Neuromuscular Diseases



Neuromuscular Diseases





General Approach to Peripheral Neuropathies


I. Evaluation and Classification



  • Thorough history



    • Nature of chief complaint: weakness versus sensory disturbance versus pain versus autonomic disturbance versus atrophy versus ataxia versus combination thereof


    • Time course of symptoms: acute versus subacute versus chronic (relapsing, recurrent, progressive, and so forth)


    • Anatomic pattern of symptoms: symmetric versus asymmetrical, focal versus diffuse; with additional help from physical examination, determine if clinically a mononeuropathy, mononeuropathy multiplex, polyneuropathy, radiculopathy, polyradiculopathy, or plexopathy.


    • Ask specifically about the following:



      • Trauma


      • Toxic exposures (including recreational drugs such as ethanol)


      • Infections or vaccinations


      • Dietary deficiencies


      • Medications used


      • Presence of other medical conditions (such as diabetes, thyroid disease, vascular disease, liver disease, gastrointestinal [GI] disease, sarcoidosis, renal disease, connective tissue disease, cancer)


      • Constitutional symptoms (weight loss, fever, and so forth)


      • Family history


  • Thorough physical examination



    • Cranial nerves most commonly involved in Guillain-Barré syndrome (GBS), sarcoid, carcinomatosis, diphtheria


    • Motor examination



      • Look for atrophy and distribution thereof


      • Distribution of weakness:



        • Most polyneuropathies affect distal muscles of lower extremities first.


        • Most demyelinating and certain acute motor and toxic neuropathies affect all muscles of limbs, trunk, neck, and some facial muscles.


        • With help of history, try to narrow weakness into pattern of mononeuropathy, mononeuropathy multiplex, polyneuropathy, radiculopathy, polyradiculopathy, or plexopathy.



    • Sensory examination



      • Most neuropathies have distal, symmetric, sensory loss in lower extremities first (stocking-glove distribution).


      • Sensory loss exceeds weakness in most toxic neuropathies.


    • Reflex examination



      • Diminution or loss is an invariable sign of peripheral nerve disease (except in small-fiber sensory neuropathies, where reflexes may be retained).


      • May be diminished out of proportion to weakness


    • Coordination and gait



      • Proprioceptive loss may result in ataxia of limb movement and gait with positive Romberg test.


      • Fast frequency action tremor occasionally seen


    • Skin and musculoskeletal examination



      • Pes cavus: often seen in hereditary neuropathies secondary to weakness of peroneal and pretibial muscles worse than in the calf muscles


      • “Claw” hand: same principle as lower extremities


      • Kyphoscoliosis: secondary to weakness of paravertebral muscles


      • Skin ulcers, pressure sores, burns, and so forth, secondary to analgesia


      • Tight, shiny skin with sparse hair


      • Analgesic joints become traumatized and deformed (Charcot arthropathy).


      • Discoloration (erythema and hyperpigmentation)


      • Hypertrophied nerves (e.g., chronic inflammatory demyelinating polyneuropathy [CIDP], Refsum disease, leprosy, hereditary sensory motor neuropathy III > II > I, acromegaly, neurofibromatosis, amyloidosis)


      • Check for herpes zoster lesions


    • General examination



      • Cardiovascular: check pulses, listen for murmurs, check orthostatics, and so forth


      • GI: hepatomegaly (such as hepatitis, mononucleosis) or hepatic cirrhosis


      • Nodes: lymphadenopathy (HIV, lymphoma, mono, and so forth)


  • Laboratory evaluation



    • Serum for general screening laboratory results—liver function tests (LFTs), electrolytes, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), rheumatoid factor (RF), thyroid-stimulating hormone, free T4, Vitamin B12, folate, serum immunofixation electrophoresis, hemoglobin A1C. (Also consider the following based on clinical suspicions: anti-MAG, anti-GM-1, and anti-sulfatide antibodies, anti-GALOP antibodies, angiotensin-converting enzyme level; lead level, red blood cell (RBC) protoporphyrins, cryoglobulins, HIV, anti-Hu, and so forth.)


    • Consider 24-hour urine for heavy metals, porphyrins; urine immunoelectrophoresis


    • Consider chest radiograph as workup for brachial neuropathy, suspected carcinomatous neuropathy, and so forth


    • Electrophysiologic studies—can further categorize neuropathies as primarily demyelinating or axonal, sensory or motor, or both; mononeuropathy versus polyneuropathy versus mononeuropathy multiplex versus plexopathy versus radiculopathy



      • Axonal—encompasses most neuropathies



        • Clinical correlation: usually has symmetrical distal sensory loss with weakness, atrophy, and lost ankle jerks



        • Nerve conduction velocity (NCV) shows mild slowing without conduction block or temporal dispersion, plus significantly decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (often no obtainable potential)


        • Electromyography (EMG) shows evidence of distal denervation


        • Many toxic and metabolic neuropathies are in this category.


