Neuropathy in Rheumatic Diseases BY Dr: Hegazy Mogahed

1. Neuropathy in Rheumatic Diseases BY Dr: Hegazy Mogahed Ass.Prof. of Rheumatology ,Physical Medicine & rehabilitation Al_ Azhar University

2. Neuropathy in Rheumatic Diseases Neurological involvement is associated with significant morbidity in patients with rheumatic diseases, and may indicate disease activity. Although certain neurological complications such as entrapment neuropathies are common. The most prominent features of neurological involvement in rheumatic diseases include cerebral ischaemia, polyneuropathyand psychiatric symptoms

3. Peripheral nerve • Types:Motor, sensory and autonomic fibers • Fiber types according to diameter: • A fibers- 1-17 μm in diameter; myelinated motor and sensory fibers • B fibers- 1-3 μm in diameter; myelinated autonomic fibers • C fibers- 0.3-1.3 μm in diameter; non-myelinated autonomic and pain fibers

4. Neuropathy • Neuropathy means a pathological process affecting a peripheral nerve or nerves. • Neuropathy has many causes, and any number of the three nerve types can be affected at any one time. • Mononeuropathy refers to a single nerve being affected • Polyneuropathymeans several nerves are affected • Mononeuropathy multiplex refers to simultaneous or sequential involvement of individual noncontiguous nerve trunks.

5. Neuropathy Radiculopathymeans disease affecting nerve roots, can cause pain and the loss of sensation along the nerve's pathway ,cab be monoradiculopathy and polyradiculopathy. Polyradiculopathy means disease of multiple peripheral nerve roots Plexopathy: results from injury to the brachial and lumbosacral plexuses.  Asymmetric Painful onset Multiple nerves in a single limb Rapid onset of weakness , atrophy Isolated reflex loss

6. MONONEUROPATHY • Mononeuropathy is damage to a single nerve which results in loss of movment sensation, or other function of that nerve. • Long-term pressure on the nerve due to swelling or injury can result in mononeuropathy. • The myelin sheath or the axon is destroyed. This damage slows or prevents signals from traveling through the nerves.

7. Mononeuropathy may involve any part of the body. Entrapment Neuropathy(RA ,SS &Amyloidosis) • Median nerve : 1-Elbow :(pronatorsyndrome,anteriorinterosseous nerve syndrome) 2-Wrist : (carpal tunnel syndrome) • Ulnar nerve : 1-Elbow (cubital tunnel syndrome) 2-Wrist (ulnar tunnel syndrome, Guyons canal syndrome • Radial nerve : Axilla (Saturday night palsy, sleep palsy) Elbow (posterior interosseousnerve syndrome)

8. Mononeuropathy • Posterior Tibial nerve : Ankle (tarsal tunnel syndrome) • Lateral femoral cutaneous nerve : Anterior superior iliac spnine (meralgiaparaesthetica • Sciatic Nerve: Sciatic foramen (including piriformis syndrome) • Idiopathic isolated facial nerve palsy (Bell's palsy)

9. Entrapment neuropathies • Entrapment neuropathy is a common finding in patients with rheumatic disease as joint swelling and deformities exert some pressure on nerve components. • Carpal tunnel syndrome (CTS) is the most common type of entrapment neuropathy. • The diagnosis when clinically suspected, is usually easily confirmed by nerve conduction studies. • Median nerve compression is thought to be induced by tenosynovitis of the flexor tendons of the fingers • Importantly, subclinical rheumatoid neuropathy can occur before the onset of CTS. • Systemic amyloid light-chain amyloidosis (9.3% of these patients have CTS • Ulnar neuropathy at the elbow is the second most common entrapment neuropathy and can be caused or exacerbated by joint swelling or deformity.

