The peripheral neuropathy

The peripheral nervous system, through its motor, sensory, and autonomic divisions,
serves as a major interface between the central nervous system and the
environment. Diseases of the peripheral nervous system, termed peripheral
neuropathies, are among the most prevalent neurologic conditions.

Differential diagnosis of peripheral nerve disease can be challenging because the

catalogue of disorders that can produce neuropathies is extensive. Although a wide
variety of symptoms and signs can result from diseases of the peripheral nervous
system, the spectrum of underlying cellular abnormalities is limited, so that only a few
clinical or pathologic features are specific to individual neuropathies.

Differential diagnosis in the peripheral nervous system begins with classification of

the clinical features of the neuropathy and uses elucidation of the underlying
pathophysiologic characteristics, primarily as reflected in electrodiagnostic tests, as a
differential

Peripheral nerves consist of an electrically active core, or axon, and an external fatty
layer of electrical insulation known as myelin. Axonal integrity is critical to action
potential propagation along the cellular membranes of either motor or sensory
nerves. Injury to the axon at any point along its course may block transmission.
Myelin is also critical to impulse transmission along the length of the axon and
increases conduction velocity through salutatory conduction, in which an impulse
leaps from node to node between myelin segments. Demyelination disrupts
salutatory conduction, slowing nerve conduction velocity. In addition, focal
demyelination can cause sufficient leakage of axonal current to halt action potential
propagation at a specific point along the nerve, causing conduction block.

The term peripheral neuropathy designates a disturbance in function of one or

more peripheral nerves. Several types of peripheral neuropathy are distinguishable
by the extent of involvement.
Depending upon the underlying cause, there may be selective involvement of motor,
sensory, or autonomic fibers or more diffuse involvement of all fibers in the peripheral
nerve.
The clinical deficit is usually a mixed one, and sensory symptoms and signs are often
the initial feature of peripheral nerve involvement.

Pathogenesis
Pathologically, nerve injury can be divided into four major categones.
1. Neuronal degeneration results from damage to the motor or sensory nerve
cell bodies, with subsequent degeneration of their contiguous peripheral axons.
2. Wallerian degeneration results from damage to the axon at a specific point
below the cell body, with degeneration distal to the injury.
3. Axonal degeneration results from diffuse axonal damage. Because the distal
portion of the axon is the furthest from the cell body, it undergoes the earliest and
most severe change during diffuse neuronal injury, accounting for initial symptoms in
the feet and hands, followed by gradual proximal ascent with continued injury (the so-
called dyingback phenomenon). Recovery from axonal degeneration requires nerve
regeneration, a disgracefully slow process.
 4. Finally, segmental demyelination results from injury to the myelin sheath
without injury to the axon.
Demyelination of a peripheral nerve at even a single site can block conduction,
resulting in a functional deficit identical to that seen after axonal degeneration. In
contrast to repair by regeneration, however, repair by remyelination can be quite
rapid. Autoimmune attack on the myelin sheath occurs in the inflammatory
demyelinating neuropathies. On the basis of the clinical features alone, it is difficult to
predict whether a patient has a predominantly axonal or demyelinating pattern of
peripheral nerve injury. Electrodiagnostic tests nerve conduction studies and
electromyography provide tools for assessing the relative contributions of axonal loss
and demyelination.

Approach to a patient with peripheral neuropathy

1. Temporal profile.
Acute, subacute, or chronic.
Progressive course or relapse-remitting.
2. Pattern of involvement.
3. Sensory or motor or mixed.
4. Painful or painless.
5. Autonomic involvement.
6. Cranial nerve involvement.
7. Past medical history.
8. Family history.
9. Hypertrophic nerve.
10. Myelinated or axonal or mixed nerve fibers involvement. Small or large nerve
fibers.
11. Skin, nail and hair manifestations.

Pattern of involvement.
1. MONONEUROPATHY refers to focal involvement of a single nerve trunk and
therefore implies a local cause.

Mononeuropathy simplex there is involvement of a single peripheral nerve. Direct

trauma, compression, and entrapment are the usual causes.
Ulnar neuropathies, due to lesions either at the ulnar groove or in the cubital tunnel,
and median neuropathy due to compression in the carpal tunnel constitute the great
majority of mononeuropathies encountered in clinical practice.

