the world, such as China,
are the axonal patterns.
 acute motor axonal neuropathy (AMAN)
 acute motor-sensory axonal neuropathy (AMSAN)

14. GBS
 C. jejuni
 CMV
 EBV
 M. pneumoniae
 Hepatitis E virus
 Zikavirus
 2009 H1N1 influenza vaccine
 Coronavirus

15.  antigens in the LPS of C. jejuni  production of
crossreactive antibodies against gangliosides in the
myelin sheath or axolemma

16.  CSF: cytoalbuminologic dissociation (elevated
protein and with a normal cell count).
 The CSF protein is normal in one-half in the first
week and elevated in up to 88% at 2 weeks after
symptom onset
 Pleocytosis  malignant or infectious process
(human immunodeficiency virus, Lyme,
cytomegalovirus) or sarcoidosis?

17. EMG
 The electrodiagnostic hallmarks may take days or
even weeks to develop.
 The earliest features:
 Prolonged and absent H reflexes and F waves
 Normal sural sensory amplitude
 Reduced median sensory amplitude

18. EMG
 With time, other electrodiagnostic features of primary
demyelination become apparent:
 partial motor conduction block,
 temporal dispersion,
 nonuniform slowing of motor conduction velocities

19. IMAGING
 MRI of the spine:
 hypertrophic, contrast-enhancing nerve roots
 When anterior spinal roots are solely involved, GBS
should strongly be considered.
 USG: enlargement of nerve roots and peripheral
nerves

20. TREATMENT
 Frequent measurement of forced vital capacity and
maximal expiratory and inspiratory pressures
 Close monitorisation of autonomic function with
particular vigilance for cardiac arrhythmias, urinary
retention, and constipation.
 2 first-line treatments for GBS, IVIg and plasma
exchange are equally efficacious.
 Either should be started immediately in patients with
clinically defined GBS, even in the setting of normal
electrodiagnostic studies and CSF analysis

21. TREATMENT
 The standard dosing for IVIg is 2 g/kg divided over 2 to 5
days.
 Alternatively, 4 to 6 plasma exchanges on alternate days
may be used.
 Caution must be used with plasma exchange owing to
the risk of hypotension in someone with autonomic
dysfunction.
 The usefulness of either is not proven after 2 months of
onset if there is a lack of improvement.

22. TREATMENT
 Physical therapy, occupational therapy, and
neurorehabilitation are imperative.
 Patients should be queried regarding neuropathic pain,
and appropriate therapy instituted.

23. TREATMENT
 Treatment-related fluctuations occur in about 10% of
patients within the first 2 months.
 It is recommended to treat the patient with IVIg or
plasma exchange, whichever treatment they responded
to initially.
 Clinical deterioration beyond the first 2 months should
raise the possibility of acute-onset chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP).

24. CASE 2.
 47-year-old man
 History of juvenile rheumatoid arthritis
 One week of blurry vision
 intermittent diplopia
 gait instability
 He had a sinus infection treated with antibiotics 1
week before the onset of neurologic symptoms.

25. CASE 2.
 He denied any dysarthria, dysphagia, dyspnea, or
generalized weakness.
 He reported patchy sensory changes that were
resolving.
 Examination: complete ophthalmoplegia, areflexia,
and impaired tandem gait.

26. CASE 2.
 Brain MRI and CSF analysis were normal.
 Electrodiagnostic studies were normal apart from
reduced recruitment of the right frontalis muscle.

27. CLINICAL QUESTIONS
 Which of the following would be in your differential
diagnosis?
A. Wernicke’s encephalopathy
B. Miller-Fisher syndrome
C. Parinaud’s syndrome
D. Myasthenia gravis

28. CLINICAL QUESTIONS
 Which of the following laboratory studies would support a
diagnosis of Miller-Fisher syndrome?
A. Anti-GM1 antibodies
B. Anti-MAG antibodies
C. Anti-GQ1b antibodies
D. Antineurofascin antibodies

29. CLINICAL QUESTIONS
 Which of the following laboratory studies would support a
diagnosis of Miller-Fisher syndrome?
A. Anti-GM1 antibodies
B. Anti-MAG antibodies
C. Anti-GQ1b antibodies
D. Antineurofascin antibodies
Anti-GQ1b titer:
Positive at a titer of 1:1600 (normal <1:100).