10. Idiopathic isolated facial nerve palsy (Bell's palsy) 1/3 of acute peripheral facial weakness are caused by: Trauma. DM. Guillain-Barre Syndrome Eclampsia. Ramsay Hunt syndrome (facial palsy with zoster oticus caused by varicella–zoster virus) Lyme disease. Sarcoidosis, Behçet's disease.. Sjogren’s syndrome Amyloidosis HIV The remaining 2/3 are idiopathic (Bell’s palsy).

11. Causes of Recurrent idiopathic facial paralysis 1-might occasionally be a symptom of the neurological involvement of Behçet's disease. 2-Another rare cause of recurrent alternative facial palsy is Melkersson-Rosenthal syndrome. In this syndrome, recurrent episodes of swelling of the lips ,face and Fissured tongue with positive family history. 3-Lyme disease is among the very common causes of bilateral or recurrent facial paralysis Sjögren's syndrome should be considered in the differential diagnosis of patients presenting with multiple recurrent cranial nerve palsies, even if prominent sicca symptoms are absent. Often multiple and recurrent cranial nerves neuropathy may be present in pSS. The most common is trigeminal neuropathy, followed by facial and oculomotor nerves involvement

12. MONONEUROPATHY MULTIPLEX Mononeuropathy multiplex refers to simultaneous or sequential involvement of individual noncontiguous nerve trunks, either partially or completely Affects peripheral nerves in a multifocal and random fashion Pattern of early symptoms is important in making the judgment that a particular neuropathy is indeed a mononeuropathy multiplex and not a polyneuropathy

13. MONONEUROPATHY MULTIPLEX • A)-Common causes of mononeuritis multiplex include: • Blood vessel diseases such as polyarteritisnodosa • Connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus • Diabetes mellitus • Connective tissue disease is the most common cause of mononeuritis multiplex in children. • B)-Less common causes include: • Amyloidosis • Disorders of the blood (such as hypereosinophilia and cryoglobulinemia) • Infections such as Lyme disease • Leprosy • Sarcoidosis • Sjogren syndrome • Wegener's granulomatosis

14. Polyneuropathy • Polyneuropathy:describes diffuse, symmetrical disease, usually beginning peripherally • Many symptoms possible • Symmetric, distal paraesthesia, pain and hypaesthesia in stocking – glove distribution; • feet are affected first • Allodynia • Depressed or absent tendon reflexes • Distally muscle weakness, with wasting, fasciculation • Gait disorder • Sensory ataxia • Weakness • Autonomic dysfunction (reduced sweating, tachycardia, urinary disturbances, gastroparesis etc.) • Vasculitis (Polyarteritis nodosa, SLE,) • Infectious: lepra, Lyme-disease, HIV

15. Pathological Classification Axonal Degeneration: It the most common Signifies distal axonal breakdown and progresses toward the nerve cell body and caused by ischemia. Distal>proximal ------------distal weakness Mainly affect Pain&temp ------Slow recovery Vasculitis, Lyme, sarcoidosis,Amyloid , Cryoglobulinaemia and sever entrapment Demyelinated Degeneration: The term implies injury of either myelin sheaths or Schwann cells, resulting in breakdown of myelin with sparing of axons Proximal=distal------------------ weakness Vibration&proprioception---- Rapid recovery GBS,Leprosy,sjogren and entrapment enuropathy Wallerian degeneration: Any type of mechanical injury that causes interruption of axons leads to wallerian degeneration (degeneration of axons and their myelin sheaths) distal to the site of transection.

16. weakness Polyneuropathy : Demyelinating type

17. Guillain-Barre Syndrome Acute immunmodulated poly-radiculo-neuro-pathy Most common type --- (AIDP) Acute, symmetric ascending flaccid paralysis Variable severity Respiratory insufficiency Bilateral facial palsy Ascending numbness to a lesser degree Radicular pain Areflexia Autonomic symptoms- tachycardia, cardiovascular instability

