1. DISORDERS OF THE PERIPHERAL NERVOUS SYSTEM
Prepared by:
Dr. Sarwer Jamal Al-Bajalan
M.B.Ch.B, F.I.B.M.S(Neurology)
2014

2. Disorders Of The Peripheral Nervous System
Introduction and clinical approach
Acquired polyneuropathies(PNP)
Hereditary neuropathies
Mononeuritis Multiplex
Mononeuropathies

3. Peripheral neuropathy: Introductionand clinical approach
General considerations
Peripheral neuropathy or polyneuropathy:
diffuse peripheral nerve lesion, often symmetrical
Mononeuropathy—lesion of a single nerve (i.e., median, femoral, or abducens). Often entrapment or trauma
Mononeuritis multiplex—focal involvement of two or more individual nerves, often asymmetric

4. Types and causes of peripheral neuropathy

6. Polyneuropathy: clinical manifestations
Age of onset varies, for example
Childhood—CMT
Adulthood—Diabetes
Older adult—Paraproteinemia
Acuity of onset
Acute—AIDP, porphyria, toxic, tick paralysis, diphtheria, vasculitis
Chronic—B12 deficiency, paraproteinemia, diabetes, most other causes
Symptoms
Motor symptoms—distal weakness predominates in most neuropathies. Diffi culty opening jars, tripping over feet
Sensory symptoms—may be
positive (tingling, burning) or
negative (numbness).
Autonomic symptoms—orthostatic lightheadedness, gastroparesis, sweating abnorma ities, erectile dysfunction, tachycardia

7. Positive Sensory symptoms
Paresthesia — spontaneous abnormal sensations, which are not unduly painful
Dysesthesia — painful paresthesia
Allodynia — painful sensation resulting from a nonpainful stimulus, such as stroking, high sounds
Hyperesthesia — increased sensitivity to a stimulus
Hyperalgesia — increased sensitivity to a painful stimulus

8. Signs of PNP Large-fiber neuropathy Small-fiber neuropathy
• Loss of vibration and position sense
• Diminished or absent reflexes
• Positive Romberg sign
• Pseudoathetosis
Small-fiber neuropathy
• Loss of pain and temperature sensation
• Reflexes may be normal.
Autonomic dysfunction
• Miosis
• Orthostatic hypotension (BP supine and erect after 3 minutes)
Cutaneous sensory loss in a stocking-glove distribution
Foot deformities such as pes cavus, pes planus, or hammertoes may indicate a hereditary neuropathy.
Nerve thickening may be seen in CMT, leprosy, Refsum disease, amyloidosis, or HNPP.

9. Investigations in PNP CSF examination; (AIDP/CIDP) EMG and ENG
Can distinguish polyneuropathy from polyradiculopathy or plexopathy
Can identify mononeuropathy and mononeuritis multiplex
Can distinguish axonal and demyelinating neuropathies
Can identify subclinical sensory or motor involvement
Blood tests
I) 75 gram 2 hour oral GTT, B12, TSH, SPEP, immunofixation, ESR, renal and liver function tests
II) ANA, dsDNA, anti-Ro, anti-La, HIV, Lyme
III) Others…
CSF examination; (AIDP/CIDP)
Nerve biopsy: sural, radial, superficial peroneal(vasculitis)

10. Investigation of peripheral neuropathy

12. Acquired polyneuropathies
Diabetic neuropathies
Guillain–Barre syndrome (GBS)
Chronic demyelinating polyneuropathy
Chronic axonal polyneuropathy
Brachial plexopathy
Lumbosacral plexopathy
Spinal Root Lesions

13. Diabetic neuropathies
Commonest cause of neuropathy worldwide.
8% have neuropathy at diagnosis;
50% after 25 years.
Diagnosis
Diabetes = fasting glucose >126, 2 hr postprandial glucose of 200 mg/dL
Impaired fasting glucose = fasting glucose 100–125 mg/dL
Impaired glucose tolerance = 2 hr postprandial glucose 140–199 mg/dL
Classification of diabetic neuropathies:
Diabetic polyneuropathy
Diabetic neuropathic cachexia
Diabetic amyotrophy
Diabetic cranial neuropathies
Diabetic mononeuropathies