Cranial Mononeuropathy: Mononeuropathy affecting individual cranial nerves is a

large subject and is dealt with separately

Mononeuropathy multiplex (multifocal neuropathy): This term signifies that there

is involvement of various nerves but in an asymmetric manner and at different times,
so that the individual nerves involved can usually be identified until the disorder
reaches an advanced stage.

2. POLYNEUROPATHY refers to symmetrical simultaneous involvement of various

nerves. The first symptoms tend to be sensory and consist of tingling, prickling,
burning, or bandlike dysesthesias in the balls of the feet or tips of the toes, or in a
general distribution over the soles. Glove and stocks loss of sensation.
 CLINICAL MANIFESTATIONS
It depends on the type and distribution of the nerves that are affected as well as on
the severity of the disease.
MOTOR, SENSORY AND AUTONOMIC.
MOTOR: features of lower motor neuron lesion
SENSORY: features of positive or negative phenomena
AUTONOMIC: secretory (dry skin, eyes and mouth) and vasomotor symptoms
(tempreture instability, coldness, flushing), postural hypotension, disturbances of
cardiac rhythm, bladder, bowel, gastric, and sexual function.

Causes of peripheral neuropathy

 HEREDITARY NEUROPATHIES
 AQUIRED

1. IMMUNE-MEDIATED NEUROPATHIES
2. METABOLIC NEUROPATHIES
DIABETIC NEUROPATHIES
HEPATIC NEUROPATHY
UREMIC NEUROPATHY
3. TOXIN NEUROPATHIES
4. DRUGS NEUROPATHIES
5. ALCOHOL-NUTRITIONAL NEUROPATHY
6. NEUROPATHIES ASSOCIATED WITH INFECTIOUS DISEASES
7. ENTRAPMENT AND COMPRESSIVE NEUROPATHIES
8. PARANEOPLASTIC NEUROPATHIES
10. CRITICAL ILLNESS (SEPSIS) NEUROPATHY

 IDIOPATHIC

HOW DO YOU INVESTIGATE A PATIENT WITH PERIPHERAL NEUROPATHY

EMG and nerve conduction studies, the single most important diagnostic test for
the evaluation of neuropathy.

Several blood studies should be considered. Commonly ordered laboratory tests for
evaluation of peripheral neuropathy includes:
1. All patients with a peripheral neuropathy should have a complete blood count,
erythrocyte sedimentation rate or C-reactive protein, comprehensive metabolic
panel (fasting blood glucose, HbA1C, renal function, liver function), thyroid
function tests, urinalysis, serum B-12 and folate, and a serum protein
electrophoresis with immunofixation.
2. Immunologic screening (connective tissue screen, serum protein
electropheresis and Quantitative immunoglobulins).
3. Searches for infectious processes, particularly HIV and hepatitis, lyme titers
and rapid plasma regain.
 4. Other blood studies may also be indicated, including assays for antibodies
directed against specific nerve or myelin component. Serum cryoglobulins and
serum and urine heavy metal screening may be needed.

Lumbar puncture is especially important for the diagnosis of acute inflammatory

demyelinating polyradiculopathy and chronic inflammatory demyelination
polyradiculopathy, and may provide additional information regarding infectious and
neoplastic diseases as well, but is not needed for most neuropathy evaluations.

The indications for nerve biopsy are highly limited, and it should be used sparingly,
as harvesting of the sural nerve at the ankle (the most common procedure) carries a
10-15% risk of chronic neuropathic pain at the biopsy site. Biopsy can help to
establish the diagnosis in suspected. More refined diagnostic tools include
quantitative sensory testing, autonomic studies, and skin biopsy with staining and
quantitation of intraepidermal small sensory nerve fibers.

METABOLIC NEUROPATHIES

DIABETIC NEUROPATHIES
Diabetes is the most common cause of neuropathy. Approximately 50 percent having
some degree of neuropathy. This includes type I (insulin dependent, or juvenile,
diabetes) and type II (adult onset diabetes). However, only 20 percent of people with
diabetes have symptoms of neuropathy, with the others often unaware that they have
it, unless it is identified during examination.

