Theme: Hereditary neuro-muscular diseases:

primary myodystrophies (Erb-Rot, Duchenne, Dejerine),

neurogenic amyotrophies

(Werdnig-Hoffmann, Kugelberg-Velander, Aran-Duchenne, Charcot-Marie-Tooth),

Thomson myotonia, paroxysmal myoplegia, Myasthenia Gravis

Hereditary - degenerative diseases with dominant lesion of pyramidal (Schtrumpel’s paraplegia), extrapyramidal (Parkinson’s disease, Hepatolenticular degeneration (Wilson’s disease), Torsion dystonia (spasm), Huntington’s chorea) system and cerebellum (Friedreich’s and Mary ataxias)

All the hereditary diseases of nervous system are divided into:

1. Diseases with involvement of nervous – muscle synapse:

A. Myasthenia

B. Myasthenic syndromes

2. Hereditary diseases with involvement of pyramidal system:

A. Spastic paraplegia of Shtrumpel

B. Family spastic paralysis with amyotrophy, oligophrenia, retina degeneration (described by Kellin)

C. Family spastic paralysis with ichthyosis and oligophrenia

3. Diseases with involvement of extrapyramidal system:

A. Hepato – cerebral degeneration

B. Dystonia

C. Double athetosis

D. Huntington disease

E. Parkinson disease

F. Myoclonus – epilepsy

G. Tourette syndrome

H. Hereditary trembling

I. Rulph seizure

J. Palpebral – mandibular synkinesis

4. Hereditary ataxia

A. Spinal ataxia of Fridreich

B. Hereditary cerebellar ataxia of Pier – Mary

C. Olivo – ponto – cerebellar degeneration

D. Refsum disease

E. Rusi – Levina disease

F. Marinesku – Shagrena disease

G. Lichtenshtein – Knorr disease

5. Diseases with involvement of neuro – muscular junction:

I. Progressive muscular dystrophy

A. Dushen pseudo – hypertrophic muscle dystrophy

B. Late Bekker pseudo – hypertrophic muscle dystrophy

C. Myodystrophy Emeri – Dreiphus

D. Family visceral myopathy

E. Shoulder – scapula – facial form of Landuzi – Degerina

F. Scapula – peroneal form of Davidenkova

G. Erba dystrophy

H. Ophthalmoplegic myopathy

I. Dystal myopathy of Wallender

J. Inborn nonprogressive forms of myopathy

II. Amyotrophy as a result of peripheral neuron lesion

A. Spinal amyotrophy of Werding – Hoffman

B. Proximal amyotrophy of Kukelberg – Welander

C. Kennedy amyotrophy

D. Sharkot – Marie – Tooth disease

E. Hypertrophic neuritis

6. Family – hereditary myotonia:

A. Myotonia Tomsena

B. Atonic myotonia

C. Paramyotonia of Alenburg

D. Chondro – dystrophic myotonia

7. Hereditary diseases with paroxysmal states:

A. Paroxysmal family myoplegia

B. Episodic hereditary adynamia

C. Mac – Ardel disease

D. Episodic myotonic adynamia of Bekker

Myasthenia

Myasthenia gravis (MG) is caused by a defect of neuromuscular transmission due to an antibody-mediated attack on nicotinic acetylcholine receptors (AchR) at neuromuscular junctions. It is characterized by fluctuating weakness that is improved by inhibitors of cholinesterase.

Incidence

MG is a common disease. An apparent increase in the incidence of the disease in recent years is probably due to improved diagnosis. According to Phillips and Torner (1996), the prevalence rate is 14 per 100,000 (or about 17,000 cases) in the United States. Before age 40 years, the disease is three times more common in women, but at older ages both sexes are equally affected.

Etiology

How the autoimmune disorder starts is not known. In human disease, in contrast to experimental MG in animals, the thymus gland is almost always abnormal; there are often multiple lymphoid follicles with germinal centers ("hyperplasia of the thymus"), and in about 15% of patients, there is an encapsulated benign tumor, a thymoma. These abnormalities are impressive because the normal thymus is responsible for the maturation of T-cells that mediate immune protection without promoting autoimmune responses.

There are few familial cases of the disease, but disproportionate frequency of some HLA haplotypes (B8, DR3, DQB1) in MG patients suggests that genetic predisposition may be important. Other autoimmune diseases also seem to occur with disproportionate frequency in patients with MG, especially hyperthyroidism and other thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, and pemphigus.

Pathogenesis

The polyclonal IgG antibodies to AChR are produced by plasma cells in peripheral lymphoid organs, bone marrow, and thymus. These cells are derived from B cells that have been activated by antigen-specific T-helper (CD4+) cells. The T-cells have also been activated. In this case by binding to AChR antigenic peptide sequences (epitopes) that rest within the histocompatibility antigens on the surface of antigen-presenting cells.

The AChR antibodies react with multiple determinants, and enough antibody circulates to saturate up to 80% of all AChR sites on muscle. A small percentage of the anti-AChR molecules interfere directly with the binding of ACh, but the major damage to endplates seems to result from actual loss of receptors due to complement-mediated lysis of the membrane and to acceleration of normal degradative processes (internalization, endocytosis, lysosomal hydrolysis) with inadequate replacement by new synthesis. As a consequence of the loss of AChR and the erosion and simplification of the endplates, the amplitude of miniature endplate potentials is about 20% of normal, and patients are abnormally sensitive to the competitive antagonist curare. The characteristic decremental response to repetitive stimulation of the motor nerve reflects failure of endplate potentials to reach threshold so that progressively fewer fibers respond to arrival of a nerve impulse.

Most AChR antibodies are directed against antigenic determinants other than the ACh binding site. Nevertheless, the summed effects of the polyclonal anti-AChR antibodies with differing modes of action result in destruction of the receptors. Physiologic studies indicate impaired postsynaptic responsiveness to ACh, which accounts for the physiologic abnormalities, clinical symptoms, and beneficial effects of drugs that inhibit acetylcholinesterase.

Clinical features

The typical sign of myasthenia is muscles weakness. One of the most specific features of this weakness is its increasing with movements. The disease develops at the age of 20 – 30 years old. Before age 40 years, the disease is three times more common in women, but at older ages both sexes are equally affected. The disease is developed subacutely or chronically in most cases.

According to the course of the disease there are such forms:

1. Progressive

2. Stationary

3. Mysthenic episodes

Clinical forms:

1. Ophthalmic

2. Bulbar

3. Skeletal

4. General

Ophthalmic The most common signs are ptosis, diplopia and eyes movement disturbances. Typical features:

1. Asymmetric lesion

2. Dynamic symptoms (the signs increase in the evening)

Ophthalmoplegia is a very common symptom. The other ones are:

- Weakness of mimic muscles – especially oral muscles.

- Weakness of chewing muscles.

- Weakness of pharyngeal, laryngeal muscles and muscles of tongue

- Tongue muscles function disorders

- Breathing disturbances

- Extremities function disturbances (especially proximal parts)

- Neck muscles weakness – hanging of the head

- Body muscles weakness that leads to duck – like gait

Sensory and pelvic disorders usually are not observed.

Diagnosis

1. Complains on general weakness that increases in the evening

2. Early symmetric lesion of external eyes muscles

Tests for this disease revealing

The patient is asked to look upwards or inside during 30 seconds in order to cause ptosis. He is asked to read text aloud in order to cause dysarthria. The patient is asked to make 100 chewing movements in order to reveal the weakness of these muscles.

Proserine test. Proserine is introduced in dose 1.5 – 3 ml s/c, sometimes Atropinum is used in order to prevent side effects. In 20 – 40 min all the signs of myasthenia disappear. In 2 – 3 hours all the symptoms appear again.

EMG – myasthenic reaction. Test is positive in 85% of patients with skeletal form.

Muscle biopsy – muscle atrophy and signs of degeneration.

CT reveals timoma signs. In 90% of all patients antibodies to ACHR are found.

X-rey examination

Differential diagnosis

§ Botulism

§ Neurasthenia

§ LAS

§ Polineuropathy

§ Muscles dystrophy

§ Inflammatory myopathy

§ MS

§ Stroke in v/b region

§ Brain stem tumor

Treatment

1. Compensation of neuro – muscular transference

2. Thymus influence

3. Correction of immune disorders

1. Anticholinestherase medicines –

Caliminum – 30 mg 3 times per day.

Proserinum – 0.5 – 1.5 mg s/c

2. K drugs 3 – 4 g per day.

3. Corticoids – we start from 15–20 mg a day, than increase gradually on 5 mg every 3 day

4. Anabolics – Retabolil 50 mg once every 3 days, 5 – 6 injections.

5. Immune suppressors – Asatioprinum in dose 50 – 150 – 200 mg per day

6. Plasmapheresis - at acute and progressive form

7. Radiation therapy of thymus

8. Methabolic drugs

At myasthenia crisis:

§ Plasmapheresis

§ Ig i/v (2 g per kg 2 – 5 days)

§ Corticoids (100 mg prednisonum)

§ Proserinum 1 – 2 ml i/v

§ SLV, oxygen

§ Halloperidolum at excitation

Cholinergic crisis

There fasciculations, seizures, bradycardia, salivation, hyperhydrosis and abdominal pain.

Treatment – Atropinum 1 ml 0.1 % s/c or i/v.

DISORDERS OF THE NEUROMUSCULAR JUNCTION

Myasthenia Gravis

Definition

Myasthenia gravis is characterized by progressive muscular weakness on exertion, followed by recovery of strength after a period of rest. It is an autoimmune condition in which there is an antibody-mediated autoimmune attack directed against acetylcholine receptors at neuromuscular junctions.

The Normal Neuromuscular Junction The neuromuscular junction is illustrated schematically m Figure 20-3. Acetylcholine is contained in synaptic vesicles that fuse with the presynaptic membrane and Myelin sheath Axon release a small quantity of acetylcholine into the synaptic cleft. The acetylcholine then diffuses across the cleft and binds to acetylcholine receptors on the postsynaptic membrane. The attachment produces a conformational change that opens the sodium and potassium channels of the postsynaptic membrane. There is a constant and spontaneous release of acetylcholine in small quantities, which is not sufficient to depolarize the membrane but does result in what has been termed "miniature end plate potentials." Bound acetylcholine is removed by diffusion or hydrolyza-tion by the enzyme acetylcholine esterase, which is concentrated in the postsynaptic membrane. The receptor probably remains refractory for some time after this hydrolysis has occurred.

In physiological muscle contraction, the impulse generated in the motor neuron reaches the presynaptic membrane, causing depolarization, which results in a coordinated release of acetylcholine. The acetylcholine diffuses across the cleft in sufficient quantity to produce a wave of depolarization that is propagated down the muscle fiber. The propagated electrical discharge produces changes in the sarcoplasmic reticulum of the muscle fiber, with release of calcium ions, which promotes fiber contraction. There is an ample reserve of acetylcholine receptors sufficient in number to allow repetitive depolarization of the membrane and repeated muscle fiber contraction.