14. Diabetic polyneuropathy
Length dependent, painful sensory > motor neuropathy
Autonomic dysfunction is common.
NCS:
Show length-dependent axonal polyneuropathy.
May be normal if only small fibers involved.
Rx :
Foot care,
Control of hyperglycemia, and
Medications for neuropathic pain (i.e., gabapentin, nortriptyline, duloxetine, pregabain).

15. Diabetic amyotrophy Clinical manifestations
Abrupt onset of severe pain in backs, hips, and thighs followed by weakness and wasting of proximal muscles > distal muscles
Usually unilateral, but may progress to be bilateral
Associated with weight loss
D Dx : Vasculitis, malignant infiltration
Investigations
NCS(ENG) usually show distal sensorimotor polyneuropathy
Needle EMG shows denervation in proximal lower extremity muscles including paraspinals
Consider MRI to rule out structural or infi trative process causing radiculopathy or plexopathy
Management
Spontaneous recovery over 1–3 years
Methylprednisolone (1g iv tiw x 1, then qweek x 3, then q2 weeks x 4) may speed recovery
IVIG reported to be beneficial as well

16. Diabetic amyotrophy

17. Diabetic cranial neuropathies
Oculomotor (III) palsy — pupil sparing
Abducens (VI) palsy
Diabetic mononeuropathies
DM patients are prone to entrapment syndromes.
Surgery should be considered if motor involvement, but results may not be as good as in nondiabetics.
Median at the wris(CTS)
Ulnar at the elbow
Common peroneal at the fibular neck

18. Guillain–Barre syndrome (GBS)
1. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
Epidemiology:
The most common cause of acute neuromuscular
weakness.
Annual incidence 1–2 /100,000
Two-thirds are preceded by a GI or upper respiratory tract infection (Campylobacter jejuni, CMV, EBV, haemophilus influenzae, mycoplasma).

19. Pathogenesis
There is a predominantly cell-mediated inflammatory response directed at the myelin protein of spinal roots, peripheral and extra-axial cranial nerves, possibly triggered by molecular mimicry between epitopes found in the cell walls of some microorganisms and gangliosides in the Schwann cell and axonal membranes. The resulting release of inflammatory cytokines blocks nerve conduction and is followed by a complement-mediated destruction of the myelin sheath and the associated axon

20. Clinical features
Neurologic symptoms begin 5 days to 3 weeks after antecedent event.
Ascending weakness. Proximal weakness may occur as well because of root demyelination
Early loss of reflexes
Paresthesias common. Actual sensory loss is variable.
Progressive over days to weeks, nadir by 4 weeks
Often associated with back pain
Involvement of cranial nerves can cause facial and bulbar weakness.
Up to 25% have respiratory involvement requiring mechanical ventilation.
Autonomic dysfunction (hypotension, hypertension, cardiac arrhythmia)

21. Diagnostic studies NCS: CSF:
May be normal early in the course of the disease
Prolongation of F-responses,
Prolongation of motor latencies, and
Prolongation of motor conduction velocities.
Conduction block correlates with degree of weakness.
CSF:
Elevation of protein (may be normal first 10 days).
Little or no CSF pleocytosis, unless associated with HIV or Lyme.