Classification of Diabetic Neuropathies

A. Symmetric Diabetic (polyneuropathies)

1. Distal, primarily sensory symmetric polyneuropathy
2. Sensorimotor polyneuropathy
3. Autonomic neuropathy
4. Chronically evolving proximal motor neuropathy

B. Asymmetric (Diabetic mononeuropathies and plexopathies)

1. Cranial mononeuropathy
i. Diabetic third nerve palsy
ii. Diabetic fourth nerve palsy
2. Entrapment neuropathy in the limbs
3. Asymmetrical proximal motor neuropathy (Diabetic amyotrophy )

The incidence of peripheral nerve involvement may be influenced by the adequacy of

diabetes control, which should, in any event, be optimal.

The likelihood of developing neuropathy and the degree of severity increase with the
duration of the diabetes and the increase in blood sugar levels.
CLINICAL FEATURES
The most common manifestation is a distal sensory or mixed polyneuropathy, which
is sometimes diagnosed, before it becomes symptomatic, from the presence of
depressed tendon reflexes and impaired appreciation of vibration in the legs.
Symptoms are generally more common in the legs than in the arms and consist of
numbness, pain, or paresthesias. In severe cases, there is distal sensory loss in all
limbs and some accompanying motor disturbance. Diabetic dysautonomia leads to
many symptoms, including postural hypotension, disturbances of cardiac rhythm,
impaired thermoregulatory sweating, and disturbances of bladder, bowel, gastric, and
sexual function. Diabetic mononeuropathy multiplex is usually characterized by pain
and weakness and often has a vascular basis. The clinical deficit will depend on the
nerves that are affected. Diabetic amyotrophy is due to radiculoplexopathy,
polyradiculopathy, or polyradiculoneuropathy. Pain, weakness, and atrophy of pelvic
girdle and thigh muscles are typical, with absent quadriceps reflexes and little
sensory loss. Diabetic mononeuropathy simplex is typically abrupt in onset and often
painful. Cerebrospinal fluid (CSF) protein is typically increased in diabetic
polyneuropathy and mononeuropathy multiplex.

TREATMENT
No specific treatment exists for the peripheral nerve complications of diabetes except
when the patient has an entrapment neuropathy and may benefit from a
decompressive procedure.
Postural hypotension may respond to treatment with salt supplementation; sleeping
in an upright position; wearing waist-high elastic hosiery; fludrocortisone, 0.1–1 mg/d;
and midodrine, 10 mg three times daily.
Treatment is otherwise symptomatic.
Diabetic amyotrophy and mononeuropathy simplex usually improve or resolve
spontaneously.

IMMUNE-MEDIATED NEUROPATHIES
1. GUILLAIN-BARRE SYNDROME (ACUTE INFLAMMATORY
DEMYELINATING POLYNEURORADICULOPATHY).
2. CHRONIC INFLAMMATORY DEMYELINATING NEURORADICULOPATHY.

Acute Idiopathic Polyneuroradiculopathy (Guillain-Barré Syndrome)

Guillain-Barré syndrome is an acute polyneuroradiculopathy that develops after 1-4
weeks after minor infective illnesses (respiratory infection or diarrhea particularly
Campylobacter jejuni infection), inoculations, or surgical procedures or may occur
without obvious precipitants.
CLINICAL FEATURES
Symptoms and signs cease to progress by about 4 weeks into the illness. Patients
generally present with distal parasthesia and limb pain precede a rapidly ascending
weakness that is symmetric, usually begins in the legs, is often more marked
proximally than distally, and is sometimes so severe that it is life-threatening,
especially if the muscles of respiration or swallowing are involved. Facial weakness
commonly develops. Muscle wasting develops if axonal degeneration has occurred.
The deep tendon reflexes are typically absent. There may be marked autonomic
dysfunction, with tachycardia, cardiac irregularities, labile blood pressure, disturbed
sweating, impaired pulmonary function, sphincter disturbances.
INVESTIGATIVE STUDIES
The CSF often shows a characteristic abnormality, with increased protein
concentration but a normal cell count; abnormalities may not be found in the first
week, however. Electrophysiologic studies may reveal marked slowing of motor and
sensory conduction velocity. The time course of the electrophysiologic changes does
not necessarily parallel any clinical developments.
TREATMENT
Plasmapheresis appears to reduce the time required for recovery and may decrease
the likelihood of residual neurologic deficits. It is best instituted early, and it is
indicated especially in patients with a severe or rapidly progressive deficit or
respiratory compromise. Intravenous immunoglobulin (400 mg/kg/d for 5 days)
appears to be equally effective and should be used in preference to plasmapheresis
in adults with cardiovascular instability and in children; the two therapies are not
additive.
Therapy is otherwise symptomatic, the aim being to prevent such complications as
pressure sores, venous thrombosis, respiratory failure and vascular collapse. During
the phase of deterioration, regular monitoring of respiratory function is required. For
this reason, patients who are severely affected are best managed in intensive care
units, where facilities are available for monitoring and assisted respiration if
necessary.