30. MILLER-FISHER SYNDROME
 GBS variant
 ophthalmoplegia,
 ataxia,
 Areflexia
 other cranial neuropathies,
 dysesthesia,
 micturition problems

31. MILLER-FISHER SYNDROME
 Comprises 5% to 10% of GBS cases in Western countries and a higher
proportion in Asia.
 It often follows C jejuni or Haemophilus influenzae infection
 Anti-GQ1b ganglioside antibodies react with C jejuni surface epitopes
supporting molecular mimicry between nerve and bacteria.
 Electrodiagnostic studies may demonstrate sensory predominant
axonopathy

32. MILLER-FISHER SYNDROME
 The prognosis is generally good, regardless of whether IVIg or plasma
exchange is given.
 Many experts do not treat patients with classic Miller- Fisher syndrome
 Although patients with progressive weakness and ophthalmoplegia
(“ophthalmoplegic GBS”) should be treated.

34. CASE 3.
 61-year-old man with type 2 diabetes
 4 months of progressive muscle weakness
 Affected his arms and legs symmetrically, both
proximally and distally
 He went from walking independently, to using a
cane, then a walker, and ultimately became
wheelchair bound.

35. CASE 3.
 The progressive finger and hand weakness resulted
in trouble with activities of daily living.
 He reported mild numbness in the feet, but no
paresthesia or neuropathic pain.
 He denied bowel, bladder, or bulbar dysfunction.

36. CASE 3.
 On examination the patient had symmetric weakness of
his proximal and distal lower extremities. (4/5
throughout, exc. dorsiflexion 3/5)
 Pinprick sensation was decreased to the level of the
knees and hands.
 Vibratory sensation was absent to the level of the ankles
and normal in the fingers.
 He was areflexic.

37. CLINICAL QUESTIONS
 Which of the following clinical features would support a
diagnosis of CIDP?
A. Autonomic dysfunction
B. Symmetric proximal and distal weakness
C. Respiratory impairment
D. Dysphagia

38. CLINICAL QUESTIONS
 What would be the highest yield diagnostic study at this
point?
A. CSF analysis
B. Nerve conduction studies and electromyography
C. Voltage-gated calcium channel antibodies
D. MRI of the brain

39. CLINICAL QUESTIONS
 What would be the highest yield diagnostic study at this
point?
A. CSF analysis
B. Nerve conduction studies and electromyography
C. Voltage-gated calcium channel antibodies
D. MRI of the brain
 On nerve conduction studies, there were no elicitable
sensory responses. The motor nerve conduction studies
illustrated in Table.

41. Fig. 1. Conduction block is represented in the left median–abductor
pollicis brevis compound muscle action potential waveforms.

42. CLINICAL QUESTIONS
 Unlike GBS, CIDP is often managed with which
treatment?
A. Plasma exchange
B. IVIg
C. Prednisone or other corticosteroid
D. Rituximab

43. CIDP
 CIDP is the most common, chronic autoimmune polyneuropathy.
 The estimated incidence: 0.33 per 100,000
 Prevalence: 2.81 per 100,000
 Both cellular and humoral mechanisms are involved.

44. CLINICAL PRESENTATION
 CIDP is an acquired demyelinating polyradiculoneuropathy that primarily
involves large diameter myelinated nerve fibers resulting in weakness,
loss of sensation, and sensory ataxia.
 One-half of patients have typical CIDP, which is characterized by
symmetric, proximal, and distal generalized weakness; distal large fiber
sensory impairment; and areflexia.
 A postural tremor may accompany the typical features of CIDP and is
often treatment refractory.

45. CLINICAL PRESENTATION
 In contrast with GBS, CIDP usually spares the cranial nerves, respiratory
muscles, and autonomic function.
 Patients reach clinical nadir more than 2 months after symptom onset.
 The disease course may be monophasic, relapsing remitting, or
progressive.