      • Demyelinating



        • Clinical correlation: early generalized reflex loss, mild atrophy, proximal and distal muscle weakness, sensory loss of large-fiber > small-fiber modalities, motor usually > sensory involvement, tremor, and hypertrophied nerves common.


        • NCV shows marked slowing, conduction block, temporal dispersion, prolonged F-wave, and distal latencies


        • EMG may show denervation, based on chronicity


        • Examples: GBS, CIDP, some hereditary neuropathies, paraproteinemias, anti-MAG and anti-GM-1 related neuropathies


      • Many neuropathies are mixed axonal and demyelinating


    • Consider lumbar puncture if suspect GBS, CIDP, and so forth


    • Consider nerve biopsy (sural) if you suspect a treatable disease (such as vasculitic neuropathy, CIDP, sarcoid, leprosy) or need to make diagnosis of hereditary neuropathy.


    • If paraprotein is found on serum immunofixation electrophoresis or urine immunofixation electrophoresis, consider skeletal survey, bone marrow biopsy, and so forth.


II. Treatment



  • Specific treatment modalities aimed at the underlying cause are not possible in most neuropathies (especially chronic sensory motor polyneuropathies); nevertheless, the search for a specific, treatable cause should be undertaken.



    • In approximately 25% of all chronic polyneuropathies, a cause cannot be determined.


    • Treatments for specific neuropathies are discussed in a later section of this chapter.


  • General treatment modalities



    • Management of neuropathic pain



      • Sympathetically independent pain—seen in most generalized neuropathies; paroxysmal pain, paresthesias, spontaneous burning pain, tactile hyperalgesia, and occasional cold hyperalgesia; allodynia—perversion of sensation (touch induced burning pain); usually worse in feet/hands



        • Treat underlying cause, if present (e.g., glucose control in diabetes).


        • Antidepressants including duloxetine (Cymbalta), tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, desipramine) and selective serotonin reuptake inhibitors



          • Start at 10 to 25 mg of amitriptyline or nortriptyline every night and increase every 2 weeks to 75 to 150 mg every night (may go higher if no side effects)


          • Six weeks may be required for proper trial.


          • Amitriptyline—most studied; highest incidence of side effects (e.g., orthostatics, urinary retention, dry mouth, early-morning “hangover,” constipation, somnolence, nightmares)


          • Side effects usually decrease after first few weeks.


          • If patient has cardiac-conduction defects or orthostatic hypotension, tricyclic antidepressants should be used with caution if at all.



          • Desipramine may be tried if anticholinergic side effects or somnolence are bothersome (also nortriptyline).


          • If no response or intolerable side effects after 6 weeks, try another drug.


        • Antiepileptic drugs (e.g., carbamazepine, clonazepam, topiramate, phenytoin, valproic acid, gabapentin, tiagabine, levetiracetam)



          • Start with low doses and increase to effect or clinical toxicity (much like epilepsy treatment).


          • Always taper (never stop) antiepileptic drugs if ineffective.


          • Work well for sharp, lancinating pain


        • Local anesthetics (mexiletine)



          • Start with prognostic intravenous lidocaine test (if no cardiac conduction defects)—5 mg/kg over 1 hour; perform in blinded fashion using saline infusion as placebo.


          • If >50% pain relief, try oral mexiletine, 150 mg/d, increased by 150 mg every 3 to 4 days to total dose of 10 mg/kg per day, divided three times a day.


          • Side effects: nausea/vomiting, altered taste, dizziness, uncoordination, tremor, tinnitus


        • Opiates (e.g., oxycodone, hydromorphone, morphine sulfate sustained-release, codeine/acetaminophen, hydrocodone, fentanyl)



          • Use with extreme caution, if at all.


          • Use longer-acting preparations.


          • Maintain control over the number prescribed.


          • Warn patient of possible side effects: addiction and physical dependence, respiratory depression, nausea/vomiting, constipation, sedation, euphoria, confusion, urinary retention, myoclonus, allergy, headaches, “histamine” reaction.