22. Management IVIG 0.4 g/kg/day x 5 days
Plasma exchange (2–5 exchanges, depending on the severity of the disease)
No benefit from corticosteroids
Supportive measures
Follow vital capacity (VC) and negative inspiratory force (NIF
Transfer patient to the I CU and consider elective intubation IF:
fVC <20 mL/kg (1.5 L for an average adult) or
NIF is worse than –30 cm H2O,
Do not wait for O2 saturation or PO2 to drop.
Swallowing assessment
Cardiac monitoring in all patients who are severely affected, at least until they start to improve.
Treat neuropathic pain
(gabapentin, pregabalin, or tramadol).
Avoid tricyclic antidepressants early, which may lower threshold for arrhythmia.
DVT prophylaxis
Bowel regimen for constipation
Physical therapy to prevent contractures and speed recovery of function

23. Prognosis
Overall, 80% of patients recover completely within 3–6 months.
Untreated, about 35% of patients have residual weakness, atrophy, hyporeflexia, and facial weakness.
Partial recovery followed by relapse occur in <10% of patients.
Recurrence after full recovery is 2%.
Mortality is 4 %.
Poor outcome associated with
Older age
Preceding diarrheal illness
Rapid deterioration and severe weakness
Electrically inexcitable nerves and muscle wasting (axonal loss)

24. Other Variants of GBS 2. Acute motor axonal neuropathy (AMAN)
Little or no demyelination
Often associated with Campylobacter jejuni infection
A subset of patients will recover rapidly
3. Acute motor sensory axonal neuropathy (AMSAN)
Poorer prognosis than AIDP and AMAN
3. Miller Fisher syndrome
Ophthalmoplegia
Ataxia
Areflexia
Associated with GQ1b antibody
4. Acute sensory neuropathy
6. Acute pandysautonomia

25. Chronic polyneuropathy
A chronic symmetrical polyneuropathy, evolving over months or years, is the most frequently seen form of neuropathy.
In about 30% of patients no cause can be established, even after thorough investigation.
These patients usually have a mild axonal neuropathy which, whilst causing unpleasant symptoms, does not lead to motor disability.
Therefore, if a patient with what seems to be an idiopathic polyneuropathy progresses to significant disability, further thought needs to be given to finding a specific cause (usually inflammatory or genetic).

26. Chronic Demyelinating Polyneuropathy
This type of chronic polyneuropathy is often : Hereditary or Immune -mediated (including those caused by abnormal paraproteins).
Causes:
Hereditary
CIDP
Lymphoma
Osteoclastic myeloma
IgM paraproteinaemia
Arsenic toxicity
Amiodarone toxicity
Diphtheria

27. Heriditary Demyelinating Polyneuropathy
Many inherited disorders cause demyelinating peripheral neuropathies and one of the best known is Charcot–Marie–Tooth disease (CMT).
This neuropathy produces:
Distal wasting (‘inverted champagne bottle’ or ‘stork’ legs),
Often with pes cavus, and
Predominantly motor clinical involvement.
In 70–80% the cause is duplication of the PMP-22 gene on chromosome 17 (autosomal dominant CMT type 1)
Similar phenotypes are produced by mutations in other genes with differing modes of inheritance

28. CMT
Pes cavus, Inverted champagne bottole, Samll muscle atrophy

29. Hereditary peripheral neuropathies

30. Hereditary demyelinating neuropathies

31. Chronic Inflammatory Demyelinating Polyradiculopathy (CIDP)
Presents with a relapsing or progressive generalised neuropathy.
Sensory, motor or autonomic nerves can be involved but the signs are predominantly motor;
A variant causes only motor involvement (multifocal motor neuropathy, MMN). RX
Immunosuppressive treatment:
Corticosteroids ,
Methotrexate or
Cyclophosphamide , or
Plasma exchange
Intravenous immunoglobulin, IVIG
MMN is best treated by IVIG.
Some 10% of patients with acquired demyelinating polyneuropathy have an abnormal serum paraprotein, sometimes associated with a lymphoproliferative malignancy.