PROGNOSIS
The disorder is self-limiting, and improvement occurs over the weeks or months
following onset. About 70–75% of patients recover completely, 25% are left with mild
neurologic deficits, and 5% die. The prognosis is poorer when there is evidence of
preceding Campylobacter jejuni infection, and a more protracted course and less
complete recovery are also likely when axonal degeneration rather than
demyelination is the primary pathology. Advanced age, the need for ventilatory
support, or more rapid onset of symptoms may also predict a poorer prognosis.

Chronic Inflammatory Demyelinating Polyneuroradiculopathy

Chronic inflammatory demyelinating polyneuroradiculopathy is clinically similar to
Guillain-Barré syndrome except that it follows a course characterized by relapses or
a chronic progressive course and no improvement is apparent within the 6 months
after onset. Its cause is not known. Examination of the CSF reveals findings
resembling those in Guillain-Barré syndrome. The electrophysiologic findings indicate
a demyelinative neuropathy with superimposed axonal degeneration. The disorder is
often responsive to treatment with corticosteroids, which may have to be continued
on a long term basis. Treatment with intravenous immunoglobulin is also effective as
initial or later therapy. When used as the initial therapy, it has the advantage of fewer
side effects than prednisone. Plasma exchange is another effective
immunomodulator therapy. In nonresponsive patients, treatment with azathioprine or
cyclophosphamide may be helpful.
Entrapment neuropathy
Certain peripheral nerves are particularly susceptible to mechanical injury at
vulnerable sites. The term entrapment neuropathy is used when the nerve is
compressed, stretched, or angulated by adjacent anatomic structures to such an
extent that dysfunction occurs.

Carpal tunnel syndrome

Compression of the median nerve can occur in the carpal tunnel at the wrist. Carpal
tunnel syndrome is common during pregnancy and can occur as a complication of
trauma, degenerative arthritis, tenosynovitis, myxedema, and acromegaly. Early
symptoms are pain and paresthesias confined to a median nerve distribution in the
hand, i.e. involving primarily the thumb, index, and middle fingers and the lateral half
of the ring finger. There may be pain in the forearm and, in occasional patients, even
in the upper arm, shoulder, and neck. Symptoms are often particularly troublesome
at night and may awaken the patient from sleep. As the neuropathy advances,
weakness and atrophy may eventually develop in the thenar muscles. Examination
reveals impaired cutaneous sensation in the median nerve distribution in the hand
and, with motor involvement, weakness and wasting of the abductor pollicis brevis
and opponens pollicis muscles. There may be a positive Tinel sign (percussion of the
nerve at the wrist causes paresthesias in its distribution) or a positive response to
Phalen's maneuver (flexion of the wrist for 1 minute exacerbates or reproduces
symptoms). The diagnosis can generally be confirmed by electrophysiologic studies,
showing sensory or motor conduction velocity to be slowed at the wrist; there may be
signs of chronic partial denervation in median-supplied muscles of the hand.
If the symptoms fail to respond to local corticosteroid injections or simple maneuvers
such as wearing a nocturnal wrist splint, surgical decompression of the carpal tunnel
may be necessary.

DISORDERS OF THE NEUROMUSCULAR

JUNCTION
Fatigue is a term used in physiological experiments on muscle to denote diminishing reaction to
stimulus applied.

Fatigue, is much more often a sign of disease outside the central and peripheral nervous system.
Depression and other psychiatric and behavioral disorders, as well as the medical illnesses
associated with a complaint of weakness, are all frequent causes of fatigue.