Etiology and Pathology

The postsynaptic membrane is abnormal in myasthenia gravis. There is a loss of secondary folds, which reduces the surface area available for binding of acetylcholine, and there is a decreased number of acetylcholine receptors. The decrease is due, in part, to the blocking of acetylcholine binding sites of the acetylcholine receptor by blocking antibodies. In addition, there is an accelerated degradation of receptors, because antibodies cross-link the receptors, which are drawn together in clusters, internalized by endocytosis, and degraded.¹⁰⁵ The antibodies vary in their capacity to block receptor binding sites or accelerate degradation, but increasing activity of antibodies appears to be associated with increasing severity of the myasthenic response. During repetitive stimulation of the nerve, the available acetylcholine receptors are quickly saturated and remain refractory. This results in a state of receptor insufficiency in which there is not a sufficient number of receptors available to bind acetylcholine and produce depolarization. Therefore, repetitive stimulation will result in a decrease in the number of muscle fibers that are able to respond, as each neuromuscular junction reaches a state of receptor insufficiency. Clinically, this is characterized by a progressive weakness.

The antibodies, which are of the IgG class, are probably produced by B lymphocytes, although T lymphocytes from patients with myasthenia gravis respond to stimulation with acetylcholine receptors, and the production of acetylcholine receptor antibodies. The autoimmune response probably arises in the thymus, because 70 percent of patients with myasthenia gravis have hyperplasia or thymomas, which are of microscopic size in rare cases, and thymectomy is an effective treatment in most cases. The normal and myasthenic thymus contains myoid (muscle-like) cells with surface acetylcholinic receptors.

These cells may be particularly susceptible to an immune reaction, possibly triggered by a viral infection, resulting in changes to the myoid cells and the surrounding lymphocytes within the thymus, and an autoimmune response. One possible mechanism is molecular mimicry, in which there is an immune response to an infectious agent such as herpes simplex virus, which contains a peptide sequence homologous to a sequence on the acetylcholine receptor subunit.

However, not all myasthenics show detectable levels of antibodies to acetylcholine receptors, implying that myasthenia gravis is not a homogenous disorder, and that other, as yet undetected, antibodies may occur in some cases.

Clinical Features

Myasthenia gravis is uncommon, with a prevalence of about 1/10,000. The disease is more common among women than men, with a ratio of 2:1. The mean age of onset is 26 years in women and 31 years in men. The incidence in men does not show a smooth distribution. The peak incidence in the early thirties declines through middle age, but there is a second peak between 60 and 78 years of age in men. Why this does not occur in women is unknown. The disease can occur at any age and has been reported in the newborn. There is no significant family occurrence and no genetic pattern has been identified.

Myasthenia gravis can be classified into four groups, or types:

Group 1. Ocular myasthenia.

Group 2. Mild generalized myasthenia.

Group 3. Severe generalized myasthenia.

Group 4. Crisis.

Ocular Myasthenia In this form of myasthenia gravis, the symptoms and signs are confined to the extraocular muscles. The paient develops diplopia and ptosis, usually toward the end of the day. Ocular myasthenia remains localized to the extraocular and eyelid muscles in about 15 percent of cases, but about 85 percent of patients develop generalized myasthenia within a period of 18 months. Nevertheless, ocular myasthenia differs from generalized myasthenia because of male preponderance, low antibody titers, and different histocompatibility and antigen association. Symptoms consist of unilateral or bilateral ptosis and diplopia. The degree of ptosis is variable and may present on one side or the other at different times. There may be quick lid retraction or twitching of the levator palpebrae elicited by having the patient rapidly redirect the gaze from a downward to a neutral position. Eye movements may be saccadic, jerking, or quivering, with gaze-evoked nystagmus.

Mild Generalized Myasthenia Mild generalized myasthenia may be preceded by ocular myasthenia or may present with symptoms of mild weakness involving the extraocular muscles and other muscle groups. There is usually some involvement of the facial muscles, muscles of mastication, and the proximal limb-girdle muscles, while the extraocular muscles are frequently but not invariably involved. This may present with some difficulty in diagosis, particularly when the proximal limb-girdle musculature is the sole site of presentation. When mild generalized myasthenia develops into the severe generalized form of the disease, the transition usually occurs within a period of 18 months.

Severe Generalized Myasthenia In the severe generalized form of myasthenia gravis, there is sufficient weakness of the bulbar and limb girdle musculature to produce marked restriction in activity. Exercise tolerance is reduced, the patient has a sedentary existence, and there is a constant risk of respiratory insufficiency, respiratory infection, or respiratory failure.

Crisis Myasthenic crisis may be defined as myasthenia gravis with respiratory failure. This is a life-threatening situation that develops in patients with severe generalized myasthenia. The onset is often sudden, and crisis is often precipitated by an infection. This usually takes the form of an upper respiratory tract infection that progresses to severe bronchitis or pneumonia.

The stages of myasthenia are not fixed, and it is not unusual for progression to occur from one stage to another within a period of 18 months. Remission can occur in any of the first three stages of myasthenia gravis. However, remission usually occurs within

the first 18 months of the disease and is rare at a later stage. Spontaneous remission can be expected in about 25 percent of cases but lasts no longer than 2 years"⁰ in most cases. Some patients experience several periods of remission.

At the initial interview, the patient with myasthenia gravis should receive a full generalized physical examination, which helps to exclude a number of conditions known to be associated with myasthenia gravis, particularly thyrotoxicosis. This is followed by a full neurological examination, with careful documentation of the degree of muscle involvement. The examiner should attempt to demonstrate progressive weakness of the affected muscles. In the patient with ptosis, the examiner measures the widths of the palpebral fissures, and the patient is then asked to sustain upward gaze. This will produce an increasing degree of ptosis, which can be observed and measured. Similarly, patients with diplopia can be asked to sustain gaze in the direction of the pull of the involved muscle, and the examiner may observe increasing deviation of the ocular axis while the patient complains of progressive diplopia and further separation of the two images. Patients with weakness of the masseters can be asked to bite down on a tongue blade while the examiner attempts to withdraw it. This maneuver will produce fatigue of the masseters, and biting will not be sustained after a short period of time. The patient with a generalized form of the disease may show increasing weakness on stressing any of the muscles involved in the disease process. When the hands are involved, it is possible to obtain a quantitative measure of weakness using a dynamometer.

Diagnostic Procedures

1. Edrophonium (Tensilon) test. Edrophonium is a rapidly acting anticholinesterase inhibitor that blocks the action of acetylcholinesterase. Hydrolysis of acetylcholine is prevented, thus allowing more time for an attachment of acetylcholine molecules to receptor sites. The test is performed as follows:

The examiner selects a weak muscle. For example, if the patient has ptosis, the width of the palpebral fissure can be measured. If the patient has diplopia, the degree of deviation of the ocular axis can be estimated; or if the patient has weakness on chewing, the time that the patient is able to sustain biting of the tongue blade can be recorded. The examiner then draws 10 mg (1 mL) edrophonium into a syringe. The test begins with the intravenous injection of 2 mg (0.2 mL) edrophonium into a vein in the forearm. The examiner then waits 30 s to make sure that the patient does not have any muscarinic reaction to edrophonium. This usually consists of bradycardia, hypertension, lacrimation, sweating, or abdominal colic. If this does not occur, the remaining 8 mg (0.8 mL) edrophonium is injected. If the test is positive, there will be a dramatic response, with increasing strength of the paretic muscle within a period of 30 s. This increasing strength usually lasts about 2 min, then disappears. However, the patient will usually express an appreciation of the increasing strength of the weakened muscle, and the examiner will be able to observe this effect. The test is safe to perform, and adverse effects are unusual. If severe muscarinic adverse effects occur, they can be rapidly resolved by intravenous injection of 0.4 mg atropine.

2. Electromyography and repetitive nerve stimulation. Needle electrode myography is performed in patients with suspected myasthenia gravis or in those who have disorders affecting the neuromuscular junction, which may mimic or coexist with myasthenia gravis, including Lambert-Eaton myasthenic syndrome, drug-induced myasthenic syndrome, peripheral neuropathies, or myopathies, all of which may present with progressive fatigue on exertion. This is particularly valuable when the Tensilon test is equivocal but should also be performed when it is positive. In myasthenia gravis, the electromyogram shows variation in amplitude of motor unit action potentials measured on an oscilloscope on sustained voluntary contraction. This is a result of intermittent failure of synaptic transmission of some of the muscle fibers involved in the motor unit action potential. The abnormality is reversed by administration of edrophonium in patients with myasthenia gravis.

Conventional electromyography should be followed by repetitive nerve stimulation. Cholinesterase inhibitors should be discontinued for at least 12 h before testing. Repetitive nerve stimulation at rates of 3 to 5 Hz, and a supramaximal stimulus of 25 to 50 percent greater than the stimulus intensity necessary to activate all muscle fibers, should be used. In myas-

thenia gravis, the result is a decremental response greater than 10 percent to trains of 3 to 5 Hz stimuli, indicating abnormal neuromuscular transmission.¹¹¹ Maximal voluntary contraction for 30 to 60 s may be followed by partial repair of the decremental response, followed by postcontraction exhaustion 3 to 4 min later.

3. Elevated levels of antibodies to acetylcholine receptors occurs in most cases. Titers do not provide a measure of the severity of the disease but can be used to monitor the effect of treatment on an individual basis.

Failure to detect antibody levels occurs in about 10 to 15 percent of cases, with a generalized form of myasthenia in about 50 percent of cases with ocular myasthenia.

Patients with the generalized form of myasthenia gravis and negative serum antibodies, who fail to respond to repetitive nerve stimulation, often have abnormal response to single fiber electromyography. This technique can also be applied to the extraocular muscles for the diagnosis of ocular myasthenia gravis.¹¹²

4. Muscle biopsy should be performed when the diagnosis is uncertain, and there is a suspicion that there may be an underlying myopathic process with myasthenic features, such as polymyositis. Techniques for immunohistologic study of motor end plates, and quantification of acetylcholine receptors, are available.