46. DIAGNOSTIC APPROACH
 Electrodiagnostic testing is mandatory in patient with suspected CIDP.
Classic features include:
 Prolonged distal motor and peak sensory latencies
 Slowing of motor conduction velocity that varies between nerves
(nonuniform slowing)
 Prolonged minimal F-wave latencies
 Partial motor conduction block and abnormal temporal dispersion
 A sural-sparing pattern (similar to GBS)

47. DIAGNOSTIC APPROACH
 Certain laboratory studies are necessary, including:
 Serum electrophoresis,
 immunofixation,
 free light chains
 glycosylated hemoglobin,
 liver, renal, thyroid function studies,
 vitamin B12 level

48. DIAGNOSTIC APPROACH
 CSF analysis is not required for all cases of CIDP, but when collected also
classically demonstrates cytoalbuminologic dissociation.
 MRI may demonstrate contrast enhancing, hypertrophied nerve roots,
plexuses, and proximal peripheral nerves.
 There are more than 15 electrodiagnostic criteria published for CIDP.
 The European Federation of Neurologic Societies/Peripheral Nerve
Society criteria are recommended, given their well-balanced sensitivity
and specificity and high diagnostic accuracy.

49. TREATMENT APPROACH
 There are 3 first-line treatments for CIDP:
 IVIg,
 subcutaneous immune globulins,
 corticosteroids.
 Plasma exchange is considered second line given the logistical
challenges of administering it chronically in the outpatient setting.

50. TREATMENT APPROACH
 IVIg is typically administered at a 2 g/kg dose divided over 2 to 5 days,
followed by every 3 to 4 week doses of approximately 1 g/kg.
 The dose and frequency should constantly be assessed and adjusted
depending on treatment response.
 Subcutaneous immune globulins
 0.4 g/kg/wk for 5 weeks
 maintenance dose: either 0.2 or 0.4 g/kg weekly
 Corticosteroids are options for induction therapy.
 (prednisone at a daily dose of 1–1.5 g/kg, high-dose dexamethasone 40
mg/d for 4 days every 4 weeks, or IV methylprednisolone weekly)

51. TREATMENT APPROACH
 Plasma exchange is considered in refractory disease with 5 to 10
exchanges over 2 to 4 weeks followed by 1 to 2 sessions every 3 to 4
weeks.
 Steroid-sparing agents such as mycophenolate mofetil and azathioprine
are often used to facilitate tapering of corticosteroids.
 In patients refractory to these approaches, pulse intravenous
cyclophosphamide 1 g/m2 monthly for 6 months may be effective.
 The dose should be assessed and appropriately modified based on nadir
white blood cell counts.

52. TREATMENT APPROACH
 The overall likelihood of improvement on one of these first-line CIDP
treatments is approximately 70%.
 This likelihood increases to approximately 80% when patients are
included who switch to a different first-line therapy.

53. CASE 4.
A 68-YEAR-OLD WITH LEFT HAND WEAKNESS
 The patient presented with left hand weakness
upon waking up in the morning.
 Months later, she realized she has difficulty
pressing the gas pedal or the brakes completely
with her right foot.
 On examination, she had a left finger and wrist drop
as well as right foot drop

54. Fig. 2. Left wrist and finger drop.

55. CASE 3.
 Electrodiagnostic studies:
 conduction blocks of multiple motor nerves at
noncompressive sites suggesting a diagnosis of
multifocal motor neuropathy (MMN)

56. CLINICAL QUESTIONS
 Which of the following autoantibodies is present in
approximately 50% of MMN patients?
A. Anti-GQ1b antibodies
B. Anti-GD1a antibodies
C. Anti-MAG antibodies
D. Anti-GM-1 antibodies

57. CLINICAL QUESTIONS
 Which of the following treatments, which is effective for
CIDP, may worsen MMN?
A. Corticosteroids
B. Plasma exchange
C. IVIg
D. Rituximab

58. DISCUSSION
 MMN is an acquired neuropathy that affects individual
motor nerves.
 Males are affected more than females at a ratio of
2.7:1.34
 Nerve conduction studies demonstrate multiple areas of
partial motor conduction block in 60% of patients.
 Evolving evidence suggests GM1 antibodies impair
function at the node of Ranvier, calling into question
whether MMN is truly a demyelinating neuropathy or a
nodopathy.