        • Topical agents (e.g., capsaicin, lidocaine)



          • More effective if used with oral agents


          • Capsaicin—deactivates heat-sensitive nociceptors; 0.075% cream two to four times a day × 4 weeks; initial intolerable burning sensation common


          • Lidocaine: 3 to 5 mL ointment applied every day, covered with plastic film or by patch form


        • Neurostimulation techniques



          • TENS unit (transcutaneous electrical nerve stimulation)—more useful in mononeuropathies


          • Spinal cord stimulation—mainly for lower extremity pain; epidural percutaneous multielectrode device implanted over lower thoracic segments; more effective if radicular component


        • Surgery—dorsal root entry zone lesions for selected cases (e.g., postherpetic neuralgia)


      • Sympathetically maintained pain (causalgia)—distal, severe, burning pain in single extremity associated with hyperalgesia to touch and cold; usually associated with trauma to a major nerve in the affected extremity; associated with vasomotor, sympathetic and trophic changes; relieved with sympathetic block



        • Document response to intravenous phentolamine


        • If >50% relief of pain with phentolamine, try α-adrenergic blockade with phenoxybenzamine (10 mg two times a day; increase by 10 mg every week to maximum 120 mg every day), clonidine (0.1 mg two to three times a day), or prazocin (2 mg two times a day).



        • Watch for impotence and postural hypotension.


        • Guanethidine regional sympathetic block or surgical sympathectomy, if pharmacologic therapy fails


    • Other considerations



      • Hereditary neuropathies



        • Proper shoes with sole cushioning


        • Ankle foot orthoses (over entire calf) for footdrop


        • Physical or occupational therapy—stretching and mild strengthening, provide assist devices, encourage self-reliance, writing assistance


        • Early orthopaedic consultation for pes cavus, kyphoscoliosis,and so forth


        • Counseling


      • Ataxic neuropathies—physical therapy for gait training and gait prosthetics, home improvement


      • Many physicians prescribe B vitamins for chronic sensorimotor polyneuropathies, especially if thought to be partially related to nutritional insufficiency (e.g., alcoholic neuropathy).


Peripheral Neuropathy Syndromes


I. Acute Ascending Motor Neuropathy with Variable Sensory Disturbance































































































































Cause

Onset

Type

CSF prot

CSF wbc

Special Features


Mononucleosis

Infection midphase

D

I

I

—


Viral hepatitis

Follows jaundice

D

I

N

Hep screen often negative


Uremia

Rapid

D

I

N

Transplant curative


Diphtheria

5-8 wk postinfection

D

I

N

No inflammation, loss of pupil accommodation


Porphyria

Rapid

A

N

N

Retained ankle jerk, bibrachial weakness, whisper


Tick paralysis

Rapid

A

N

N

Rapid recovery with tick removal


Tetanus

Rapid

A

N

N

Asymmetric sensory and motor responses


Hypophosphatemia

Rapid

D

I

N

Resolves with PO4 correction


Organophosphates

Rapid




Acute paralysis, alopecia


Thallium

Rapid

A

I

N

Sensory and autonomic > motor responses


Arsenic

Subacute


Tetrodotoxin

Rapid

D



Sodium blocker, motor tongue numb


Saxitoxin

Rapid

D



Sodium blocker, motor


Ciguaratoxin

Rapid




Prolongs sodium channel sensory > motor response


Lupus

Rapid

D/V

+/−

+/−

—


Polyarteritis nodosa

Chronic

A/V



Occurs in 70% of these patients


Lymphomatous HIV

Acute at conversion

D

I

I

HIV often negative, p24 PCR +


A, axonal; CSF, cerebral spinal fluid; D, demyelinating; I, increased; N, normal; PCR, polymerase chain reaction; prot; protein; V, variable; wbc, white blood count.




I. Subacute Sensorimotor Paralysis



  • Symmetrical polyneuropathies: usually axonal in type



    • Deficiency states



















































      Vitamin

      Neuropathy

      Type

      CSF Protein

      Special Features


      Thiamine (beriberi)

      Axonal

      S>M

      Increased

      Postural hypotension,burning pain


      Niacin (pellagra)

      Axonal

      S>M

      Increased

      Delirium, dementia


      Vitamin B12

      Axonal

      S>M

      Normal

      Subacute combined degeneration


      Vitamin B6 (pyridoxine)

      Neuronopathy

      S>M

      Normal

      Occurs with INH/hydralazine


      Pantothenic acid

      Axonal

      S>M

      Normal


      Folate

      Axonal

      S>M

      Normal


      Vitamin E

      Axonal

      S

      Normal

      Increased CK, ataxia, ophthalmoplegia


      CK, creatine kinase; INH; M, motor; S, sensory.



    • Metals/solvents















































      Substance

      Course

      Neuropathy

      Type

      Special Features


      Arsenic

      Acute

      Axonal

      S

      Mees lines


      Lead

      Chronic

      Axonal

      M

      Radial (wrist drop)


      Mercury

      Chronic

      Axonal

      S

      Encephalopathy, acrodynia


      Thallium

      Chronic

      Axonal

      S/M

      Imitates GBS


      Gold

      Chronic

      Axonal

      S

      Myokymia


      N-Hexane

      Chronic

      Axonal

      S

      Giant axonal neuropathy (slowing)


      M, motor; S, sensory.



