Peripheral Neuropathies

Peripheral Neuropathies
Common disorder
Prevalence of non-traumatic peripheral
neuropathies
2.4% in general population
15% over the age of 40

Peripheral Neuropathies

Motor neuron disorders

Radiculopathies
Plexopathies
Single and Multiple Mononeuropathies
Symmetric Polyneuropathies
Motor Neuropathies
Sensory Ganglionopathies

Symptoms

Positive and negative phenomena

Sensory symptoms early
Typically symmetric in onset
Weakness later
Distal symptoms predominant
Worse at night
Other Symptoms-Imbalance, Fatigue, Falls

Early Signs
Distal sensory loss:
Large Fibers
loss of vibration before proprioception
decreased ankle reflexes
Small fibers
Loss of pinprick and temperature

Stocking-glove distribution

Early Signs
Distal weakness
Toe extensors
Foot dorsiflexors
Finger extensors

Common Causes
Diabetes
Leprosy
Vitamin B12 deficiency

Approach
Acute vs. chronic onset
Acute fulminant and live threatening

Axonal vs. demyelinating

Demyelinating forms respond well to
immunotherapy

Acute Polyneuropathies
Guillain-Barre Syndrome or Acute
Inflammatory Demyelinating
Polyradiculoneuropathy
Porphyria
Toxic (arsenic and thallium)

Chronic Polyneuropathies
Inherited (CMT, HMSN, HNPP)
Family History
Foot Deformities
Foot Ulcers

Acquired
MINI

Acquired Polyneuropathy
MINI
Metabolic
Immune
Neoplastic
Infectious

Metabolic Causes

Diabetes
Uremia
Alcohol abuse
Hypothyroid
Vitamin B1 or B12 deficiency
Vitamin B6 toxicity
Medications/chemotherapy

Immune Causes
Vasculitis
Non-vasculitic
CIDP
MMN
Sarcoid
Sjogrens

Infectious Causes

Leprosy
Hepatitis C
Lyme
HIV
West Nile
Syphilis
Diptheria

Neoplastic Causes
Paraneoplastic(Poems syndrome)
Paraproteinemic

MGUS
Monoclonal gammopathy of unclear significance
Prevalence:
3% of persons >50 years
5% >70 years
1% per year risk of progression to multiple myeloma
(MM) or a related disorder

Autonomic Symptoms

Lightheadedness or dizziness
Blurred vision
Dry eyes, dry mouth
Cold feet
Early satiety, constipation, diarrhea
Urinary retention, incontinence
Erectile Dysfunction
Hypohidrosis

Dysautonomias

Diabetes
Amyloidosis (acquired and inherited)
Paraneoplastic
Inherited (HSAN)
Sjogrens Neuropathy
Porphyria

Differential Diagnosis

Small fiber neuropathy

Plantar fasciitis
Osteoarthritis
Vascular insufficiency
Cervical myelopathy
Lumbosacral radiculopathy

Electromyography (EMG)
Two part test:
Nerve conduction studies
Needle electromyography
Establish diagnosis of polyneuropathy
Distinguish demyelinating from axonal
Differentiate radiculopathy, plexopathy
Normal in small fiber and autonomic neuropathy

POEMS SYNDROME
POEMS syndrome, also known as
osteosclerotic myeloma, Takatsuki
syndrome,and Crow-Fukase syndrome,
is a rare paraneoplastic syndrome
resulting from an underlying plasma
cell disorder. There acronym POEMS
refers to several, but not all, of the
features of the syndrome:
polyradiculoneuropathy,
organomegaly, endocrinopathy,
monoclonal plasma cell disorder, and
skin changes.

Generaly

Epidemiology
Male (60% to 70%) > Female

Geography
High incidence in Japanese &
Asian males.
Frequency in Japan: 0.3 per
100,000

Onset age: Mean 51

years; younger than myeloma

Progression
Usual: Over months to years
Some patients: Acute or
Subacute

Addition of new
features over time
-Frequency: 18%
-More common with urine
M-protein.

Eventual severe

THE PATHOGENESIS of the syndrome is not

well understood. To date, VEGF is the
cytokine that correlates best with disease
activity, although it may not be the driving
force of the disease based on the mixed
results seen with anti-VEGF therapy. VEGF,
which is expressed by osteoblasts,
macrophages, tumor cells(including plasma
cells),and megakaryocytes/platelets,is
known to target endothelial cells, induce a
rapid and reversible increase in vascular
permeability, and be important in
angiogenesis. Both IL-1 and IL-6 have been
shown to stimulate VEGF production.