19. Polyneuropathy: Axonal type

20. Amyloidneuropathy Amyloid neuropathy: 1-symmetrical painful sensorimotor 2-carpal tunnel syndrome

21. Peripheral neuropathy in systemic Vasculitides

22. SLE Peripheral nervous system involvement in SLE has been subdivided into acute inflammatory demyelinatingpolyradiculoneuropathy, cranial nerve neuropathy, mononeuropathy and polyneuropathyas part of the neuropsychiatric presentation of the disease by the American College of Rheumatology. CNS affected late in the course of the diseases The pathology is due to vasculitis Sensory manifestation include polyneuropathy, mononeuritis multiplex and myopathy Sensory manifestation Usually asymmetrical

23. Rheumatoid arthritis Disease characterized by morning stiffness, symmetrical polyarthritis, and subcutaneous nodule. The predominant neurological complication is atlantoaxialsubluxation involving C1 and C2 Cervical myleopathy Peripheral neuropathy Carpal tunnel syndrome , ulnar neuropathy and tarsal tunnel syndrome

24. Sjögren's syndrome (SS) • the prevalence of mononeuropathy and peripheral neuropathy in patients with primary Sjögren's syndrome (SS) is higher than in any other rheumatic disorders • Symmetric pure sensory peripheral neuropathy(small fiber neuropathy) • Trigeminal and other cranial nerves neuropathies • Autonomic neuropathies---Acute transverse myelitis • Demyelinatingpolyradiculoneuropathy • Lower motor neuron disease---Neurogenic bladder • Central nervous system vasculitic involvement

25. Behcets syndrome • Behçets syndrome is a syndrome of recurrent, painful oral and genital lesions associated with uveitis and other forms of systemic inflammation. • Neurological involvement is classified into: (i) inflammation of CNS tissue or (ii) vasculitis with a stroke-like presentation and sinus venous thrombosis. • The wide variety of neurological findings that occur are headaches, ocular and other cranial nerve palsies, seizures, cerebrovascular insufficiency, brainstem syndrome leading to cerebellar ataxia and pseudobulbar palsy. • Spinal cord disease, hemisphere lesions and meningoencephalitis also occur. • Treatment of CNS lesions includes steroid pulse therapy (typically prednisolone 1 mg/kg/day) and long-term immunosuppression with steroid-sparing agents. • Headaches can be treated with tricyclic antidepressants and topiramate.

26. Ankylosingspondylitis Ankylosingspondylitis is an inflammatory arthropathy that affects predominantly the axial skeleton. It often begins in the sacroiliac joints. The main neurological complications in ankylosingspondylitis occur due to axial disease with spinal cord impingement at multiple levels. Surgical procedures in patients with atlanto-occipital disease, atlantoaxialsubluxation and spinal stenosis have been performed for pain and neurological deficit. However, surgery is not without risk of permanent neurological damage.

27. Inflammatory bowel diseases • It seems that involvement of the PNS occurs mostly in ulcerative colitis (UC), whereas myopathy and myelopathy characterize Crohn's disease (CD). • Peripheral neuropathy is the most common neurological complication associated with CD. Polyneuropathy can be associated with chronic inflammatory bowel diseases. • Symptoms of neuropathy usually develop 10 years after the onset of CD. • An inflammatory neuropathy may be seen in as many as 1.5% of CD patients. This is predominantly axonal.

28. Scleroderma A distal symmetric, mainly sensory, polyneuropathy complicates 5-67% of cases. Cranial mononeuropathies can also develop, most commonly the trigeminal nerve, leading to numbness and dysesthesias in the face. Occasionally, seventh and ninth cranial neuropathies develop. Mutiplemononeuropathieshave been described in a small percentage (1-2%) of patients with CREST syndrome. The electrophysiological and histological features of nerve biopsies are those of an axonal sensory greater than motor polyneuropathy .

29. Vitamin B12 deficiency caused by lack of 1-loss of intrinsic factor in the parietal cells 2- malabsorption Causes of malabsorption include Crohn’s disease Whipple’s disease Tuberculosis Surgical resection of the distal ileum • Sub acute combined degeneration of the cord Neurological symptoms include: • numbness and paresthesias • sensory loss.