Peripheral fatigue could be an appropriate term for muscle fatigability due to disorders of muscle
and neuromuscular junction. Muscle fatigability, which is characterized by failure to sustain the
force of muscle contraction.
By contrast, the subjective sense of fatigue is essentially perceived at the level of the CNS, i.e.
central fatigue. This fatigue can be present in disorders of the peripheral, autonomic, and central
nervous system. It is consistently seen with lesions in pathways associated with arousal and
attention, reticular and limbic systems, and the basal ganglia. Central fatigue, however, is not
simply a sense of physical exhaustion; it also has an important cognitive component (mental
fatigue).

There are at least four different ways of thinking about symptomatic fatigue that reported
from patients:

 The first is a generalized lack of energy, often referred to as asthenia or neurasthenia.

 The second symptom of fatigue is mental exhaustion, similar to what one experiences after
a rigorous written examination.

 The inability to perform tasks that previously presented no challenge.

 The fourth type of symptomatic fatigue is delayed recovery following exercise.

MYASTHENIA GRAVIS

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission

that presents clinically as fluctuating skeletal muscle weakness often affecting
particular muscle groups preferentially. It is characterized by fluctuating weakness
and easy fatigability of voluntary muscles; muscle activity cannot be maintained, and
initially powerful movements weaken readily. There is a predilection for the external
ocular muscles and certain other cranial muscles, including the masticatory, facial,
pharyngeal, and laryngeal muscles. Respiratory and limb muscles may also be
affected. The target of the autoimmune attack is the skeletal muscle acetylcholine
receptor. Weakness is due to a variable block of neuromuscular transmission related
to an immune-mediated decrease in the number of functioning acetylcholine
receptors.
Myasthenia gravis can occur at any age and is sometimes associated with thymic
tumor, thyrotoxicosis, rheumatoid arthritis, or disseminated lupus erythematosus.

Clinical Findings
This disease usually presents between the ages 15 and 50 years, with women
affected more than men in the younger age groups and the reverse at older ages.
Although the onset of the disease is usually insidious, the disorder is sometimes
unmasked by a concurrent infection, which leads to an exacerbation of symptoms.
Exacerbations may also occur in pregnancy or before menses. Pregnancy may affect
the course of MG in an unpredictable way. Generally speaking, worsening of
symptoms most frequently occurs in the first trimester, or in the first 3 to 4 weeks
postpartum.
Symptoms may be worsened by medications that may exacerbate myasthenia gravis
which should therefore be avoided in such patients.
Patients present with ptosis, diplopia, difficulty in chewing or swallowing, nasal
speech, respiratory difficulties, or weakness of the limbs. These symptoms often
fluctuate in intensity during the day, and this diurnal variation is superimposed on
longer-term spontaneous relapses and remissions that may last for weeks.
Clinical examination confirms the weakness and fatigability of affected muscles. The
weakness does not conform to the distribution of any single nerve, root, or level of
the central nervous system. In more than 90% of cases the extraocular muscles are
involved, leading to often asymmetric ocular palsies and ptosis. Pupillary responses
are not affected. The characteristic feature of the disorder is that sustained activity of
affected muscles leads to temporarily increased weakness. Thus, sustained upgaze
for 2 minutes can lead to increased ptosis, with power in the affected muscles
improving after a brief rest.
Sensation is normal, and there are usually no reflex changes.

Diagnosis
The major tools used to confirm the clinical diagnosis of a disorder of neuromuscular
transmission may be divided into three main groups: pharmacologic,
electrophysiologic, and immunologic.
The diagnosis of myasthenia gravis can generally be confirmed by the benefit that
follows administration of anticholinesterase drugs; the power of affected muscles is
influenced at a dose that has no effect on normal muscles and slight, if any, effect on
muscles weakened by other causes.
The most commonly used pharmacological test is the edrophonium (Tensilon) test.
Edrophonium is given intravenously in a dose of 10 mg, of which 2 mg is given
initially and the remaining 8 mg about 30 seconds later if the test dose is well
tolerated. In myasthenic patients, there is an obvious improvement in the strength of
weak muscles that lasts for about 5 minutes.
Alternatively, 1.5 mg of neostigmine can be given intramuscularly, with a response
that lasts for about 2 hours; atropine sulfate (0.6 mg) should be available to
counteract the muscarinic cholinergic side effects of increased salivation, diarrhea,
and nausea. Atropine does not affect nicotinic cholinergic function at the
neuromuscular junction. The longer-acting neostigmine reduces the incidence of
false-negative evaluations.