After a diagnosis of myasthenia gravis has been established, a series of tests should be performed to rule out associated diseases. These include: (1) a CT scan or MRI scan of the chest should be obtained to eliminate the possibility of a thymic tumor, which occurs in about 18 percent of cases with myasthenia gravis, particularly in elderly men; (2) thyroid function tests should be performed to eliminate the possibility of hyperthyroidism. Thyrotropin-binding inhibitory immunoglobulin determination is indicated in myasthenia gravis patients with exophthalmus and normal thyroid function"¹; (3) an associated collagen vascular disease should be ruled out by appropriate testing, including antinuclear antibodies (ANA), anti-DNA antibodies, anticardiolipin, SSA and SSB antibodies, rheumatoid factor, and complement C3, C4, and CH-50. This will tend to eliminate collagen vascular diseases such as systemic lupus erythematosus,¹¹⁴ myxedema, thyrotoxicosis, or rheumatoid arthritis; (4) patients with a severe generalized form of the disease should have respiratory function tests performed as soon as the diagnosis is suspected, and every 12 h during treatment, or whenever respiratory insufficiency is suspected. Tests include determination of respiratory muscle strength by testing maximal expiratory pressure (PE_max), maximal inspiratory pressure (PI_max), and vital capacity. PE_m]n and PE_max are more sensitive indicators of early respiratory muscle weakness than vital capacity. However, in general, elective endotracheal intubation is performed when the vital capacity is less than 10 to 15 mL/kg. Although respiratory impairment is usually attributed to weakness of the diaphragm and chest wall muscles, upper airway obstruction should also be considered and can be demonstrated by inspiratory and expiratory flow volume loop determination.

Arterial blood gases are not a reliable method of monitoring patients with myasthenia gravis because the carbon dioxide level can remain deceptively normal until just before respiratory failure.

Differential Diagnosis

1. Polymyositis. The patient with polymyositis may have symmetrical proximal limb-girdle muscle weakness. Some patients show a positive response to edrophonium and the diagnosis can be established only by electromyography and muscle biopsy.

2. Thyrotoxicosis. Thyroid myopathy presents as a proximal limb-girdle muscle weakness. The association of myasthenia gravis and thyrotoxicosis is not unusual, and the presence of myasthenia gravis in a patient with thyrotoxicosis can be suspected if improvement is seen following the edrophonium test. Patients with thyroid myopathy usually do not show improvement following the intravenous administration of edrophonium.

3. Exophthalmic ophthalmoplegia may be progressive and may resemble myasthenia gravis in the early stages. There is progressive weakness of the extraocular muscles, with replacement of muscle by fat and marked fatty infiltration of the orbit, producing ex-ophthalmus. The response to edrophonium is absent,

but thyrotropin-binding inhibitory immunoglobulin determination is positive and particularly indicated in myasthenia gravis patients with exophthalmus and normal thyroid function. Exophthalmic ophthalmoplegia and myasthenia gravis can coexist, in which case the response to edrophonium may be positive.

4. Myasthenic syndrome (Lambert-Eaton syndrome). This condition is rare and occurs in association with neoplasia. The muscle weakness involves the proximal limb-girdle muscles and the diagnosis can be established by the characteristic findings on electromyography (see p. 649).

5. Mitochondrial myopathies (see p. 649) including chronic progressive external ophthalmoplegia, presenting with ptosis and weakness, increasing with exertion, will occasionally respond to anticholinesterase therapy. Such cases have appropriate responses on electrophysiological testing, including single fiber electromyographic studies. However, anti-acetylcholinesterase antibodies are negative. Muscle biopsy will confirm the presence of mitochondrial myopathy in seronegative cases.

6. There may be more than a chance but rare association between myasthenia gravis and sarcoidosis.

7. The association of myasthenia gravis in lymphoma has been reported.

8. Myasthenia gravis might be one of the neuromuscular complications of HIV infection.

9. Periodic paralysis.

10. Botulism.

11. Miscellaneous (penicillamine, acetylcholinesterase agents, particularly organophosphorous compounds).

Table 20-3

Drugs Which May Induce or Exacerbate Myasthenia Gravis

Antibiotics
ampicillin	kanamycin
ciprofloxacin	lincomycin
clindamycin	neomycin
colistin	polymyxin
erythromycin	streptomycin
imipenem	tobramycin
Anesthetics
ether	ketamine
halothane	methoxyflurane
Anticonvulsants
phenytoin sodium	trimethadione
Antiarrthymics
beta adrenergic receptor	Other agents
blockade	procainamide
acebutolol	quinidine sulfate
oxprenolol	verapamil
practolol
propranolol
timolol
Anticholinergics
trihexyphenidyl HC1
Antirheumatic
chloroquine	D-penicillamine
Immunosuppressives
corticosteroids	interferon alpha
Psychotropics
amphetamines	bromperidol
amitriptyline	haloperidol
barbiturates	imipramine
chlorpromazine	lithium
Miscellaneous
Anticoagulants
amantadine	procaine
carnitine	radiocontrast media
chlorine gas	a) iothalamic acid
levonorgestrel	b) diatrizoate megulmine
methocarbamol	magnesium citrate
nicotine transdermal

Modified from Wittbrodt ET: Drugs and myasthenia gravis. An update. Arch Intern Med 157:399, 1997.

Treatment

Group 1 and group 2 patients may be treated as outpatients. Group 3 patients should be admitted to the hospital. Certain drugs may induce or exacerbate myasthenia gravis (Table 20-3).

1. The anticholinesterase drugs were the first effective treatment for myasthenia gravis and are still widely used. Some evidence suggests that anticholinesterase drugs may increase damage to the postsynaptic membrane, and there is a present trend to restrict the use of anticholinesterase drugs to those with mild disease who show good response.

Patients with mild myasthenia should be given pyridostigmine bromide (Mestinon) 30 mg q4-6 h or neostigmine bromide (Prostigmin) 15 mg over the same time period. Pyridostigmine bromide time-tablets (180 mg) have a longer duration of action and may be used at night. At the next outpatient visit, a Tensilon test should be performed immediately before the next dose of the anticholinesterase preparation. If the test is positive, the physician has the option of increasing the dosage or decreasing the time between administration of the anticholinesterase drugs. In this way, the optimum dose of pyridostigmine or neostigmine can be calculated for each patient. The response to anticholinesterase drugs is good in about 50 percent of patients. Administration of anticholinesterase drugs may be limited by the development of cholinergic side effects, including colic, diarrhea, blurred vision, and bradycardia. Care is needed in administration of anticholinesterase drugs to the elderly because accumulation of acetylcholine at receptor sites in the heart may result in bradycardia, nodal rhythm, atrial fibrillation, or flutter. Hypotensive syncope has also been recorded.

Patients with group 3, or the severe generalized form of myasthenia, should always be admitted to the hospital for treatment. Following admission, an intravenous catheter should be placed; this facilitates the performance of the Tensilon test. The patient is then given 60 mg pyridostigmine orally. The Tensilon test is performed just before the next dose is due, and the dose of medication is increased if the test is positive. Again, this method allows the development of the optimum dose for the patient.

2. Corticosteroids are widely used in the treatment of myasthenia gravis and probably act as an immunosuppressant, suppressing the action of B lymphocytes. All patients scheduled to receive corticosteroids should be screened for tuberculosis, and those with oropharyngeal involvement or respiratory impairment should be treated with plasmapheresis until there is improvement in muscle strength. At that point, prednisone 100 mg/day (methylprednisolone 96 mg/day) is started and maintained for 10 days, followed by alternate-day therapy at the same dose, which is monitored until the maximum benefit is ob tained. The dose is gradually decreased until the patient shows signs of weakness, then increased by a small amount. This is the maintenance dose, which can be continued indefinitely in most cases. Anticholinesterase drugs can be reduced or eliminated in many cases, and the morbidity of thymectomy is reduced, particularly following surgery.

Remission or marked improvement can be expected in 75 percent of cases treated with high-dose oral corticosteroids. Nevertheless, about 30 percent of patients show temporary worsening, lasting about 6 days, during the first 3 weeks of high-dose therapy.This complication can usually be managed with anticholinesterase drugs or can be avoided by introducing steroids in low dosage (prednisone 10 to 25 mg/day) and gradually increasing by 10-mg increments every 5 days until maximum improvement occurs. The dose can then be decreased, using an alternate-day regimen, as described above, until the maintenance dose is established.

Adverse effects of corticosteroid therapy are inevitable if high-dose therapy is prolonged. The adverse effects include cushingoid appearance, weight gain, hypertension, cutaneous striae, diabetes melli-tus, cataracts, peptic ulcer, osteoporosis, and aseptic necrosis of the femoral head. A weight maintenance diet with low sodium and supplementary calcium is indicated. At the patient's first complaint of gastritis, H₂ antagonists should be used to prevent the development of peptic ulcer.

3. Thymectomy is recommended for patients between the ages of puberty and 60 years or those who have generalized myasthenia gravis. Thymectomy is usually delayed until after puberty because of the significant role of the thymus in the development of the immune system. The results of thymectomy are better in those with nonneoplastic thymic hyperplasia than in those with thymoma, but the latter should always be removed, because of the propensity for local invasion, including spread into the lungs.

The surgical approach to thymectomy involves splitting the sternum and exploring the anterior mediastinum. This permits the removal of the thymus (or thymoma) and any ectopic thymic tissue in the mediastinum or lower cervical area. The alternative methods of cervical thymectomy and transcervical thymectomy carry less morbidity but may fail to detect

ectopic thymic tissue. This is less likely with newer fiberoptic technology (thoracoscopy) or visual-assisted thoracoscopy, which provides complete visualization of the thorax. The midline sternotomy is necessary when the thymus is large or when a thymoma is adherent to vascular structures.

Recurrence of thymoma is rare, the reoperative rate reported as 3.6 percent. Thymectomy may be followed by a drug-free remission or by marked reduction in the need for anticholinesterase drugs or other therapies. In some cases, improvement is delayed for months or years after thymectomy, suggesting the presence of residual thymic tissue. This is often ectopic thymic tissue which was not removed during surgery.

4. Immunosuppressant drugs. Azathioprine (Imuran) acts predominantly on T cells and is useful in patients with myasthenia gravis when corticosteroids are ineffective or contraindicated. Treatment begins with a first dose of a 50 mg tablet daily for 1 week. If there are no adverse reactions to the drug, the dose can be increased gradually to 3.0 mg/kg per day if necessary. This is usually effective, but the response is slow, and improvement may not occur for many months.

Adverse effects include an influenza-like reaction in about 10 percent of cases. Other adverse effects include leukopenia, anemia, thrombocytopenia, increase in liver enzyme levels, and gastrointestinal upset. Azathioprine is often used in conjunction with corticosteroids and has a steroid-sparing action, delaying the development of steroid side effects. Many patients require lifelong azathioprine therapy, and any attempt to withdraw the drug without introducing another therapy results in clinical relapse in approximately 50 percent of cases. A short course of corticosteroids or plasmapheresis can be used to control symptoms in such patients, while azathioprine is reintroduced.

5. Plasmapheresis acts by reducing circulating antibodies against acetylcholine receptor and is an accepted method for treating patients with myasthenia gravis when other treatments have been ineffective.¹²⁶ Plasmapheresis is effective alone or in combination with azathioprine. The patient will show a good response to plasmapheresis within a short period of treatment, and this response may be maintained for as long as 6 months. At present, it seems that this form of therapy may have to be repeated at intervals varying from 3 weeks to 6 months.