30. Cryoglobulinaemia • Cryoglobulinaemia is often linked to infections with hepatitis C virus and is associated with peripheral neuropathy in >10% of cases. • Peripheral neuropathy associated with cryoglobulin is often a mononeuritis multiplex caused by vasculitis,although patients can present with distal painfulperipheral neuropathy without overt evidence of vasculitis in nerve samples.

31. Anti-TNF-associated neuropathies • Several investigators have described cases of Guillain–Barré syndrome (GBS) after treatment by the TNF antagonists infliximab, etanercept and adalimumab. • Onset of GBS usually occurs <6 months after initiation of therapy, although it can occur as long as 2 years after treatment onset. • The mechanism by which anti-TNF agents could trigger GBS remains incompletely understood; one can speculate that it could be by increasing the number of activated peripheral T cells or by disturbing the intrinsic balance of TNF and its receptors in the local peripheral nervous system compartment. • Chronic forms of immune-mediated neuropathies (CIDP, sensory and motor neuropathy with conduction block, multifocal motor neuropathy, mononeuropathy multiplex) have also been described in patients receiving TNF antagonists, as extensively reviewed elsewhere. • Although data are scarce on the long-term course of these disorders, response to conventional immunotherapy (for example, IVIg and plasma exchange) seems good and the decision to definitively stop anti-TNF agents should be discussed on a case by case basis by the rheumatologist and the neurologist according to the severity of the neuropathy and the effectiveness of TNF antagonists for the rheumatic disease.

32. SARCOID NEUROPATHY • Sarcoidosis is a chronic inflammatory disease characterized by non-caseatinggranulomata at affected sites • Neurologic symptoms appear in 4% of patients with sarcoidosis. • Most commonly, there are single or multiple cranial nerve palsies that fluctuate in intensity. Of the cranial nerves, the seventh is most commonly affected, and, as in diabetes mellitus, the facial nerve syndrome in sarcoidosis is indistinguishable from idiopathic Bell palsy. • Patients with sarcoidosis occasionally experience symmetricpolyneuropathy months or years after the diagnosis is established. • The neuropathy may be the first manifestation before the diagnosis of sarcoidosis is made. • The clinical syndromes may include GBS, lumbosacralplexopathy, mononeuritis multiplex, or pure sensory neuropathy. • Almost all patients, however, have cranial nerve symptoms. • Nerve biopsy shows a mixture of wallerian degeneration and segmental demyelination with sarcoidgranulomasin endoneurium and epineurium. • Sarcoid neuropathy may respond to steroid therapy

33. LYME NEUROPATHY Lyme disease is increasingly diagnosed in the United States and Europe It is caused by a tick-borne spirochete, Borreliaburgdorferi. Neuroborreliosis is a painful sensory radiculitis, which may appear about 3 weeks after the erythemamigrans. Typically, multiple nerve roots are involved, including cranial nerves (most often the facial nerve unilaterally or bilaterally). Radicular pain is constant (even at rest and at night), and weakness can occur in the affected areas. The triad of painful radiculitis, predominantly cranial mononeuritis multiplex, and lymphocytic pleocytosis in the CSF is known as Bann-warth syndrome in Europe.

34. Leflunomide-associated neuropathy • Leflunomide, an indirect inhibitor of pyrimidine synthesis, several reports have emphasized the occurrence or worsening of sensory symptoms owing to an axonal (mostly sensory) peripheral neuropathy in patients receiving this drug. • Leflunomide-associated neuropathy is usually mild, but rare cases of severe neuropathy have been described. • Therefore, the decision to stop the treatment must take into account the severity of neuropathic symptoms and the individual benefit in patients with RA