    • Medications















































































































      Medication

      Course

      Neuropathy

      Type

      Special Features


      Isoniazid

      Chronic

      Axonal

      S>M

      Treat with vitamin B6


      Hydralazine

      Chronic

      Axonal

      S>M

      Treat with vitamin B6


      Pyridoxine

      Chronic

      Axonal

      S

      Sensory neuronopathy


      Nitrofurantoin

      Chronic

      Axonal

      S/M

      Uremic patients


      Vincristine

      Chronic

      Axonal

      M

      Dose-related


      Cisplatin

      Chronic

      Axonal

      S

      Dose-related


      Phenytoin

      Chronic

      Axonal

      S


      Chloramphenicol

      Chronic

      Axonal

      S


      Amitriptyline

      Chronic

      Axonal

      S/M


      Colchicine

      Chronic

      Axonal

      S/M

      Vacuolar degeneration


      Dapsone

      Chronic

      Axonal

      M


      Ethambutol

      Chronic

      Axonal

      S

      Optic neuropathy


      Lithium

      Chronic

      Axonal

      S/M


      Metronidazole

      Chronic

      Axonal

      S


      Disulfiram

      Chronic

      Axonal

      S/M

      Giant axons


      Nitrous oxide

      Chronic

      Axonal

      S

      Giant axons, myelopathy


      Amiodarone

      Chronic

      Demyel

      S/M


      Perhexiline

      Chronic

      Demyel

      S/M


      Demyel, demyelinating; M, motor; S, sensory.




  • Asymmetrical polyneuropathies (mononeuropathy multiplex)



    • Major players: diabetes, vasculitides


    • Definition: simultaneous or sequential involvement of three individual noncontiguous nerves in a random fashion (two or more nerves in more than one extremity)


    • Diabetic neuropathy



      • Most common cause of neuropathy in United States


      • 15% to 25% of diabetic patients have both symptoms and signs of neuropathy, and 50% have either neuropathic symptoms or slowing of NCV. (Some say 75% to 85% of diabetic patients have NCV evidence of peripheral nerve dysfunction.)


      • Most common over age 50 years; uncommon under 30 years


      • Pathologic findings: loss of myelinated fibers most prominent finding; segmental demyelination/remyelination; also have axonal degeneration; also find this abnormality in posterior roots, posterior columns, sympathetic ganglia.


      • Pathogenesis: ischemic versus metabolic—ischemic cause favored in painful, asymmetrical neuropathy of sudden onset, mononeuropathy, and cranial neuropathy; metabolic cause favored in other forms (although this is debated).


      • NCV/EMG: “Gray zone”—both axonal and demyelinating features; NCVs mildly reduced with diminished amplitudes; focal slowing at sites of infarct or compression/trauma; sensory NCVs more sensitive; peroneal NCV best predictor of severity; NCV worse in poorly controlled and long-standing diabetic patients


      • Cerebrospinal fluid (CSF) protein may be elevated (50 to 200 mg/dL)


      • Neuropathy can be initial manifestation of diabetes.


      • Types (Remember, traumatic neuropathies are more common in diabetic patients.)



        • Symmetrical, distal, sensory greater than motor, chronic polyneuropathy (most common)



          • Nighttime paresthesias (painful) in feet


          • Lost ankle jerks, skin ulcers, and neuropathic joints present


          • Occasionally combined with proximal weakness and wasting and sensory loss on lower abdomen


          • May have severe sensory loss (dorsal column) with ataxia, bladder atony, unreactive pupils, limb weakness, neuropathic joints (diabetic pseudotabes)


        • Ophthalmoplegia



          • Usually pupil-sparing third nerve lesion; may affect sixth and seventh nerves


          • Usual spontaneous recovery in 6 to 12 weeks


        • Mononeuropathy or mononeuropathy multiplex



          • Mononeuropathies most commonly involve femoral and sciatic nerves, and, less commonly, median and ulnar nerves and lumbosacral plexus.


          • Compression neuropathies more common in diabetic patients


          • Acute onset, painful, motor sensory, usually remits, ischemic in nature


        • Diabetic amyotrophy



          • Painful, asymmetrical, unilateral or bilateral—lumbosacral plexopathy/mononeuropathy multiplex


          • Begins with pain in low back or hip, spreads to thigh/knee (aching with lancination), worse at night


          • Pelvofemoral muscle weakness and atrophy with lost knee jerks


          • Sphincter muscles may be involved; sensation may be spared.