DIAGNOSTIC CRIETERIA

In the Mayo Clinic series of 99 patients, the

following features were present :
Polyneuropathy 100 percent
Monoclonal plasma cell disorder 100 percent
Increased cerebrospinal fluid protein (>50 mg/dL) 100
percent
Osteosclerotic bone lesions 97 percent
Skin changes 68 percent
Endocrinopathy 67 percent
Organomegaly (hepatomegaly, splenomegaly,
lymphadenopathy) 50 percent
Weight loss (>10 pounds) 37 percent

Peripheral neuropathy
Symptoms usually begin in the feet and consist of tingling, paresthesias, and
feelings of coldness. Motor involvement follows the sensory symptoms. Both
are distal, symmetric, and progressive, with a gradual proximal spread. Severe
weakness occurs in more than half of patients and results in an inability to
climb stairs, rise from a chair, or grip objects firmly with the hands, consistent
with a predominantly motor chronic inflammatory demyelinating
polyneuropathy. The course is progressive and patients may be confined to a
wheelchair. Autonomic symptoms are not a feature.
Physical examination reveals a symmetric sensorimotor neuropathy
involving the extremities. Muscle weakness is more marked than sensory loss.
Touch, pressure, vibratory, and joint position senses are often involved. Less
frequently, loss of temperature discrimination and nociception occur. Cranial
nerves are not affected.
Electromyographic studies show slowing of nerve conduction, prolonged
distal latencies, and severe attenuation of compound muscle action
potentials . Conduction block is rarely found , but slowing of motor conduction
is proportionately greater than the reduction in the compound muscle action
potential amplitude. Distal fibrillation potentials are found on needle
electromyography.
Biopsy of the sural nerve usually shows both axonal degeneration and
demyelination; severe endoneurial edema may also be seen, along with high
expression of VEGF in vasa nervorum and some non-myelin-forming Schwann
cells .Endoneurial deposits of immunoglobulins of the same type as in the
serum have been reported in three of four patients with POEMS syndrome .

DIFFERENTIAL DIAGNOSIS
- Multiple myeloma- Polyneuropathy is uncommon in classical
multiple myeloma, and when present is usually due to the presence
of amyloidosis. Features suggestive of multiple myeloma include the
presence of osteolytic bone lesions, anemia, hypercalcemia, renal
failure, pathologic fractures, and a high percent of plasma cells in the
bone marrow.

- Monoclonal gammopathy of undetermined

significance
- Waldenstrm macroglobulinemia
- Primary amyloidosis

-Cryoglobulinemia Mixed cryoglobulinemia (Type II) may be

associated with peripheral neuropathy and the presence of a

monoclonal gammopathy. It is most often associated with an
underlying lymphoma, viral infection (eg, hepatitis C virus, HIV), or a
chronic inflammatory state, such as a connective tissue disease. The
diagnosis rests principally in the laboratory demonstration of serum
cryoglobulins in association with characteristic clinical signs and

DIFFERENTIAL
DIAGNOSIS(continue)
- CIPD

Both chronic inflammatory demyelinating

polyradiculoneuropathy (CIDP) and POEMS syndrome are
characterized by a subacute motor-dominant demyelinating
polyradiculoneuropathy. Nerve conduction study and
electromyography can effectively distinguish POEMS syndrome from
CIDP. Compared with CIDP, POEMS demonstrates greater axonal loss
(reduction of motor amplitudes and increased fibrillation potentials),
greater slowing of the intermediate nerve segments, less common
temporal dispersion and conduction block, and absent sural sparing.

Different neurological and physiological profiles in

POEMS syndrome and chronic inflammatory
demyelinating polyneuropathy

Treatment approach

Cases
History
physical exam
workup
treatment&management

History A 55-year-old , previously healthy patient

presented to a neurology ward because of a 17week history of progressive gait difficulties
associated with distal paresthesias in her upper and
lower limbs that gradually confined her to a
wheelchair. Physical examination found four-limb
areflexia, severe symmetrical motor deficits of the
four limbs (predominantly in the legs), sensory
impairment of the four limbs and disability of the
arms and legs (functional disability scale score 9 out
of 10).1The patient had no dermatological or
endocrinological manifestations, organomegaly,
papilledema, extravascular volume overload, or
pulmonary manifestations.

Neurophysiological examination 18 weeks after

presentation revealed a frank decrease in the amplitude of
compound muscle action potentials (CMAPs) and sensory
nerve action potentials (SNAPs) with markedly slowed
conduction in the upper limbs. Distal CMAPs and SNAPs were
absent in the lower limbs. Needle electromyography showed
diffuse fibrillation potentials at rest in lower limb muscles.
laboratory analyses 18 weeks after presentation were
remarkable for thrombocytosis, a monoclonal IgG-component
(4 g/l), increased concentration of serum vascular endothelial
growth factor (VEGF, 1,050 pg/ml; normal <350 pg/ml),
elevated fasting glycemia (7.4 mmol/l; normal 3.95.8 mmol/l)
and hypoalbuminemia (27.7 g/l; normal 3550 g/l).
Intravenous immunoglobulin (IVIg; 30 g/day for 5 days)
was given for a supposed chronic inflammatory
demyelinating neuropathy, without any clinical benefit.
Results of a myelogram and bone-marrow biopsy (including
immunohistochemical staining) were normal. Thoracic and
abdominal CT scans demonstrated three mainly lytic lesions
with peripheral sclerosis of the iliac bones (Figure 1).
Histological examination of CT-guided bone-marrow biopsy
samples from the iliac bone lesions showed interstitial

CT scan of the pelvis of

this patient

The scan shows a lytic

acetabular lesion with
irregular sclerotic
margins.