Plasmapheresis carries a risk of anaphylactic reaction and viral infections, which can be eliminated by immunoadsorption. This technique selectively removes acetylcholine receptor antibodies by adsorption from the plasma, with reinfusion of fluid in the system at the end of the procedure, thus eliminating the need for infusion of plasma proteins used in plasmapheresis.

6. Intravenous immunoglobulin (IVIG). Improvement in myasthenia has been reported following a high dose of intravenous human immunoglobulin 2 g/kg over 2 to 5 days, with increased muscle strength lasting several weeks. Adverse effects including headaches, chills, fever, impaired renal function, cerebral infarction, and aseptic meningitis have been reported. All patients should be screened for impaired renal function before contemplating therapy.

7. Other therapies. Antilymphocytic globulin and antithymocytic globulin have produced improvement in some patients with myasthenia. Aminopy-ridines, particularly 4-amino pyridine, facilitate transmitter release at central and peripheral synapses, and may be of benefit in refractory cases.

Treatment of Myasthenic Crisis

Myasthenic crisis should be regarded as a medical emergency. The condition generally results from gradual failure of response to anticholinesterase drugs. This failure may be precipitated by an upper respiratory tract infection, pneumonia, extreme fatigue, or alcoholic intoxication. The artificial division of patients into myasthenic crisis and cholinergic crisis is no longer tenable. The patient who develops respiratory failure (vital capacity less than 10 to 15 mL/kg) should be diagnosed as crisis and treated as follows.

1. The patient should be intubated, receive mechanical ventilation, and be treated in an intensive care unit.

2. All medications should be discontinued.

3. Because myasthenic crises are precipitated by infection, a diligent search should be made for an infectious process. A chest film should be taken to rule out pneumonia or atelectasis. Infection requires prompt treatment with appropriate antibiotic therapy.

4. The patient should be instructed to suction secretions from the mouth and pharynx using a soft plastic catheter. In cases of extreme weakness, this must be done regularly by those in attendance.

5. The patient should be turned q2h in bed to prevent atelectasis and encourage the flow of secretions from the lungs. This also helps to prevent the development of decubiti.

6. When patients are free from infection, or when infection is controlled by appropriate antibiotics, corticosteroid therapy can be commenced with 100 mg mefhylprednisolone intravenously piggyback daily. Corticosteroid therapy should be supplemented by antacid therapy. The corticosteroids occasionally produce increasing weakness beginning on the second or third day after therapy is started, reaching a maximum effect on the fifth day. This is followed by rapid recovery of strength. Some patients show an increase in strength immediately following the administration of corticosteroids, and in other patients, there may be no response for as long as 3 weeks. When improvement occurs, the dosage of corticosteroids can be converted to an alternate-day basis and then gradually reduced once the patient shows good response to therapy.

7. The patient should have respiratory function tests performed at the bedside at least twice a day. The determination of vital capacity is often all that is necessary, and the patient should be removed from the mechanical ventilator and placed on a T-bar with oxygen when the vital capacity reaches 10 mL/kg.¹³²

8. Once the patient is extubated, treatment should be continued for a severe generalized form of myasthenia gravis.

9. An alternative form of treating patients in crisis is to perform plasmapheresis, which reduces the circulating acetylcholine receptor antibodies and often produces dramatic improvement.

10. The treatment of myasthenia gravis has improved dramatically following the introduction of corticosteroids, immunosuppressants, plasmaphere sis, and IVIG. The prognosis of crisis has improved following the widespread use of mechanical ventilators and the wide range of drug therapies available.

DRUG-INDUCED MYASTHENIA SYNDROME

Drug-induced myasthenia is characterized by reversible myasthenic symptoms associated with a particular drug. Several drugs have been reported to cause a reversible myasthenic syndrome (see Table 20-3).

Lambert-Eaton Syndrome (Myasthenic Syndrome)

Definition Lambert-Eaton syndrome is believed to represent failure of release of acetylcholine at the neuromuscular junction.

Etiology

The syndrome represents an autoimmune condition associated with a number of neoplasms, more than 50 percent of which are small-cell carcinoma of the lung. Noncancerous Lambert-Eaton syndrome occurs in about one-third of cases and is associated with other autoimmune disorders, including multiple sclerosis, rheumatoid arthritis, scleroderma, psoriasis, asthma, and ulcerative colitis. The syndrome is believed to be due to the binding of an IgG antibody to voltage-gated calcium channels in the nerve terminal. These channels fail to function when depolarization occurs, leading to failure of fusion of acetylcholine-containing vesicles within the nerve terminal membrane, and reduction and release of acetylcholine into the synaptic cleft.

Clinical Features

The disorder is characterized by proximal muscle weakness, hyporeflexia, and autonomic dysfunction. The weakness affects the proximal lower limb-girdle muscles, with minimal involvement of the upper extremities and the ocular and facial muscles.

Autonomic dysfunction results in sluggish pupillary reaction to light and photophobia, dryness of the mouth and failure of erection in men. Hypo-hidrosis, orthostatic hypotension, and bladder dysfunction may occur in some cases. Spontaneous respiratory failure has been reported and there may be prolonged apnea or hypoventilation after anesthesia.

Diagnostic Procedures

1. On electromyography, there is a low-amplitude response to single stimulation and further decrease occurs with low rates of stimulation. Higher rates of stimulation, such as 50 evoked potentials per second, produce a marked increase in amplitude of the evoked motor unit potential.

2. Between 50 and 60 percent of patients show antibodies directed at voltage-gated calcium channels in the nerve terminal.

3. Chest MRI and CT scans to reveal small-cell carcinoma of the lung are indicated in all new cases of Lambert-Eaton syndrome.

Treatment

1. Remission will occur in some cases, after removal of the neoplasm, but others remain symptomatic despite tumor removal. Resumption of symptoms after tumor removal indicates tumor recurrence.

2. There may be some improvement in strength with anticholinesterase medication such as pyridostigmine, but the response is usually less effective therapy than in myasthenia gravis.

3. 4-Aminopyridine, a potassium channel-blocking agent, enhances acetylcholine release and improves muscle strength in Lambert-Eaton syndrome. Seizures may occur with doses necessary to produce improved strength. 3-4-Diaminopyridine, with more potent action at the neuromuscular junction and less convulsant properties, can be used alone or in combination with pyridostigmine and anticonvulsant medication, if necessary.

4. Immunosuppressant therapy using prednisone or azathioprine, singly or in combination, is effective in some cases.

5. Plasmapheresis or IVIG may be effective, but the benefits are usually temporary.

6. Guanidine hydrochloride 25 mg tid, increasing slowly up to 35 mg/kg per day, can be used as a last resort, because of adverse effects including nausea, colic, renal and hematological complications.

Congenital Myasthenic Syndromes

These rare disorders usually present in infancy or childhood, but symptoms may be delayed in mild cases until adult life. There are several conditions included in the syndrome, which should be suspected in individuals showing progressive weakness on exertion, who have a negative intravenous edrophonium test, and absence of acetylcholine receptor antibodies. Electromyography, including single fiber electromyogram, and muscle biopsy with electron microscopy are required to establish the diagnosis.

Tick Paralysis

Definition

Tick paralysis is an acute onset of muscle weakness proceeding to generalized paralysis associated with injection of venom through the skin by a gravid female tick of Dermacentor andersoni, Der-macentor variabilis, and Dermacentor occidentalis in North America and Ixodes holocyclus or Ixodes cor-nuatis in Australia. Although the disease has been described throughout North America, it is usually encountered in the states west of the Rocky Mountains and in British Columbia and Alberta in Canada.

Etiology and Pathology

The condition appears to be caused by the absorption of a toxic substance that prevents depolarization of the neuromuscular junction. There are no described pathological changes.

Clinical Features

Tick paralysis has been reported in children of both sexes, and there may be a history of exposure to ticks by playing in infested grass or woods. The symptoms appear 3 to 5 days after the tick attaches itself to the skin and are often preceded by malaise, irritability, and diarrhea. Weakness begins in the lower extremities and spreads rapidly, so that the child shows complete symmetrical paralysis of all voluntary muscles within 24 h. Bulbar or respiratory muscle involvement can occur, and assisted ventilation may be necessary. Examination reveals the presence of a tick that is attached to the skin and frequently obscured by hair on the scalp of the patient.

Diagnostic Procedures

1. The history of possible exposure to ticks may be obtained.

2. The diagnosis is established by finding the tick.

Treatment Improvement occurs when the tick is removed. This can be accomplished by the application of petroleum jelly and removal some 20 min later, with forceps pressed down on either side of the mouth parts, to grasp the hypostome of the tick, the gentle detachment by lifting or an upward levering action.

Parkinsonism

Parkinsonism – is a chronic progressive neurodegenerative syndrome that is characterized by motor disorders as a result of extrapyramidal system involvement.

Parkinson disease (PD) – is a chronic progressive degenerative disease of CNS that manifest as voluntary movements disorders. PD was described by James Parkinson for the first time in 1817 as shaking paralysis.

Epidemiology The prevalence of PD is 133 per 100 000 people. This disease is considered to be one of the most common ones among old people after dementia, epilepsy, cerebral vascular diseases. The beginning of the disease is at the age of 55. The most common factors that lead to the disease are – old age, inheritance, toxic agents.

Old age Every 10 years the person looses 8% of all neurons. But the symptoms of PD manifest only when 80% of all neurons will be lost.

Inheritance The inheritance of the disease can be proved by:

· Association of PD with dementia

· Rapid progress of the disease

Toxins There are a lot of toxic substances that can provoke PD.

The other reasons of PD development are:

· Viral infections

· Cerebral vessels sclerosis

· Severe cranial trauma

· Long lasting usage of neuroleptics, reserpinum medicines

Pathogenesis The core biochemical pathology in parkinsonism is decreased dopaminergic neurotransmission in the basal ganglia. Degeneration of the nigrostriatal dopamine system results in marked loss of striatal dopamine content. Drug-induced parkinsonism is the result of blockade of dopamin receptors or depletion of dopamine storage. It is not known how hydrocephalus or abnormal calcium metabolism produces parkinsonism. Physiologically, the decreased dopaminergic activity in the striatum leads to disinhibition of the subthalamic nucleus and the medial globus pallidus, which is the predominant efferent nucleus in the basal ganglia. Understanding the biochemical pathology led to dopamine replacement therapy; understanding the physiologic change led to surgical interventions, such as pallidotomy, thalamotomy, and subthalmic nucleus stimulation.

Clinical features The main signs of PD are:

1. Hypokinesia

2. Rigidity

3. Resting trembling

4. Loss of postural reflexes.

The clinical features of tremor, rigidity, and flexed posture are referred to as positive phenomena as reviewed first; bradykinesia, loss of postural reflexes, and freezing are negative phenomena. In general, the negative phenomena are the more disabling. Rest tremor at a frequency of 4 to 5 Hz is present in the extremities, almost always distally; the classic "pill-rolling" tremor involves the thumb and forearms Rest tremor disappears with action but reemerges as the limbs maintain a posture. Rest tremor is al: common in the lips, chin, and tongue. Rest tremor of the hands increases with walking and may be early sign when others are not yet present. Stress worsens the tremor.