          • Subacute onset in older diabetic patients with poorly controlled or unrecognized diabetes and severe weight loss



          • Tendency for recurrence on opposite side


          • Improvement or recovery in 6 to 18 months


          • Femoral NCV abnormal in two thirds of cases, and EMG invariably shows denervation


        • Diabetic polyradiculopathy



          • Syndrome of severe thoracoabdominal pain and dysesthesia, usually in older male type II diabetic patients who have experienced weight loss


          • Subacute onset with maximal intensity in weeks


          • Initial symptoms are sensory, but motor weakness develops in most patients, unilaterally in one third of them.


          • Increased CSF protein almost universal


          • Thoracic roots most commonly involved, especially T8 to T12


          • Usually asymmetrical and involves two or more contiguous roots


          • May occur in association with severe diffuse polyneuropathy, producing diabetic neuropathic cachexia


          • EMG is essentially sole means of confirming diagnosis—shows fibrillations and positive sharp waves in involved thoracic paraspinous muscles.


          • Commonly associated with sensorimotor polyneuropathy


          • Good prognosis for recovery


        • Autonomic neuropathy



          • Often superimposed on sensorimotor polyneuropathy


          • Pupillary and lacrimal dysfunction, impairment of sweating and vascular reflexes, nocturnal diarrhea, atonicity of GI and genitourinary tracts, impotence, postural hypotension


          • Pathologic evaluation shows degeneration of neurons in sympathetic ganglia, loss of myelinated fibers in vagus and splanchnic nerves, and loss of neurons in intermediolateral cell column.


          • Therapy



            • Postural hypotension—elevate head of bed 5 to 20 degrees, avoid certain drugs, liberal salt diet, elastic stockings; fludrocortisone (0.1 mg/d, increase to 0.5 mg two times a day), indomethacin (25 to 50 mg three times a day), dihydroergotamine (DHE) and caffeine (6.5 to 10 µg subcutaneously—plus 200 mg caffeine orally 30 minutes before breakfast)


            • Delayed gastric emptying—metoclopramide (10 mg before every meal and at bedtime)


            • Diarrhea—tetracycline (250 to 500 mg orally at onset)


            • Facial sweating after meals—propantheline bromide (15 mg 30 minutes before every meal and at social occasions)


        • Proximal symmetrical polyneuropathy



          • Symmetrical, proximal weakness and wasting usually without pain; insidious onset and chronic progression


          • Lower extremities more commonly involved


          • Sensory changes usually mild, if present


          • May be associated with distal, sensory polyneuropathy


        • Treatment



          • Control glucose (NCV improves with normalization of glucose.)


          • Meticulous foot care



          • Pain control (glucose control, tricyclics for burning pain, anticonvulsants for stabbing pain, fluphenazine for deep aching pain, mexiletine or capsaicin cream for painful mononeuropathies)


          • Avoid trauma.


          • Myoinositol, aldose reductase inhibitors, gangliosides may improve NCV.


          • May be subcategories of patients who would respond to immune-modulating therapy including those who have demyelinating neuropathy similar to CIDP and those who have mononeuropathy multiplex picture with inflammatory vasculopathy on biopsy pathologic findings.


    • Vasculitic neuropathies—most commonly mononeuropathy multiplex, but also see symmetrical or asymmetrical distal sensorimotor polyneuropathy; associated with systemic symptoms (weight loss, fever, malaise, anorexia), and evidence of multiple end-organ involvement and high ESR. Pathologically, see axonal degeneration, usually secondary to systemic necrotizing vasculitis; NCV shows sensory conduction more often affected. Diagnosis made by sural nerve biopsy; treatment with steroids and other immune-modulating therapies often beneficial



      • Polyarteritis nodosa


      • Rheumatoid arthritis


      • Systemic lupus erythematosus


      • Wegener granulomatosis


      • Progressive systemic sclerosis


      • Sjögren syndrome


      • Churg-Strauss syndrome


      • Temporal arteritis


      • Lymphomatoid granulomatosis


      • Hypersensitivity vasculitis


      • Amphetamine-induced vasculitis


      • Hypereosinophilic syndrome


      • Nonsystemic vasculitic neuropathy


    • Multifocal motor neuropathy (multifocal demyelinating neuropathy)



      • Subacute progression of mononeuropathy multiplex usually in arms, with pure motor weakness in 50% of cases


      • More common in men; two thirds of patients are younger than 45 years


      • Asymmetrical, distal weakness, beginning in hands in more than 80% of cases


      • Slow progression up to 20 years


      • Pain prominent with tender nerves


      • May be associated with optic neuropathy


      • Can mimic motor neuron disease (fasciculations in 25%, normal reflexes in 15%)


      • CSF protein increased in one third of cases


      • High anti-GM-l titer (350 or more) in 60% to 80% of cases, most common neuropathy associated with anti-GM-l antibodies (primarily polyclonal IgM)


      • NCV shows nonuniform demyelinating pattern with focal conduction block in multiple motor nerves, usually in short segments and not confined to usual sites of compression.