32. Treatment flowchart for CIDP

33. Chronic axonal polyneuropathy
This is the most common type of chronic polyneuropathy.
Where the cause can be found, it is usually a disorder affecting axonal metabolism and transport, either acquired (drugs and toxins) or genetically determined
Metabolic/endocrine diseases (including diabetes)
Alcohol
Drugs and toxins
Vitamin deficiency
Hereditary
IgG paraproteinaemia
Paraneoplastic
Primary amyloidosis

34. Brachial plexopathy
Trauma usually damages either the upper or the lower parts of the brachial plexus, according to the mechanics of the injury.
The clinical features depend upon the anatomical site of the damage .
Causes of Lower Brachial Plexopathy:
Infiltration from breast or apical lung tumours (Pancoast tumour).
Therapeutic irradiation
Thoracic outlet syndrome: which may be accompanied by circulatory changes in the arm due to subclavian artery compression.

35. Brachial plexus anatomy: L, lateral; M, medial; P, posterior

36. Neuralgic Amyotrophy
An acute brachial plexopathy of probable inflammatory origin.
In this syndrome, a period of very severe shoulder pain precedes the appearance of a patchy upper brachial plexus lesion.
Often affecting the long thoracic nerve which produces winging of the scapula.
Recovery occurs over months and is usually complete.

37. Lumbosacral plexopathy
May be caused by:
Neoplastic infiltration or
Compression by retroperitoneal haematomas in patients with a coagulopathy.
A small vessel vasculopathy can produce a lumbar plexopathy, especially in elderly patients when it may be the presenting feature of;
Type 2 diabetes mellitus (‘diabetic amyotrophy’) or
A vasculitis.

38. Spinal Root Lesions
Compression at or near their spinal exit foramina by prolapsed intervertebral discs or degenerative spinal disease.
Infiltration by spinal and paraspinal tumour masses and
Inflammatory or infective processes.
The clinical features include:
Muscle weakness and wasting and
Dermatomal sensory loss with
Reflex changes that reflect the pattern of roots involved.
Pain in the muscles whose innervating motor roots are involved.

39. Mononeuritis Multiplex
Lesions of multiple nerve roots, peripheral nerves or cranial nerves.
It is due either to involvement of the vasa nervorum or to malignant infiltration of the nerves.
The clinical expression of a very widespread multifocal neuropathy may become confluent so that the clinical picture eventually resembles a polyneuropathy.
In this case neurophysiology may be required to identify the multifocal nature of the problem.

40. Causes of Mononeuritis Multiplex
Infections:
Lyme disease
Leprosy
Acute viral hepatitis A
Hepatitis B
Hepatitis C
Acute parvovirus B-19 infection
Herpes simplex virus infection
AIDS and HIV infection
Rheumatological:
Wegener granulomatosis
Henoch-Schönlein syndrome
Sjögren syndrome
Behçet’s disease
Temporal (giant cell) arteritis
Systemic lupus erythematosus
Rheumatoid arthritis
Polyarteritis nodosa
Scleroderma
Chronic:
Diabetes mellitus
Amyloidosis[8]
Neurosarcoidosis[36, 37]
Cancer -related:
Chronic graft versus host disease (GVHD)
Direct tumor invasion with intraneural spread of Lymphoma 
B-cell leukemia 
carcinoid tumor
Paraneoplastic – Small cell lung cancer
Hematologic:
Churg-Strauss syndrome
Hypereosinophilia
Cryoglobulinemia
Atopy-related peripheral neuritis
Idiopathic thrombocytopenic purpura
Miscellaneous:
Amphetamine angiitis
Gasoline sniffing
Genetic disorder; Tangier disease.
Multiple compression neuropathies.

41. Mononeuropathies Facial mononeuropathy (Bell palsy)
Weakness: Upper and lower face, inability to close the eye, mouth drawn to the affected side.
Patients often describe the face as ‘numb’, but there is no objective somatosensory loss.
Loss of direct & consensual corneal reflex on the affected side.
Decreased tearing, hyperacusis, and loss of taste to the anterior two thirds of the tongue may be present.
Onset is sudden, usually over hours.
EMG/NCV are rarely necessary to make the diagnosis, but can be used to determine prognosis.
DDx: Herpes zoster, HIV, Lyme, facial tumor, sarcoidosis & neuro-brucellosis. Rx
Artificial tears, protective goggles, eye patch at night
Prednisone 40–60 mg/d for a week ; speeds recovery if started within 72 hrs.
Anti-virals probably not beneficial?? ( Acyclovior 400x5 for 10 days)