Rigidity is an increase of muscle tone that is elicited when the examiner moves the patient's limbs, neck or trunk. This increased resistance to passive movement is equal in all directions and usually is mat by a ratchety "give" during the movement. This so-called cogwheeling is caused by the underlying tremor even in the absence of visible tremor. Cogwheeling also occurs in patients with essential tremor. Rigidity of the passive limb increases while another limb is engaged in voluntary active movement

The flexed posture commonly begins in the arms and spreads to involve the entire body . The head is bowed, the trunk is bent forward, the back is kyphotic, the arms are held in front of the body, and the elbows, hips, and knees are flexed. Deformities of the hands include ulnar deviation of the hands, flexion of the metacarpal-phalangeal joints, and extension of the interphalangeal joints (striatal hand). Inversion of the feet is apparent, and the big toes may be dorsiflexed (striatal toe). Lateral tilting of the trunk is common.

Akinesia is a term used interchangeably with bradykinesia and hypokinesia. Bradykinesia (slowness of movement, difficulty initiating movement, and loss of automatic movement) and hypokinesia (reduction in amplitude of movement, particularly with repetitive movements, so-called decrementing) are the common features of parkinsonism, although they may appear after the tremor. Bradykinesia has m; facets, depending on the affected body parts. The face loses spontaneous expression (masked facie: hypomimia) with decreased frequency of blinking. Poverty of spontaneous movement is characterized by loss of gesturing and by the patient's tendency to sit motionless. Speech becomes soft (hypophonia, and the voice has a monotonous tone with a lack of inflection (aprosody). Some patients do not enunciate clearly (dysarthria) and do not separate syllables clearly, thus running the words together (tachyphemia). Bradykinesia of the dominant hand results in small and slow handwriting (micrographia and in difficulty shaving, brushing teeth, combing hair, buttoning, or applying makeup. Playing mi instruments is impaired. Walking is slow, with a shortened stride length and a tendency to shuffle; swing decreases and eventually is lost. Difficulty rising from a deep chair, getting out of automobiles and turning in bed are symptoms of truncal bradykinesia. Drooling saliva results from failure to swallow spontaneously, a feature of bradykinesia, and is not caused by excessive production of saliva. The patients can swallow properly when asked to do so, but only constant reminders allow them to keep swallowing. Similarly, arm swing can be normal if the patient voluntarily and, with effort, wishes 1 have the arms swing on walking. Pronounced bradykinesia prevents a patient with parkinsonism fir driving an automobile; foot movement from the accelerator to the brake pedal is too slow.

Bradykinesia is commonly misinterpreted by patients as weakness. Fatigue, a common complaint in parkinsonism, particularly in the mild stage of the disease before pronounced slowness appears, may be related to mild bradykinesia or rigidity. Subtle signs of bradykinesia can be detected even in the early stage of parkinsonism if one examines for slowness in shrugging the shoulders, lack of gesturing, decreased arm swing, and decrementing amplitude of rapid successive movements. With advancing bradykinesia, slowness and difficulty in the execution of activities of daily living increase. A meal normally consumed in 20 minutes may be only half eaten in an hour or more. Swallowing may become impaired with advancing disease, and choking and aspiration are concerns.

Loss of postural reflexes leads to falling and eventually to inability to stand unassisted. Postural reflexes are tested by the pull-test, which is performed by the examiner, who stands behind the patient, gives a sudden firm pull on the shoulders, and checks for retropulsion. With advance warning, a normal person can recover within one step. The examiner should always be prepared to catch the patient when this test is conducted; otherwise, a person who has lost postural reflexes could fall. As postural reflexes are impaired, the patient collapses into the chair on attempting to sit down (sitting en bloc). Walking is marked by festination, whereby the patient walks faster and faster, trying to move the feet forward to be under the flexed body's center of gravity and thus prevent falling.

The freezing phenomenon (motor block) is transient inability to perform active movements. It most often affects the legs when walking but also can involve eyelid opening (known as apraxia of lid opening or levator inhibition), speaking (palilalia), and writing. Freezing occurs suddenly and is transient, lasting usually no more than several seconds with each occurrence. The feet seem as if "glued to the ground" and then suddenly become "unstuck," allowing the patient to walk again. Freezing typically occurs when the patient begins to walk ("start-hesitation"), attempts to turn while walking, approaches a destination, such as a chair in which to sit (destination-hesitation), and is fearful about inability to deal with perceived barriers or time-restricted activities, such as entering revolving doors, elevator doors that may close, and crossing heavily trafficked streets (sudden transient freezing). Freezing is often overcome by visual clues, such as having the patient step over objects, and is much less frequent when the patient is going up steps than when walking on a level ground. The combination of freezing and loss of postural reflexes is particularly devastating. When the feet suddenly stop moving forward, the patient falls because the upper part of the body continues in motion as a result of the inability to recover an upright posture. Falling is responsible for the high incidence of hip fractures in parkinsonian patients. Likely related to the freezing phenomenon is the difficulty for parkinsonian patients to perform two motor acts simultaneously.

The main clinical forms

1. Trembling

2. Rigidity

3. Mixed

Severity stages:

I – loss of activity, but that doesn’t influence on professional activity and working ability

II – moderate loss of professional activity

III – the patients need someone to look after him

Treatment Treatment of parkinsonism in general is based on the treatment of PD. At present, treatment is aimed at controlling symptoms because no drug or surgical approach unequivocally prevents progression of the disease. Treatment is individualized because each patient a unique set of symptoms, signs, response to medications, and a host of social, occupational, and emotional needs that must be considered. The goal is to keep the patient functioning independently long as possible. Practical guides are the symptoms and degree of functional impairment and the expected benefits and risks of therapeutic agents.

1. Synthetic holinolytics : Cyclodolum ( 0.01, 0.005 ), Romparkin, Parkopan ( 0.001, 0.002 )

Stimulators of dophamine secretion

2. Amantadine medications increase sensation of dophamine receptors to dophamine, excite dophamine receptors. Midantan ( 0.1 3 times per day ), Amantadinum.

3. Inhibitors of MAO ( Jumex ) - 5 mg 1 – 2 times per day.

4. Stimulators of dophamine receptors – Bromcriptine, Akineton, Norakin ( 0.001 – 0.002).

5. Medications that decrease converse catch of dophamine. Amitriptilinum, Amipraminum, Melipraminum.

6. Substitutional therapy . Sinemet 3 – 6 tablets per day. Nacom - 3 – 6 tablets per day.

7. In order to decrease tremor we use b – adrenoblockers : Anaprilinum 10 mg 3 times per day, Amitriptilinum 25 mg 3 times per day.

8. In order to decrease muscle tonus Midocalm, Baclofen are used.

9. Nootrops

10. Physiotherapeutic methods.

Hereditary diseases with involvement of pyramidal system

Spastic paraplegia of Shtrumpel

This disease is the result of pyramidal tracts and cerebellar connections degeneration.

The disease is genetically recessive in most cases but in some families it show dominant inheritance.

Clinical features. The first signs of the disease are observed at the age of 10–15. The typical signs of the disease are lower spastic paraplegia with increased muscle tonus, high stretch reflexes, pathological reflexes. Usually the lesion of lower extremities is symmetrical. Sometimes motor disorders can be developed in upper extremities. In some cases pseudobulbar symptoms are joined.

The typical signs of the disease:

· The dominance of spastic tonus over motor disorders

· Well preserved abdominal reflexes

· The absence of pelvic disorders

The typical clinical picture of spastic paraplegia is often associated with cerebellar symptoms and symptoms of posterior spinal columns. The progress of the disease is slow.

Recessive form of spastic paraplegia differs by early beginning and much more severe course of the disease. In some families this disease is observed in men only.

Differential diagnosis

· LAS

· Multiple sclerosis

· Vascular myelopathy

· Cerebral palsy

Hepatocerebral dystrophy (HCD)( Wilson – Konovalov disease)

This disease is connected with disorders of ceruloplasminum metabolism. Ceruloplasminum is a blood protein responsible for Cu transport. It is produced in liver. Pathologically there is accommodation of Cu in subcortical ganglions (especially n. Lenticularis), brain cortex, cerebellum, liver, spleen, iris.

The disease is genetically autosomal – recessive. And it is observed in male and female with the same frequency.

Clinical signs of the disease

The first signs of the disease are observed in early childhood. There are neck stiffness, different hyperkinesis and psychiatric changes. Sometimes seizures can be observed. There is also liver enlargement. One of the most specific changes is Kaizer – Fleishner ring in the iris.

According to the Konovalov classification there are 4 main neurological types of the disease:

1. Rigid – arythmokinetic

2. Trembling – rigid

3. Trembling

4. Extrapyramidal – cortical

Sometimes the disease manifests only as liver insufficiency and neurological signs are joined later.

Diagnosis

· Family history

· The typical signs of the disease – Kaizer – Fleishner ring, lesion of liver, low quantity of ceruloplasminum in the blood, increased quantity of Cu in urine.

Differential diagnosis

· Huntington disease

· MS

· Chronic stage of epidemic encephalitis

Torsion dystonia

The pathology of the disease includes degenerative changes of subcortical ganglions, subthalamic nuclei and n. Dentatus of cerebellum as a result of neuromediators production and metabolism disturbances.

Hyperkinetic form of the disease has autosomal – dominant type of inheritance. Rigid form of the disease is characterized by autosomal – recessive type of inheritance.

Clinical features of the disease The disease begins in early childhood and it is characterized by permanent progression. The typical signs of the disease are hyperkinesis that increases with every movement. The hyperkinesis may have a look of tonic body and extremities muscle straining. Spastic torticollis is usually one of the earliest symptoms of the disease. There are no mental disorders in typical cases. There are generalized form of the disease and local ones, such as spastic torticollis and chirospasm.

Diagnosis Family history and the evaluation of pathological process dynamics are necessary for the diagnosis putting.

Differential diagnosis

· Atypical form of Economo encephalitis

Huntington disease

It is a progressive hereditary disorder that usually appears in adult life. It is the result of systemic degeneration of extrapyramidal structures and brain cortex.

It has autosomal – dominant type of inheritance.

Clinical features of the disease The disease usually appears in adult life and it is very rare in children. Male and female can suffer from this disease.

The main clinical symptoms of classic form are:

· Choreic movements

· Extrapyramidal rigidity

· Slowly progressive dementia

Rare forms are:

· Akinetic – rigid syndrome

· Extrapyramidal immobility in children

· Epileptic attacks

· Myoclonia

Diagnosis

1. Clinical and genetic analysis

2. CT and MRI of brain (atrophic changes of brain hemispheres)

3. EEG

4. DNA – analysis

Differential diagnosis

1. Chorea

2. Hepato – cerebral degeneration

Double atetosis

The typical sign of the disease are involuntary movements in face, body and extremities muscles.