      • Pathologic evaluation shows demyelination—remyelination in 60% of cases and inflammatory cells in one-third.


      • Majority respond to immunomodulating therapy in a few weeks (cyclophosphamide greater than prednisone; also plasma exchange and intravenous immunoglobulin).



    • Sarcoidosis



      • Nervous system involvement in 5% of patients; 15% of this number have neuropathy.


      • Mononeuropathy multiplex most common, but also see cranial neuropathy (cranial nerve [CN] VII most common), symmetrical or asymmetrical polyneuropathy, or mononeuropathy


      • Neuropathy may be associated with myopathy or CNS involvement (basilar meningitis—pituitary stalk and hypothalamus).


      • Large, irregular zones of sensory loss over the trunk sometimes seen; said to distinguish sarcoidosis from other causes of mononeuropathy multiplex


      • Pathologic evaluation shows axonal degeneration, sometimes combined with segmental demyelination.


      • NCVs most consistent with axonal degeneration


      • Clinically improves with steroids


    • Lyme disease



      • Neuropathy occurs in 36% to 40% of patients with symptomatic late disease.


      • Acute and chronic forms of neuropathy



        • Acute—more severe; CN palsy and CSF pleocytosis present


        • Chronic—less severe; most common CSF finding is increased protein


        • Features in common:



          • Frequent radicular involvement


          • Features of mononeuropathy multiplex


          • Nerve biopsy findings of perivascular inflammation and axonal degeneration


          • Good response to antibiotics


      • Three patterns of Lyme neuropathy



        • Cranial neuropathy


        • Painful radiculopathy


        • Peripheral neuropathy


      • Sensory peripheral neuropathy most common, followed by painful radiculopathy and CN 7 palsy


      • Barnwarth syndrome—triad of lymphocytic meningitis with increased protein, cranial neuritis and radiculoneuritis following days to weeks after erythema chronicum migrans appears


      • Cranial neuropathy occurs early (often facial diplegia).


      • Peripheral neuropathy characterized by painful intermittent asymmetrical paresthesias, with rare motor weakness and hyporeflexia


      • Carpal tunnel syndrome incidence increased in patients with Lyme disease.


      • NCV compatible with axonal degeneration


    • Leprosy—mononeuropathy multiplex occurs in the tuberculoid form of this disease secondary to local granuloma formation (see later section).


    • Ischemic neuropathy


    • Bacterial endocarditis


    • HIV disease


III. Syndrome of Chronic Sensorimotor Polyneuropathy (less chronic acquired forms)



  • CIDP (see later section)


  • Diabetes (most common diabetic neuropathic syndrome—see previous section)


  • Alcoholic neuropathy and neuropathic beriberi—(see previous section)


  • Neuropathy associated with connective tissue diseases—(see previous section)



  • Paraneoplastic polyneuropathy—neuropathy in 2% to 5% of patients with malignancy



    • Sensorimotor polyneuropathy—not truly paraneoplastic, distal, symmetrical, and axonal; CSF protein usually normal


    • Subacute sensory neuronopathy—small-cell lung cancer, breast cancer, proprioceptive loss, paraneoplastic encephalomyelitis, anti-Hu antibodies found in 86% of cases in one series, CSF protein usually high, sensory neuronopathy inflammation and degeneration of dorsal root ganglion cells, degeneration of posterior roots and columns


    • Subacute to acute, primarily motor polyradiculoneuropathy—similar to GBS; lymphoma


    • Chronic, primarily motor polyradiculoneuropathy—similar to CIDP; demyelinating, CSF protein high


    • Paraneoplastic vasculitis—rare; lymphoma and lung cancer; high ESR and CSF protein; axonal mixed pattern


    • Autonomic neuropathy—small-cell lung cancer, pulmonary carcinoid, and Hodgkin disease


    • Paraneoplastic motor neuron syndrome—very rare; lymphoma (primarily), lung cancer, and renal cell carcinoma; mimics amyotrophic lateral sclerosis


  • Paraproteinemic or dysproteinemic polyneuropathies



    • Osteolytic multiple myeloma



      • Neuropathy present clinically in 13% of patients and electrophysiologically in another 26%


      • Two types



        • With amyloidosis (two-thirds)


        • Without amyloidosis (one-third)


      • Neuropathy without amyloidosis is heterogeneous and resembles axonal carcinomatous neuropathy.