CONTINUE

Some 20 weeks after initial presentation, an asymptomatic pulmonary embolism was detected
on an angio-CT scan. A diagnosis of polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, and skin changes (POEMS) syndrome was made on the basis of
established diagnostic criteria.2A course of intravenous methylprednisolone (1 g for 3
days) was performed during week 21 without any beneficial effect. Radiation
therapy was not possible because the bone lesions were multifocal.
We then considered high-dose chemotherapy and autologous hematopoietic stem-cell
transplantation (AHSCT), which was initiated 26 weeks after symptom onset using the
following schedule: 6 days of granulocyte-colony-stimulating factor (G-CSF; 10/kg per day),
followed by leucapheresis to collect a sufficient number of CD34 +cells. High-dose melphalan
(200 mg/m2) was delivered 15 days later followed at day 2 by reinjection of the cells collected
by leucapheresis; the injection contained 2.510 6CD34+cells.
The post-transplantation period was uneventful, except for an episode of neutropenic fever
without bacteriological documentation that resolved under broad-spectrum antibiotics.
Neutrophil (0.5109/l) and platelet (75109/l) engraftment occurred on days 12 and 20,
respectively.
28 weeks after AHSCT , Clinical status improved progressively, and the patient resumed
walking, with normalization of the disability scale score for the upper limbs 59 weeks after
AHSCT. Major improvement of neurophysiological parameters was also achieved at that time
along with normalization of biological parameters, platelet count and serum VEGF, as well as
disappearance of the monoclonal component .

Follow-up of a patient with POEMS syndrome from week 9 before autologous

hematopoietic stem-cell transplantation to week +59 thereafter

Case 2

 MRI" -

7th day

Emg Study

1. Predominantly motor primary demyelinating polyneuropathy with secondary

length dependent and some
multifocal axonal loss. This conclusion is based on the slowed conduction velocity
and conduction blocks
identified in 4 nerves in the forearms, on the background of relatively preserved
SNAPs? as well as EMG
evidence for a length dependent pattern of denervation as well as multifocal
involvement.
Intermediate segment demyelination with only mild prolongation of distal latencies
is consistent with POEMS.
However, conduction blocks are more typical for CIDP. An inching study may be
performed to further
evaluate if these are true conduction blocks or a result of uniform demyelination.
2. Left C7 active/subacute
radiculopathy. This conclusion is based on the finding of active/ongoing
denervation in the extensor digitorum communis on the background of relatively
preserved radial SNAPs. A
dedicated study to evaluate a cervical radiculopathy can be performed if clinically
indicated.

inching study


.

. . . 14"
- . .
. B12. .
POEMS. -
- , ,
VEGF. , PET CT
.
.
"

Neuropathy features in patients with POEMS syndrome who were treated with
autologous hematopoietic stem-cell transplantation

References
Diabetes Statistics. http://www.diabetes.org/diabetes-basics/diabetes-statistics/
Bril V et al. Evidence-based guideline: Treatment of painful diabetic
neuropathy. Neurology; Published online before print April 11, 2011; DOI
10.1212/WNL.0b013e3182166ebe
Bril V. Treatments for diabetic neuropathy. JPNS 2012:17(s2);2227.
Leishear K et al. Relationship Between Vitamin B12 and Sensory and Motor
Peripheral Nerve Function in Older Adults. JAGS 2012:60(6); 10571063.
England JD et al. Evaluation of distal symmetric polyneuropathy: the role of
autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review).
Muscle Nerve 2009 ;39: 106115.
England JD et al. Evaluation of distal symmetric polyneuropathy: the role of
laboratory and genetic testing (an evidence-based review). Muscle Nerve 2009
;39: 116125.
Service de Neurologie, Hpital Henri-Mondor, 51, Avenue du
Marchal de Lattre de Tassigny, 94010 Crteil Cedex, France

References

Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined

significance and smouldering multiple myeloma: emphasis on risk factors
for progression. BJH 2007:139(5);730743.
Mauermann ML, Burns TM. The evaluation of chronic axonal
polyneuropathies. Semin Neurol. 2008:28(2):133-51.
Ramaratnam S. Neurologic Manifestations of Leprosy.
http://emedicine.medscape.com/article/1165419-overview#aw2aab6b6
Rutkove SB. Overview of polyneuropathy.
http://www.uptodate.com/contents/overview-of-polyneuropathyUpto date