Impaired neuromuscular transmission can be detected electrophysiologically.

Electrophysiologic studies are performed to confirm a defect in neuromuscular
transmission and also to exclude other diseases of the motor unit that may contribute
to the clinical presentation.
Measuring serum acetylcholine receptor antibody levels is often helpful, since
increased values are found in 80–90% of patients with generalized myasthenia
gravis.

X-rays and CT scans of the chest may reveal a coexisting thymoma.

Because MG often coexists with other autoimmune disorders, particularly thyroid
disease, baseline testing of thyroid function should be obtained at the time of MG
diagnosis, and other autoimmune serologics should be considered if clinically
indicated.

Treatment
The principles of treatment are:
1. To maximise the activity of acetylcholine at remaining receptors in the
neuromuscular junctions.
2. To limit or abolish the immunological attack on motor end plate.

The primary aim of treatment of MG is induction and maintenance of clinical

remission while minimizing adverse effects of therapy.

The treatment of myasthenia gravis includes:

1. Symptomatic (Nonimmune) Treatment: Cholinesterase inhibitors
Treatment with these drugs provides symptomatic benefit without influencing the
course of the underlying disease. The mainstay of treatment is pyridostigmine, at
doses individually determined. Small doses of atropine may attenuate side effects
such as bowel hypermotility or hypersalivation. Overmedication can lead to increased
weakness, which, unlike myasthenic weakness, is unaffected or enhanced by
intravenous edrophonium. Such a cholinergic crisis may be accompanied by pallor,
sweating, nausea, vomiting, salivation, colicky abdominal pain, and miosis.
2. Immune directed therapy of MG may be divided into short-term (rapid onset)
therapies and long-term therapies.
Long-term immune-directed therapies.
 Corticosteroids: Corticosteroids are indicated for patients who have responded
poorly to anticholinesterase drugs. Treatment is initiated with the patient in the
hospital, as weakness may initially be exacerbated. An initial high dose of
prednisone (60–100 mg/d orally) can gradually be tapered to a relatively low
maintenance level (5–15 mg/d) as improvement occurs. Alternate-day
treatment is helpful in reducing the incidence of side effects.
 Thymectomy: Thymectomy usually leads to symptomatic benefit or remission,
but the mechanism by which it confers benefit is unclear, and its beneficial
effect may not be evident immediately.
 Azathioprine: This drug can be used in patients with severe or progressive
disease despite thymectomy and treatment with anticholinesterases and
corticosteroids. It can also be given in place of high doses of corticosteroids to
patients who show no sustained benefit with low doses.

Short-term immune-directed therapies.

 Plasmapheresis: Plasmapheresis may be used to achieve temporary
improvement in patients deteriorating rapidly or in myasthenic crisis, and in
 certain special circumstances, such as prior to surgery that is likely to produce
postoperative respiratory compromise and to overcome dipping in patient with
steroid therapy.
 Intravenous immunoglobulins: Intravenous immunoglobulins have also been
used to provide temporary benefit in circumstances similar to those in which
plasmapheresis is used.
3. Medications that impair neuromuscular transmission should be avoided.
Aminoglycosides (gentamicin, streptomycin), Macrolides (erythromycin,
azithromycin), Fluoroquinolones (ciprofloxacin), Calcium channel blockers, Beta-
blockers, Statin drugs, phenytoin, penicillamine, lithium.

Therapeutic Strategy
Treatment decisions must be individualized based on MG severity and coexisting
disease, and patient participation in these decisions is essential to successful
management.
Most patients improve, usually markedly, in response to appropriate treatment.
Myasthenic symptoms should be initially managed with a cholinesterase inhibitor with
dose optimization until it is clear that either complete control of symptoms is not
possible or the required doses are intolerable. Patients with more than mild
weakness affecting oropharyngeal and respiratory muscles should be treated with a
course of Plasmapheresis or Intravenous immunoglobulins in combination with
initiation of steroid therapy to mitigate steroid induced disease worsening. Early
addition of asteroid-sparing agent azathioprine is considered for patients with
moderate or severe disease, particularly those with an incomplete response to high
dose daily prednisone. In patients with milder disease, a steroid-sparing agent may
be added after failure of prednisone tapering. In patients with disease onset prior to
age 50, thymectomy and possibly enrollment in the ongoing multinational
thymectomy trial should be considered as a long-term option for immune modulation.
If the prednisone can eventually be tapered to zero, the dose of the steroid-sparing
agent may be reduced very slowly to determine the minimum required dose.
Improvement induced by immunotherapy rarely persists if all immune-directed
treatments are completely discontinued. As patient response to therapy is variable in
MG, a ladder of treatment choices is necessary in the event that standard drugs are
either ineffective or not tolerated.