42. Rt LMN VII palsy Prognosis some recovery within 3 weeks(85%).
Complete recovery(75%)
Poor recovery predicted if:
Complete paralysis,
Older age
Comorbidity; DM , HTN
Hyperacusis
Loss of taste for > 1wk
Reto-auricular pain
Axonal loss
Aberrant re-innervation may occur during recovery, producing unwanted facial movements such as eye closure when the mouth is moved, or ‘crocodile tears’ (tearing during salivation).
Rt LMN VII palsy

43. Hemifacial spasm
Usually presents after middle age with intermittent twitching around one eye, spreading ipsilaterally over months or years to affect other parts of the facial muscles.
The spasms are exacerbated by talking or eating, or when the patient is under stress.
The cause is probably an aberrant arterial loop irritating the nerve just outside the pons.
The facial nerve should be imaged to exclude a structural lesion, especially in a young patient.
Treatment
Drug is not effective.
Botulinum toxin (repeated every 3 months).
Microvascular decompression.

44. Trigeminal Nerve Lesions
Isolated trigeminal sensory neuropathy is rare. It causes unilateral facial sensory loss and is associated in some patients with;
scleroderma,
Sjögren’s syndrome or
other connective tissue disorder.
Trigeminal neuralgia do not have sensory loss on examination unless there have been operative procedures on the nerve.
Herpes Zoster (most frequently in the ophthalmic division) and is followed in about one-third of patients by postherpetic neuralgia).

45. Herpes Zoster Ophthalmicus

46. Entrapment neuropathy
Focal compression or entrapment is the usual cause of mononeuropathy.
The pressure damages the myelin sheath  slowing NCS.
Sustained or severe pressure  axonal loss  loss of sensory AP distal to the site of compression.
Causes:
Acromegaly ,
Hypothyroidism ,
Pregnancy
Diabetes
Osteophytes
HNPP(hereditary neuropathy with liability to pressure palsies)
multiple recurrent entrapment neuropathies,
especially at unusual sites
autosomal dominant

47. Symptoms and signs in common Entrapment Neuropathies
Median at wrist (CTS) Ulnar at elbow Meralgaia Paraesthetica

48. Differential diagnosis by pattern of symptoms
Symmetrical proximal and distal weakness with sensory loss. (Consider CIDP, vasculitis.)
Pattern 2:
Symmetrical distal weakness with sensory loss. (Consider diabetes, drugs and toxins, hereditary neuropathies, amyloidosis, paraproteinemia.)
Pattern 3:
Asymmetric distal weakness and numbness. (Consider vasculitic neuropathy, HNPP, infectious neuropathy, multifocal trauma or entrapment.)
Pattern 4:
Asymmetric distal or proximal weakness without sensor loss. (Consider multifocal motor neuropathy, motor neuron disease, inclusion body myositis.)
Pattern 5:
Asymmetric proximal and distal weakness with sensory loss. (Consider polyradiculopathy or plexopathy, ma ignant infi ltration, brachial neuritis, HNPP.)
Pattern 6:
Symmetric small fiber sensory neuropathy without weakness. (Consider diabetes, Fabry disease, amyloidosis, HIV.)
Pattern 7:
Symmetric small and large fiber sensory neuropathy without weakness. (Consider diabetes, drugs, toxins, paraproteinemia.)
Pattern 8:
Marked proprioceptive sensory loss. (Consider paraneoplastic, B6 toxicity, Sjogren, HIV.)
Pattern 9:
Autonomic predominant. (Consider autoimmune, amyloidosis, diabetes, AIDP.)
Pattern 10:
Neuropathy with cranial nerve involvement. (Consider Lyme, HIV, AIDP, sarcoidosis, malignant infiltration, Tangier disease, trichloroethylene toxicity, anti-Gd1b neuropathy.)