The disease has autosomal – dominant type of inheritance. Both – male and female suffer from this disease.

Clinical picture of the disease The typical sign of the disease are slow warm – like movements in fingers and toes. Usually the lesion is bilateral. But sometimes hemiatetosis can be observed. Spasmus molibilis is also one of the typical sign of the disease. The signs of the disease are developed usually just after birth and are preserved during the whole life of the patient.

Diagnosis

· Peculiarities of clinical picture.

· Family anamnesis

Differential diagnosis

· Hepato-cerebral dystrophy

· Huntington disease

Generalized Tourette tic

The disease is characterized by local face, larynx muscles. That causes gait disorders and complex movements. Sometimes mental disorders can be observed.

The genetic base of the disease is still being studied.

Clinical features The disease develops in childhood and progresses gradually.

Diagnosis

· Anamnesis

· The results of complex neurological examination

· Emotional state evaluation

· Dynamic changes of clinical changes

Differential diagnosis

· Torsion dystonia

· Huntington disease

Essential tremor of Minor (hereditary trembling)

The most earliest symptom is hands’ trembling, which is preserved while resting and increases at emotional stress. Sometimes head trembling is associated. There are no other neurological signs of the disease. Sometimes there are some of extrapyramidal disorders – rigidity, gait disorders.

The disease is inherited according to the autosomal – dominant type.

Clinical features The disease begins at the age of 50. Men suffer much more often than women from this disease.

Differential diagnosis

· Parkinson disease

· Huntington disease

· Tireotoxic tremor

Hereditary ataxias

Spinal Fridreich ataxia

The disease is characterized by spinal cord degeneration and degenerative – dystrophic changes in posterior and lateral columns.

The disease is characterized by autosomal – recessive type of inheritance.

Clinical features of the disease The disease begins at the age of 10 – 12 and then slowly progresses. The main clinical signs are sensitive – cerebellar ataxia, nystagmus, muscle hypotonia and areflexia, gait disorders. At the beginning of the disease there is deep sensation disorders according to the conductive type on lower extremities. In the course of the disease coordination disorders, scan speech, body and upper extremities ataxia appear. The disease is characterized by some bone abnormalities, cardiomyopathy, mental disorders and the symptoms of lesion of pyramidal tracts.

Differential diagnosis

· MS

· Neurosyphilis

Hereditary cerebellar ataxia of Pier – Mary

The main signs of the disease are:

· The beginning at the age of 30 – 50

· Cereballar ataxia

· Dysarthria

· Hyperreflexia

· Spastic muscle hypertonia

The inheritance of the disease is autosomal – dominant.

Clinical feature of the disease The disease begins gradually with gait disorders, disorders of coordination, nystagmus, dysarthria. There are high reflexes, increased muscle tonus according to spastic type (mainly in lower extremities), pathologic reflexes. Eye movements disorders are often observed in such patients. There are mental, memory and emotional disorders.

The course of the disease is progressive.

Differential diagnosis

· Olivo-ponto-cerebellar degeneration

· MS

Olivo-ponto-cerebellar degeneration

It is the group of the diseases that are connected by system lesion of cerebellar cortex, pons and lower olives. Sometimes the neurons of anterior horns of the spinal cord and basal ganglia are involved.

The inheritance of the disease is autosomal – dominant.

Clinical features of the disease The disease begins at the age of 15 – 20, sometimes 30 years. Cerebellar symptoms dominate in clinical features. There are also extrapyramidal and pyramidal symptoms, peripheral polineuropathy. Sometimes retina is involved in pathological process. Mental disorders are often observed.

There are several types of olivopontocerebellar degeneration

· Olivopontocerebellar degeneration of Mentsel. The disease begins at the age of 20 – 25. There are cerebellar ataxia, bulbar disoders, extremities paresis, high reflexes and pathological reflexes.

· Olivopontocerebellar degeneration of Degerina – Tomas. It develops at the age of 7 – 12. There are cerebellar disorders, distal hyperesthesia, areflexia, ptosis, convergence disturbances.

· Olivopontocerebellar degeneration of Holms. It develops at the age of 20 – 25. It is characterized by cerebellar ataxia, dementia, ophthalmoplegia.

· Olivopontocerebellar degeneration with macular degeneration. It develops at the age of 20 – 25 with progressive decreasing of visual acuity, central scotoma. In several years ataxia, intention, choreic hyperkinesis and spastic lower paraparesis are developed.

Differential diagnosis

· Ataxia of Fridreich.

Students’ practical Study Program.

Step I: Aim: to determine the clinical diagnosis. Definition of the clinical form of genetically - degenerative disease with a lesion of pyramidal, extrapyramidal system and cerebellum. It is necessary:

1. To examine patient (genetic anamnesis, somatic status);

2. To conduct differential diagnostic according to algorithm of the differential diagnosis of genetically - degenerative diseases with a lesion propulsion systems;

3. To formulate the clinical diagnosis.

Step II: Aim: To prescribe treatment. It is necessary to use the principle of pathogenetic correction of disorders at:

а) Parkinson’s disease - cholynolitics, dofaminergical drugs, relaxants, tranquilizers and antihistaminics;

б) Hepatolenticular degeneration (Wilson’s disease) - Cuprenilum (Д-penicylaminum), Unithiolum, diet, poor on brass, by liver therapy

в) Huntington’s chorea - Reserpinum (dopegitum), Haloperidolum, small tranquilizers, Triphtazinum.

Step III: Aim: Medical genetic consultation. It is necessary, taking into account a mode of inheritance and penetrance of a gene, to evaluate probability of birth of the ill child.

Diseases with involvement of neuro – muscular junction:

a. Progressive muscular dystrophy (Myopathies)

Myopathies are conditions in which the symptoms are due to dysfunction of muscle with progressive weakness, impaired relaxation (myotonia), cramps or contracture (in McArdle disease), or myoglobinuria. Dystrophies are myopathies with four special characteristics:

1. They are inherited.

2. All symptoms are due to weakness.

3. The weakness is progressive.

4. There are no abnormalities in muscle other than degeneration and regeneration, or the reaction to these changes in muscle fibers (infiltration by fat and connective tissue), and there is no storage of abnormal metabolic products.

Etiology. These inherited diseases are separated from each other on the basis of clinical and genetic criteria, but the inherited biochemical abnormality has not been identified in any of them. Therefore, the pathogenesis of these disorders is not known.

Pathology. In the majority of the cases, the significant pathological findings are confined to the muscles. There may be a few degenerative changes in the ventral horn cells or a slight reduction in their number, but as a rule the peripheral and central nervous systems are normal. In the early stages of the disease, the muscle fibers are rounded and enlarged to more than twice their normal size.

With progress of the disease, there is a longitudinal splitting of some of these large fibers with resulting admixture of fibers of various sizes. This splitting of the fibers is accompanied by hyaline degeneration of the myoplasma, evidence of regeneration, an increase in the number of sarcolemmal nuclei and replacement of the muscle substance by fat and connective tissue.

Classification. They divide the cases into sach groups:

a. Dushen pseudo – hypertrophic muscle dystrophy

b. Late Bekker pseudo – hypertrophic muscle dystrophy

c. Shoulder – scapula – facial form of Landouzy – Degerina

d. Erba dystrophy

Clinical features of all myopathies.

Symptoms. The symptoms are essentially those due to the muscular weakness. In the majority of cases the proximal musculature is more severely affected than that of the distal parts of the extremities. The child is clumsy in walking and has difficulty in climbing up and down stairs. Toe walking is a common early symptom. The weakness of the shoulder proximal muscles makes it difficult for the child to raise the arms over the head or lift heavy objects. The weakness of the pelvic proximal muscles gives rise to the characteristic waddling gait and attempts to turn result in much commotion but little progression because the knees cannot be raised properly. The boy may fall frequently and then has trouble rising without assistance.

Signs. Cardiac failure as the result of involvement of the heart muscles has been reported in a few cases. In the majority of cases, the dystrophy is limited to the muscles of the trunk and extremities. The gait and posture are characteristic. There is an advanced degree of lumbar lordosis as a result of weakness of the trunk muscles. There is a stoppage, waddling gait. Movements of the arm may be accompanied by winging of the scapula. Weakness of the shoulder proximal muscles causes the child to slip through the hands when attempts are made to lift him by placing the hands in the axillar.

Another characteristic and diagnostic feature of the disease is the manner in which the patient rises from the supine to the erect position (Gower's sign). The patient first turns over onto the abdomen and raises the trunk to the crawling position. He then places the feet firmly on the floor with the aid of his arms and gradually elevates the upper part of the body by "climbing up his own trunk" with the arms. With progression of the weakness, the patient is able to rise from the floor only by pulling himself up with his hands on a chair or some other fixed object.

On palpation the hypertrophic muscles feel firm and rubbery. The wasted muscles are often difficult to feel on account of the overlying fat. Pseudohypertrophy may precede the onset of wasting, or it may affect muscles which have never hypertrophied. The involvement of the musculature is usually symmetrical. There are some variations in the degree of weakness on the two sides but involvement limited entirely to one side does not occur. Abnormal movements and fibrillary twitchings of the muscles are not present.

The sensory examination is normal and there are no sphincter disturbances. The deep reflexes may be lost early in the course of the disease or they may persist in wasted muscle. The knee jerks usually disappear before the ankle jerks. Cutaneous reflexes are preserved and the plantar responses are usually flexor.

Duchenne Muscular Dystrophy

Definition

Duchenne muscular dystrophy is the most common form of muscular dystrophy and is seen almost exclusively in young males, with a prevalence of 1 in 3500 newborn boys. This type of muscular dystrophy is a result of a mutation of the dystrophin gene located on the short arm of the X chromosome, localized to Xp2. The disease is caused by a new mutation in one-third of the cases.

Dushen pseudo – hypertrophic muscle dystrophy occurs entirely in males and the onset is usually in the first four years of life.

The transmission is as sex-linked recessive trait and the mutation rate is high. The rate of progression is relatively rapid, with death in the second or third decade. A milder form of X-linked recessive dystrophy was described by Becker. The clinical features are similar to those of Duchenne dystrophy but the onset is later in childhood or adolescence and the rate of progression is much slower, so that survival into adult years is common.

In Duchenne dystrophy the child is clumsy in walking and has difficulty in climbing up and down stairs. Toe walking is a common early symptom. There are no cerebral symptoms, but mental retardation seems to be unduly common in the Duchenne type. In Duchenne dystrophy, pseudohypertrophy is present in some muscles of the extremities and in others it is entirely absent. More often, there is wasting of some muscle groups and pseudohypertrophy in others. The gastrocnemius, deltoid and triceps are most frequently affected by the pseudohypertrophy.