Special Therapeutic Situations

Myasthenic crisis.
The classic definition of myasthenic crisis is weakness from MG that is severe
enough to necessitate intubation for ventilator support or airway protection. It is
estimated that one of every five patients with MG will suffer myasthenic crisis at
some point during their illness. All patients with severe MG exacerbations, producing
prominent oropharyngeal and respiratory muscle symptoms, should be managed in
an intensive care setting with frequent and close monitoring.
Indications for intubation generally include evidence of respiratory muscle fatigue
with increasing tachypnea and declining tidal volumes, hypoxemia, hypercapnia, and
difficulty with secretions. In general patients with a forced vital capacity of below 1L
will require mechanical ventilatory support.
A precipitating factor can be identified in most cases of myasthenic crisis and most
commonly include one or more of the following: bronchopulmonary infections,
aspiration, surgical procedures including thymectomy, corticosteroid-induced
worsening, rapid tapering of immune modulators, and exposure to drugs that may
increase myasthenic weakness. Excessive dosing of cholinesterase inhibitors can
potentially increase weakness due to depolarization blockade. In addition to
weakness, signs of cholinergic hyperactivity will be present, such as excessive
salivation, increased bronchial secretions, muscle fasciculations, and abdominal
cramping. It is recommended practice to discontinue the use of cholinesterase
inhibitors following intubations reduce these symptoms, as they may complicate the
management of airway secretions. Because of its rapid onset of action,
plasmapheresis is the favored treatment for myasthenic crisis. Similar efficacy of
Intravenous immunoglobulins compared with plasmapheresis.
Weaning trials should begin after patients demonstrate a clear trend of improved
respiratory muscle strength (usually at a vital capacity greater than15 mL/kg). The
trial should be terminated if the patient exhibits any sign of respiratory fatigue
(tachypnea, tachycardia, diaphoresis, or agitation).

Ocular myasthenia gravis.

Ocular MG is the designation given to patients who have signs and symptoms solely
in the ocular muscles (eyelid elevators and extraocular muscles). Ptosis and/or
diplopia are the initial symptoms of MG in up to 85% of patients, and almost all
patients have both symptoms within 2 years of disease onset. If weakness remains
limited to the ocular muscles after 2 years, there is a 90% likelihood that the disease
will not generalize. If ocular symptoms are adequately controlled with cholinesterase
inhibitors, these patients may be reassured that immunosuppressive medications and
thymectomy may be avoided.
Treatment of ocular MG requires an accurate assessment of the patient's functional
impairment and its effects on daily life. While cholinesterase inhibitors may control
symptoms adequately in some patients, the benefit is often partial and not long-lived,
and prednisone is often quite effective. Prednisone treatment may delay or reduce
the frequency of progression of ocular MG to generalized disease.

PROGNOSIS
Early in the course of MG, symptoms may fluctuate and remissions lasting months or
longer are not uncommon, although rarely permanent. Maximum disease severity is
reached within 2 years of disease onset in two-thirds of patients. In most patients, the
active stage of disease, characterized by relapses and remission, may last 7 to 8
years. This is followed by a relatively inactive stage lasting approximately 10 years
and a final stage of ‘‘burned out’’ disease. It is important to recognize that during the
‘‘inactive’’stage, disease exacerbations may still be precipitated by intercurrent
illness, exposure to drugs that adversely effect neuromuscular transmission, or
pregnancy.
MG can now be treated effectively in most patients with minimal long-term morbidity.
The amount of fixed weakness experienced in the ultimate stage of disease may be
dependent on the effectiveness of immunotherapy during the active stage. Recent
advances in intensive care and immunotherapy have contributed to a very favorable
prognosis for MG in most patients.
The disease may have a fatal outcome because of respiratory complications such as
aspiration pneumonia.