      • Neuropathy with amyloidosis resembles that of nonhereditary systemic amyloidosis (see later section).


      • Treatment of myeloma usually does not affect neuropathy.


    • Osteosclerotic multiple myeloma



      • Associated with neuropathy 50% of time


      • Demyelinating, primarily motor neuropathy, with high CSF protein a (similar to CIDP)


      • Usually have IgG or IgA lambda light chain in serum


      • Treatment of tumor may result in remission of neuropathy.


    • Monoclonal gammopathy of undetermined significance



      • Of neuropathies associated with M-protein, 50% have monoclonal gammopathy of undetermined significance


      • Usually affects men older than 50 years


      • Insidious onset, distal (feet more so than hands) symmetrical sensory (mainly large fiber) and motor dysfunction


      • Associated with Raynaud phenomenon, ataxia, and action tremor


      • Demyelinating


      • CSF protein high


      • Anti-MAG antibodies seen in 50% of cases


      • Biopsy shows loss of myelinated fibers with monoclonal antibodies on myelin sheaths, hypertrophic changes



      • Treatment with immune modulating therapy



        • Therapeutic plasma exchange (TPE)


        • Prednisone


        • Intravenous Ig


        • Azathioprine


    • Waldenstrom macroglobulinemia



      • Neuropathy rare; usually chronic, sensorimotor, and symmetrical, but may be chiefly sensory, chiefly motor, subacute, and asymmetrical


      • Demyelinating and increased CSF protein


      • Treatment: may respond to chemotherapy and/or TPE, but less predictable and not immediate (should continue treatment at least 3 months)


    • Cryoglobulinemia



      • Neuropathy occurs in 7% of patients and is axonal and usually vasculitic (secondary to intravascular immune complex deposition and associated vasculitis).


      • Usually symmetrical or asymmetrical sensory neuropathy, associated with Raynaud phenomenon, purpuric lesions of ulcers of legs


      • Neuropathy precipitated by cold


      • Occasionally see mononeuropathy multiplex and may be acute


      • Treatment: prednisone, chlorambucil, cyclophosphamide, or TPE


    • Nonhereditary amyloid neuropathy



      • Neuropathy primarily sensory with prominent early loss of small fiber function, followed by progressive weakness and large fiber involvement


      • Dysautonomia often severe and debilitating as is pain associated with small-fiber damage


      • Sural nerve biopsy shows axonal degeneration with amyloid identifiable.


      • Carpal tunnel syndrome seen in 20% of patients


      • Secondary amyloidosis associated with malignant dysproteinemias and familial amyloid neuropathy also seen (see later section)


      • Poor response to therapy


  • Uremic polyneuropathy



    • Most common complication of chronic renal failure


    • 66% to 70% of patients on dialysis affected


    • Does not occur in acute renal failure


    • Duration and severity of renal failure and symptomatic uremia are the important factors in development of neuropathy.


    • Clinically, painless distal sensory loss followed by motor weakness of leg more so than arm


    • May begin with burning dysesthesias of feet and restless legs syndrome (creeping, crawling, itching of legs at night)


    • Pathologic evaluation shows primary axonal degeneration and secondary segmental demyelination.


    • Hemodialysis stabilizes or arrests the clinical and electrophysiologic signs.


    • Renal transplantation usually results in complete recovery after 6 to 12 months.


    • Uremia associated with two focal neuropathies:



      • Carpal tunnel syndrome


      • Ischemic monomelic neuropathy


  • Leprous polyneuritis



    • Most common neuropathy in the world


    • Neuropathy caused by direct invasion by Mycobacterium leprae



    • Initial lesion is anesthetic, hypopigmented skin macule, or papule caused by invasion of cutaneous nerves (indeterminate leprosy); after this stage, disease may take one of two forms: tuberculoid leprosy or lepromatous leprosy.


    • Tuberculoid leprosy—causes mononeuropathy multiplex by inclusion of larger nerves in region of granuloma formation (most frequently involved are ulnar, median, peroneal, posterior auricular, and facial); these nerves, as well as involved superficial sensory nerves, may be palpably enlarged.


    • Lepromatous leprosy—lack of resistance permits hematogenous spread to skin, ciliary bodies, testes, nodes, nerves; causes symmetrical or asymmetrical polyneuropathy with pain and temperature loss involving cooler body areas (pinnae of ears, dorsal hands and feet, anterolateral leg); motor dysfunction follows from invasion of nerves close to skin (ulnar at elbow, deep peroneal at ankle, superficial facial, median at wrist)


    • Deep tendon reflexes usually spared in face of widespread sensory loss (relatively sparing vibration/proprioception-syringomyelic pattern)


    • Trophic ulcers, Charcot joints, and mutilated digits common secondary to anesthesia


    • Pathologic evaluation shows segmental demyelination (organisms proliferate in Schwann cells).