35. Polyneuropathy due to infectious diseases • Leprosy • Lyme disease

36. Leprosy Leprosy, a mycobacterial infectious disease of peripheral nerves Sensory loss is the cardinal symptom of leprosy Specially over the external ears, the zygomatic arches, and extensor surfaces of joints. Involvement of cutaneous nerves is generally sharply demarcated, especially in the tuberculoid form of leprosy The overlying dermis and epidermis are affected, producing the classic anesthetic macule

37. Anti-rheumatic drugs associated with neurological side-effects

38. Diagnosis 1-A careful history must be taken with clinical Examination 2- laboratory: 3-Nerve conduction studies and Electromyography 4-Nerve biopsy Should Be differentiat between: • Establish diagnosis of polyneuropathy • Distinguish demyelinating from axonal • Differentiate radiculopathy, plexopathy • Normal in small fiber and autonomic neuropathy

39. Clinical evaluation As a general rule, a careful history must be taken (including family history) with a special emphasis on medical conditions and drugs that are associated with peripheral neuropathy. The neuropathy has then to be classified according to its spatial distribution and to the type(s) of nerve fibres involved. A thorough clinical evaluation is mandatory to look for an associated disorder. Special care must be taken when examining skin changes, lymph node enlargement, organomegaly and pulmonary function

40. Laboratory 1-Routin Investigation Hematology: • complete blood count • erythrocyte sedimentation rate • C-reactive protein • vitamin B12, folate, Biochemical and endocrine: • comprehensive metabolic panel (fasting glucose) • thyroid function tests • serum immunofixation. • glucose tolerance test if indicated Urine: • urinalysis • urine immunofixation. Drugs : • .

41. Laboratory 2-Connective tissue diseases and vasculitis: Antinuclear antigen profile Rheumatoid factor Anti-Ro/SSA, anti-La/SSB, Antineutrophilcytoplasmic antigen antibody (ANCA) profile Cryoglobulins.

42. Antibody profiles and neurological involvement in rheumatic diseases

43. Electrodiagnostic studies • (1) Confirming the presence of neuropathy, • (2) Locating focal nerve lesions, • (3) Nature of the underlying nerve pathology

44. Electrodiagnostic studies • After a careful clinical evaluation, the second step in diagnosing peripheral neuropathy is often nerve conduction studies. • Indeed, electrodiagnostic studies can help to confirm peripheral neuropathy, assess its severity and, most importantly, distinguish between an axonal neuropathy and a demyelinating one. • Decreased nerve conduction velocities, prolonged distal and F-wave latencies, and the presence of conduction block would favour a demyelinating neuropathy, whereas decreased sensory and motor amplitudes with fairly preserved nerve conduction velocities would suggest a primary axonal process. • In addition, needle electromyography can show resting abnormalities, such as fibrillation potentials and positive sharp waves, which are suggestive of recent and active axon loss.

46. Entrapment Neuropathy Right Thenar Median Normal: - Lat < 4.9 ms - Amp ≥ 5 mV - CV > 50 m/s …. Motor portion of median is OK. Mild to moderate carpal tunnel syndrome.

47. NCS :Axonal And Demyelinated Degeneration

48. Electromyography

49. Nerve biopsy Suraland sup peroneal Sarcoidosis • Sural nerve specimen shows a typical perivasculargranuloma in the epineurium. • Multinucleated giant cells are not commonly seen in neural sarcoidosis.

50. Treatment of polyneuropathies • Treat the cause! • Immune therapy • Plasmapheresis: Guillain-Barré syndrome • Immunoglobulins: Guillain-Barré syndrome • Corticosteroids: systemic vasculitis • Symptomatic treatment of paraesthesias and neuropathic pain • Antiepileptic medications ( gabapentin, pregabalin) • Tricyclic antidepressants (amitriptilin) • Other Antidepressants: (duloxetin) • Vitamin B1: alcoholism, malabsorption, malnutrition Therapies for Regeneration Thioctic Acid : Also known as Alpha Lipoic Acid 600mg daily shows moderate benefit for neuropathic pain- Thioctic Acid is also thought to serve as an anti-inflammatory by preventing cytokines from forming.