Table 20-1

Distinguishing Characteristics of Myopathic and Neurogenic Disorders

Myopathic	Neurogenic
Signs and symptoms Proximal weakness and wasting	Distal weakness and wasting ± Sensory signs and symptoms ± Fasciculations, increased tone, extenser plantar responses
Serum muscle enzymes Increased	Normal
Nerve condition velocities
Normal	Slowed
Electromyography
Low-amplitude polyphasic motor unit potentials of brief duration	Increased insertion activity Fibrillations, fasciculations Positive sharp waves
Muscle biopsy Variation in fiber diameter Internal nuclei Degeneration of fibers Increased endomysial connective tissue	Angular fibers, target fibers Pyknotic clumping Type grouping Type I fibers: small Type II fibers: hypertrophied

Etiology and Pathology

Duchenne muscular dystrophy is characterized by an absence of the protein dystrophin in the muscle fiber. Dystrophin is normally located in the muscle surface membrane and is part of the membrane cytoskeleton, acting as a stabilizing factor in membrane function. The absence of dystrophin affects the function of dystrophin-associated proteins, which provide a link between dystrophin and the extracellular matrix protein, laminin, the major component of the extracellular matrix. Dystrophin-associated protein dysfunction leads to an increased susceptibility to muscle fiber degradation.

Muscle biopsy shows abnormal variation in muscle fiber size. Other changes include central displacement of nuclei into the muscle fiber, splitting of fibers, fragmentation of the cytoplasm, focal vacuolization, hyalinization and shrinking of the sar-colemmal sheath. There are clusters of necrotic fibers, evidence of regeneration, extensive proliferation of perimysial and endomysial connective tissue, and replacement of muscle fibers by fat.

Clinical Features

Affected children appear normal at birth and may be extremely placid. There is normal achievement of early milestones, but there is delay in standing and walking. The child then develops a clumsy, waddling gait and pseudohypertrophy of the calf muscles, associated with difficulty climbing stairs and rising from a chair. Older children have a pronounced lumbar lordosis caused by weakness of the pelvic musculature and the erector spinae. This results in forward tilting of the pelvis, protrusion of the abdomen, and compensatory backward arching of the upper thoracic spine and shoulders. The affected child has difficulty rising to a standing position. He must first roll to a prone position, pull himself to his hands and knees, push with his arms until only his hands and feet are on the floor, and finally, "walk" up his lower extremities until he can extend his trunk and stand. This method of assuming a standing position in the presence of severe proximal weakness has been termed Gower's sign. Eventually the child can no longer ambulate and becomes confined to a wheelchair by the age of 10. Multiple contractures, deformities and severe scoliosis, and distal weakness and wasting are prominent features in the latter stages of the disease. Typically, the patient is bedridden in the teens and dies in the late teens or early twenties. The absence of dystrophin in cardiac muscle results in a primary progressive cardiac dystrophic process.⁵ There is a steady decline in cardiac reserve, but heart failure is rare, probably because the patient leads a sedentary life-style. Many develop gastrointestinal hypomotility because dystrophin is absent in smooth muscle. Acute gastric dilatation or fatal intestinal obstruction may occur in advanced cases.

Absence of dystrophin in the brain results in mild impairment of intellectual-cognitive functioning in a subset of patients with Duchenne muscular dystrophy. Lack of dystrophin increases susceptibility to neuronal damage, suggesting that mental impairment may be the result of ischemic insults during fetal life or parturition. Because this is an X-linked, recessive disease, males carrying the abnormal dystrophic mutation express Duchenne muscular dystrophy and females are usually nonexpressing carriers. Occasionally females carrying one copy of the abnormal mutation exhibit a milder form of Duchenne muscular dystrophy, and muscle biopsy demonstrates a mosaicism of dystrophin expression. The disease may also result from inactivation of the normal X chromosome in some female cases, or an X chromosome translocation, disrupting the dystrophin gene, with selective inactivation of the nontranslocated X chromosome.

Diagnostic Procedures

1. Muscle enzymes. Serum creatine kinase (CK) is elevated and may be abnormal before the onset of clinical signs and symptoms. There are increased serum levels or other muscle enzymes, including aspartate transaminase (AST), alanine transaminase (ALT), lactic dehydrogenase (LDH), and aldolase. The elevation is high in early cases and declines with progression of the disease. Creatinuria and myoglobulinuria may also be present.

2. The electrocardiogram is abnormal at an early age. The initial tachycardia is followed by increased R-wave voltage and eventually development of right bundle branch block and deep Q waves.

3. The electromyogram is abnormal, with myopathic features. Motor unit potentials are reduced in duration and amplitude, and there is increased polyphasic wave activity and early recruitment.

4. Between 2.5 and 10 percent of female carriers of the mutated dystrophin gene have clinical evidence of muscle weakness.

5. In asymptomatic carriers, mutation detection can be performed on lymphocytic genomic DNA obtained from a single blood specimen, using several methods, including Southern blot analysis, field inversion gel electrophoresis, or polymerase chain reaction exon amplification assays. Muscle biopsy can be omitted when mutation detection is positive.

6. Muscle biopsy was the definitive method of diagnosis before the development of genetic diagnostic techniques. Standard light and electron microscopy can be augmented by immunohistochem-istry and the use of antidystrophin antisera.

Differential Diagnosis

1. Other forms of dystrophy.

2. Neurogenic muscular atrophy.

3. Polymyositis and dermatomyositis, which are characterized by inflammatory changes on muscle biopsy.

4. Polyneuropathy differentiated by its more rapid onset slow nerve conduction velocities and muscle and nerve biopsy.

5. Benign congenital myopathies (see below).

Treatment

1. There is no specific treatment for Duchenne muscular dystrophy.

2. A physical therapy program will help to delay the development of joint contractures. Obesity should be avoided. Splinting, bracing, and surgical procedures to prevent or treat deformities can prolong the ability to walk.¹¹

3. Joint contractures can be relieved by tendon release procedures.

4. Severe scoliosis can be stabilized or reversed by orthopedic surgical techniques.

5. Mild upper respiratory infections are potentially lethal in advanced disease and should be treated with appropriate antibiotics. A decline in respiratory function with difficulty in clearing secretions can be relieved by intermittent continuous positive airway pressure.¹² Nocturnal hypoventilation based on hypoxia hypercapnia measured by blood gas determination requires intermittent noninvasive ventilator support using a nasal mask. Permanent ventilator support usually occurs when forced vital capacity declines below 1.2 L.

6. A lessening of the emotional impact of the disease on the patient and family, and the development of optimal living conditions, can be achieved by a combined effort of the neurologist, physiatrist, psychologist, and social worker.

7. Corticosteroids decrease the rate of muscle loss. Prednisone 0.75/kg daily can be given for as long as 6 months.

8. Newer techniques of gene therapy using myoblast transplantation or gene transfer by reduplication defective retroviruses, adenoviruses, or herpesviruses are currently under investigation. Results have been equivocal.

9. Genetic counseling should be provided. It is important to advise the family regarding the likelihood of involvement in a subsequent pregnancy. Carriers of Duchenne dystrophy may have elevated serum CK levels. Carrier detection or prenatal mutation diagnosis is readily established by DNA diagnostic testing.

Prognosis

Duchenne muscular dystrophy is a steadily progressive, incapacitating disease until death in the late teens or early twenties. A better understanding of pulmonary problems and improved treatment of respiratory infections has significantly increased the life span in Duchenne muscular dystrophy and other muscle diseases affecting muscle function.

Shoulder – scapula – facial form of Landouzy – Degerina (Facioscapulohumeral Muscular Dystrophy (FSH)) type occurs in both sexes. The onset of symptoms may be at any time from early childhood to late adult life. There are many mildly affected abortive cases.

Transmission is by an autosomal dominant gene. This is an autosomal dominant form of muscular dystrophy with a frequency of 1 in 20,000. The gene responsible for FSH is localized to chromosome that do not link to chromosome 4 have been reported. Ten percent of cases are the result of mutation.

Pathology The muscle changes are typically those of dystrophy, but inflammatory changes are a common feature.

Clinical Features

Symptoms and signs of FSH occur in adolescence, with 95 percent penetrance by age 20. There is initial weakness and atrophy of the facial and shoulder girdle muscles with later progression to the abdominal and pelvic girdle muscles, and foot extensors. Clinical expression shows marked variation, ranging from almost asymptomatic to quadriparesis. Hearing loss occurs in 50 percent of cases and can be severe. Retinal vascu-lopathy consisting of telangiectasias and microaneurysms has been recognized by fluorescein angiography.

Diagnostic Procedures

1. Serum CK levels are elevated in the active phase of the disease.

2. Electromyographic findings are compatible with a myopathy but may be normal.

3. Muscle biopsy will establish the diagnosis.

Treatment

There is no specific treatment for this disease. Supportive measures are indicated as the disease progresses, with emphasis on control of upper respiratory infections in advanced cases.

When the facial muscles are affected in the Landouzy-Dejerine type, the expression is mask-like, the lips are prominent, the eyes are imperfectly closed in sleeping and facial movements are absent in laughing or crying as well as on voluntary efforts in whistling and the like. Involvement of the masticator, palatal and pharyngeal muscles may occur, but is rare.

Limb-Girdle Muscular Dystrophy (Erba dystrophy) occurs in either sex and the onset of symptoms is usually in the first three decades of life. There are various modes of inheritance, but it is commonly transmitted as an autosomal recessive trait.

Definition

This is a heterogenous group of dystrophic muscle diseases, usually sporadic but occasionally inherited as an autosomal recessive trait that maps to chromosome 2pl3-16 or inherited as an autosomal dominant trait linked to chromosome 15q.l5.1-q21.1 with preferential involvement of truncal and proximal limb girdle muscles.

Pathology

There is variation in muscle fiber size, with the presence of small, angular, and hypertro-phied fibers showing internally placed nuclei. Fiber necrosis and regeneration are present, with replacement of fibers by fibrous and adipose tissue in advanced cases. Motheaten and tabulated fibers occur in most cases. The sarcolemma shows positive staining with antidystrophin antibodies.

Clinical Features

The earliest symptoms consist of weakness of the pelvic girdle or proximal lower limb muscles, which presents at any age from childhood to adulthood, with a mean age of onset of 21 years. The autosomal dominant form of the disease presents in adults and exhibits a slower progression of weakness. The initial symptoms are followed by involvement of upper limb-girdle muscles, then by progressive weakness of truncal or more distal limb muscles, with loss of walking ability 10 to 20 years after onset. Cardiomyopathy is rare and usually asymptomatic, but cardiac failure has been reported.

Examinations. Routine examinations of the blood, urine and cerebrospinal fluid are normal. The excretion of creatinine is decreased in proportion to the amount of loss of muscle substance, in a similar manner to that occurring in other diseases accompanied by muscular wasting. There is an increase in the amount of creatine excreted in the urine, and there is impairment of the ability of the body to store ingested creatine. The significance of the creatinuria is not known. There is no consistent or specific pattern of amino acid excretion.