59. CLINICAL PRESENTATION
 The initial site of onset is the distal upper extremity in the majority of
patients, with one-third first experiencing foot drop.
 Cramps and fasciculations may occur.
 Cold often exacerbates symptoms.
 Sensory signs and symptoms should not exist.

60. CLINICAL PRESENTATION
 MMN is considered in the differential diagnosis for motor neuron diseases
owing to its painless, progressive weakness.
 MMN has weakness affecting individual peripheral nerves, whereas
amyotrophic lateral sclerosis has weakness in a myotomal pattern.
 Amyotrophic lateral sclerosis is associated with upper motor neuron signs,
whereas MMN is a pure lower motor neuron syndrome.

61. DIAGNOSTIC APPROACH
 Electrophysiologic studies, which confirm the clinical diagnosis,
demonstrate conduction block at nonentrapment sites.
 The ulnar and median nerves are most commonly affected.
 Anti-GM1 antibodies are present in approximately 50%, and may be
monoclonal.
 MRI may demonstrate enlargement and enhancement of the roots,
plexuses, and peripheral nerves.
 Ultrasound examination similarly may demonstrate multifocal nerve
enlargement.

62. TREATMENT APPROACH
 IVIg is clearly the first choice treatment for MMN.
 Subcutaneous immune globulins is also likely beneficial.
 Cyclophosphamide and rituximab are considered only in the setting of
treatment refractory disease.
 Corticosteroids are ineffective and have been reported to worsen disease.

63. CASE 5.
THE 40-YEAR-OLD WITH RELENTLESSLY
PROGRESSIVE WEAKNESS
 A 40-year-old man presented as a second opinion for
CIDP.
 He developed numbness of the soles of his feet acutely
approximately 6 months before presentation.
 Over the following 2 months, the numbness ascended his
legs and into his hands, followed by progressive
weakness, resulting in a steppage gait.
 His initial electrodiagnostic studies demonstrated a
demyelinating neuropathy and he was started on IVIg.

64. CLINICAL QUESTIONS
 Which of the following clinical features would support a
diagnosis of CIDP?
A. Autonomic dysfunction
B. Symmetric proximal and distal weakness
C. Respiratory impairment
D. Dysphagia

65. CIDP
 CIDP is the most common, chronic autoimmune polyneuropathy.
 The estimated incidence: 0.33 per 100,000
 Prevalence: 2.81 per 100,000
 Both cellular and humoral mechanisms are involved.

66. CLINICAL PRESENTATION
 CIDP is an acquired demyelinating polyradiculoneuropathy that primarily
involves large diameter myelinated nerve fibers resulting in weakness,
loss of sensation, and sensory ataxia.
 One-half of patients have typical CIDP, which is characterized by
symmetric, proximal, and distal generalized weakness; distal large fiber
sensory impairment; and areflexia.
 A postural tremor may accompany the typical features of CIDP and is
often treatment refractory.

67. DIAGNOSTIC APPROACH
 Electrodiagnostic testing is mandatory in patient with suspected CIDP.
Classic features include:
 Prolonged distal motor and peak sensory latencies
 Slowing of motor conduction velocity that varies between nerves
(nonuniform slowing)
 Prolonged minimal F-wave latencies
 Partial motor conduction block and abnormal temporal dispersion
 A sural-sparing pattern (similar to GBS)

68. TREATMENT APPROACH
 There are 3 first-line treatments for CIDP:
 IVIg,
 subcutaneous immune globulins,
 corticosteroids.
 Plasma exchange is considered second line given the logistical
challenges of administering it chronically in the outpatient setting.