    • Treatment: sulfone (Dapsone), rifampin, and clofazimine; thalidomide for skin lesions


  • Hypothyroid polyneuropathy



    • Infrequent complication


    • Two types seen:



      • Carpal and tarsal tunnel syndromes


      • Diffuse sensory more so than motor polyneuropathy


    • Axonal degeneration with segmental demyelination


    • CSF protein often increased


    • Reversible with thyroid hormone replacement


  • Chronic benign polyneuropathy of the older person


  • Acromegalic neuropathy



    • Carpal and tarsal tunnel syndromes


    • Pathologic evaluation shows segmental demyelination with onion-bulb formation


  • Critical illness polyneuropathy



    • Sepsis and critical illness occur in approximately 5% of intensive care unit (ICU) patients, and critical illness polyneuropathy occurs in 50% of these; incidence is 70% in patients with sepsis and multiorgan system failure.


    • Usually patients in ICU at least 1 week when earliest signs develop (e.g., difficulty weaning from the ventilator)


    • Later signs—distal weakness, decreased deep tendon reflexes; if severe, complete quadriplegia and respiratory paralysis (signs occur in 50% of patients; the other 50% are diagnosed by NCV/EMG)


    • NCVs are compatible with primary axonal degeneration, and EMG shows signs of denervation. (Decreased diaphragmatic CMAPs and signs of chest wall denervation establish critical illness polyneuropathy as the cause of difficulty of weaning; may be the most common cause of difficulty of weaning.)


    • Pathologic evaluation shows primary axonal degeneration distally, motor > sensory fibers, without inflammation; CSF protein usually normal



    • Critical illness polyneuropathy may occur outside the ICU in patients who develop sepsis in the course of severe renal failure.


    • Mild polyneuropathies may improve; severe ones may not


    • Pathophysiology—sepsis itself is the likely cause (disturbs the microcirculation of nerves, increases capillary permeability causing endoneurial edema with resultant hypoxia and axonal damage).


  • Neuropathy associated with antisulfatide antibodies



    • Sensory > motor involvement


    • Numbness or pain in feet and spreads proximal within 1 year


    • Loss of ankle jerks; other deep tendon reflexes preserved


    • Axonal degeneration with little if any demyelination


    • Antisulfatide antibodies >1,000 in 20% to 30% of cases


    • Intravenous Ig may be helpful.


  • Neuropathy associated with liver disease



    • Clinical peripheral neuropathy reported in 9% of patients with chronic liver disease, and NCVs abnormal in 14% to 68% of patients


    • Segmental demyelination


    • Neuropathy associated with primary biliary cirrhosis is painful; xanthoma formation in and around nerves


  • AIDS neuropathy



    • Types



      • Chronic predominantly sensory polyneuropathy (most common)


      • Acute inflammatory demyelinating polyneuropathy or CIDP


      • Mononeuritis multiplex (see earlier section)


      • Sensory ataxic neuropathy


      • Lumbosacral polyradiculopathy


  • Chronic ataxic neuropathy



    • Characterized by slow progression, distal paresthesias, sensory ataxia with profound loss of proprioceptive and kinesthetic sense, with normal strength


    • Clinically not different from paraneoplastic sensory neuropathy except that carcinoma is not found in these patients


    • Monoclonal or polyclonal gammopathy may be found.


    • EMG/NCV shows sensory neuronopathy pattern (absent sensory compound nerve action potential with normal motor NCV and EMG).


    • Sural nerve biopsy shows loss of myelinated fibers (large > small); regeneration of myelinated fibers may be seen; these findings are secondary to selective destruction of the distal root ganglion neuron.


  • Neuropathy associated with HTLV-1 myelopathy—subclinical inflammatory demyelinating neuropathy has been described in this disorder (motor > sensory).


  • GALOP antibody syndrome



    • Gait disorder, autoantibody, late age onset, polyneuropathy


    • Age at onset approximately 70 years


    • Weakness and sensory loss are primarily distal


    • IgM to sulfatides and central myelin antigen


  • POEMS syndrome



    • Polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes


    • Age at onset approximately 40 to 50 years



    • Weakness is common


    • CSF protein elevated


IV. Syndrome of hereditary chronic polyneuropathy (tends to be more chronic than acquired, progressive, symmetrical, and degenerative neuropathies).

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Sep 8, 2016 | Posted by in NEUROLOGY | Comments Off on Neuromuscular Diseases

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