Increased serum levels of aldolase, lactic dehydrogenase, phosphohexoisomerase, transaminase and creatine phosphokinase have been reported. Serum enzyme levels are most consistently elevated in the early stages of the Duchenne variety of muscular dystrophy. Detection of the disease in the preclinical stage of this form of the dystrophy can be made by determination of the serum enzymes, and detection of the carrier state in unaffected females is manifested by an increase in the serum of creatine phosphokinase. When the serum CPK is definitely increased in a potential carrier of the Duchenne gene, it is likely that the woman is a carrier, but borderline or normal values do not exclude this possibility because even in known carriers (for instance, a woman with both an affected brother and an affected son), CPK is abnormal in only about 80% of the cases. A mild degree of degenerative change in the muscles has also been found in some asymptomatic carriers.

Among the biochemical abnormalities that suggest an abnormality of surface membranes in Duchenne dystrophy are impaired responses of adenyl cyclase to epinephrine and fluoride in muscle, and several abnormalities of erythrocyte membranes, including sodium-potassium ATPase, membrane phosphorylation, osmotic fragility, and some morphological characteristics.

Ultrastructural study of muscle has revealed gaps in the plasma membrane of muscle. In contrast to normal surfaces, these gaps seem to be permeable to large molecules such as the protein, horseradish perioxidase, or a dye, procion yellow. Additionally, freeze-fracture studies showed decreased numbers of membrane particles. These abnormalities bear upon theories of pathogenesis, but have not yet had an impact on diagnosis of individual cases.

The electromyogram is of considerable value in diagnosis. The pattern of voluntary effort recorded by means of concentric needle electrodes is characterized by disintegration of motor unit potentials, many of which become polyphasic and of short duration.

Course.

There is considerable variation in the course of these diseases. The prognosis is most favorable when the onset of symptoms occurs after the second decade of life. As a rule, there is a gradual increase in the weakness of the muscles which are first involved and a slow progress of the wasting to unaffected muscles. The small muscles of the hands and feet are usually last to be affected.

Contractures may appear and atrophic changes in the bones have been reported in a few cases. Formes frustes with preservation of general good health to old age are not rare in facioscapulohumeral dystrophy, and it is not unusual to find patients who have suffered with the disease for four and five decades but are still able to walk. In the Duchenne form it is common for the disease to progress within a period of five to fifteen years to the stage where the patient is confined to a bed or a wheel-chair. Death may occur from intercurrent infection or from involvement of the respiratory musculature.

Diagnosis.

The diagnosis of Duchenne dystrophy can usually be made without difficulty by the onset of muscular weakness in childhood, the presence of pseudohypertrophy of the muscles, the characteristic distribution of the weakness, the family history and the increased serum enzyme activity. When the onset is relatively late in life, as in limb-girdle or facioscapulohumeral forms, the diagnosis is made by the distribution of the weakness, the loss of deep reflexes and the absence of evidence of involvement of the spinal cord or peripheral nerves. Determination of the serum enzymes, electromyography and biopsy of the muscles are of value in establishing the diagnosis.

Differential diagnosis. Progressive muscular dystrophy must be distinguished from the diseases of infancy and childhood which are accompanied by muscular wasting. Limb-girdle and facioscapulohumeral dystrophy must be distinguished from diseases of adult life which are accompanied by muscular wasting:

1. myotonic muscular dystrophy

2. proximal spinal muscular atrophy

3. peroneal muscular atroph

4. amyotrophic lateral sclerosis

5. atypical forms of polyneuritis

6. syringomyelia and myositis.

The differential diagnosis between named diseases and progressive muscular dystrophy can be made by the lack of family history, much more rapid course, inflammatory response in muscle. Genetic analysis has shown that there is an X-linked dystrophy, the Becker type, less severe than the Duchenne type; recognition of Becker cases is facilitated by the recognition of other affected individuals in the same family who are still walking after age twenty, but in sporadic cases, the separation of Becker cases from either Duchenne or limb-girdle cases may be difficult.

In polyneuritis, particularly the Guillain-Barre form, the muscular weakness may occasionally be greatest in the girdle muscles. The acute onset of the symptoms, the increased protein content in the cerebrospinal fluid and the subsequent regression of symptoms should serve to establish the diagnosis.

Pseudohypertrophy of the muscles may occasionally be seen in syringomyelia but the other features of the disease should leave no doubt in regard in the diagnosis.

Treatment. There is no treatment which has proven to be effective in arresting the course of the disease. Stretching of contractures, bracing and tendon-lengthening operations are advocated with varying degrees of enthusiasm in different centers. When known carriers of the Duchenne gene become pregnant, fetal sex determination permits interruption of pregnancy for boys, but there is no way of identifying

Becker Muscular Dystrophy

This condition is a milder expression of a disease caused by mutation of the dystrophin gene at Xp21. Patients have an abnormal but functioning dystrophin, reduced in size. There is a wide range of presenting symptoms, varying in severity from a slightly milder form of disease resembling Duchenne muscular dystrophy to asymptomatic elevation of CK.

The affected individual appears to be normal at birth and shows normal developmental milestones; the mean age of onset is 11 years. The initial symptoms often consist of muscle cramps on exercise. Progression is slower than Duchenne muscular dystrophy and patients may walk with bracing until the late twenties or early thirties. Asymptomatic cardiac involvement is not unusual. Symptomatic cardiac involvement is unusual. Hypertrophic cardiomyopathy is rare. Because genetic analysis cannot determine the correct diagnosis in 35 percent of cases, endomyocardial biopsy specimens can be stained by immunostaining techniques in patients with cardiomyopathy suspected to be the result of Becker muscular dystrophy.

Diagnostic Procedures

Diagnostic procedures have been discussed under Duchenne muscular dystrophy.

Treatment

The most severe cases of Becker muscular dystrophy should be treated as Duchenne mus cular dystrophy. Physical therapy measures may maintain ambulation in some cases, up to the age of 30 or more, and many patients survive into their forties. Occasional patients are reported with survival into the seventh decade.²⁵

Congenital Muscular Dystrophies

Definition This heterogeneous group of muscular dystrophies is inherited as an autosomal recessive trait characterized by dystrophic changes on muscle biopsy.

Etiology and Pathology

The congenital muscular dystrophies are the result of deficient components in the dystrophin-glycoprotein complex. This complex has a structural role in muscle and probably anchors muscle cells to the extracellular matrix. This attachment stabilizes the sarcolemmal membrane and protects it from stressors that develop during muscle contraction. Disruption of this linkage leads to sarcolemmal instability and muscle cell necrosis. Dystrophin, which is localized to the sarcolemma, is completely absent in Duchenne muscular dystrophy. Absence of other proteins in the dystrophin-glycoprotein complex have been identified in other forms of congenital muscular dystrophy. A merosin-negative condition and an adhalin deficiency have been described.

Clinical Features

There is profound hypotonia and muscle weakness at birth, with arthrogryposis developing in the first year of life. The clinical course is nonprogressive or slowly progressive. Intellectual development is usually normal, and the condition may stabilize in adolescence. A variant designated as severe childhood autosomal recessive muscular dystrophy, with adhalin deficiency (Fukayama type), in which there are cerebral abnormalities and mental retardation and epilepsy, has been recognized.

Scapuloperoneal Muscular Dystrophy and the Scapuloperoneal Syndrome

Definition This is a slowly progressive syndrome of weakness involving the scapuloperoneal musculature.

Etiology and Pathology

There are several distinct forms of the disease, a myopathic or neurogenic form inherited as an autosomal dominant trait, and a sex-linked recessive myopathic form in which the affected muscles show dystrophic changes.

Clinical Features

Weakness begins in the peroneal muscles with lesser involvement of the scapula, shoulder, and upper arm musculature, and occasional mild involvement of the facial and laryngeal muscles. The dystrophic form can be accompanied by joint contractures, cardiac conduction abnormalities and cardiomyopathy. The rate of progression varies, and disability can be severe two decades from the time of onset.

The neurogenic condition can occur with or without sensory change, and both axonal and de-myelinating variants have been described. The mild facial weakness can lead to an inaccurate diagnosis of facioscapulohumeral dystrophy.

Diagostic Procedures

1. Serum CK levels are elevated.

2. Electromyography is consistent with an active, chronic myopathy.

3. Dystrophic changes are present in the muscle biopsy.

4. A normal dystrophin staining pattern on muscle biopsy excludes Duchenne and Becker-type muscular dystrophy.

Treatment Prevention of contractures and bracing to maintain mobility is required in more advanced cases.

Oculopharyngeal Muscular Dystrophy

Definition

This rare muscular dystrophy is inherited as an autosomal dominant trait characterized by late onset of chronically progressive ptosis and dysphagia.

Clinical Features

Most patients are of French Canadian descent, but the condition has been described in other ethnic groups.

Symptoms consist of chronically progressive ptosis and dysphagia beginning in the mid forties or fifties. The ptosis is a result of progressive weakness of the levator palpebrae, and there is preservation of orbicularis oculi function and Bell's phenomenon. There is chronic contraction of the frontalis muscle, and the patient maintains a chin-up head position. Dysphagia is progressive. The patient experiences difficulty with solid food initially and liquids later. The voice has a nasal quality. A late weakness of limb-girdle muscles may occur.

Diagnostic Procedures

Electromyography and muscle biopsy are compatible with a muscular dystrophy, and the muscle biopsy shows granular degeneration of muscle fibers, progressive loss of fibers, and replacement by fibrous tissue. Manometric studies are useful to assess swallowing abnormalities.

Treatment

Surgical treatment of ptosis is successful in most patients. Dysphagia may require myotomy or dilatation of the oropharyngeal sphincter.

Distal Muscular Dystrophy

There are at least four distinct forms of inherited distal myopathy. Each is characterized by initial weakness in a distal muscle group with progressive involvement of more proximal muscles.

1. Late onset, type 1 (Welander)—autosomal dominant; onset age 40 to 60 years; begins in the small muscles of the hands and spreads proximally. There is late involvement of the anterior tibial and calf muscles.

2. Late adult type 2 (Markesbery)—an autosomal dominant, late onset form beginning with tibialis anterior weakness with slow progression and spread to the calf muscles, and later involvement of the upper limbs.

3. Early adult type 1 (Nonaka)—an autosomal recessive condition with early adult onset, beginning in the tibialis anterior with later spread to the calf muscles, then upper limbs.

4. Early adult type 2 (Miyoshi)—an autosomal recessive type beginning at age 15 to 30 years with involvement of the gastrocnemius and sparing the anterior compartment muscles. There is later involvement of thighs and buttocks and mild involvement of the upper limbs.

Amyotrophy as a result of peripheral neuron lesion

A. Spinal amyotrophy of Werding – Hoffman

B. Proximal amyotrophy of Kukelberg – Welander

C. Sharko – Mary – Tooth disease

Spinomuscular Atrophies

Definition

The spinomuscular atrophies are a group of diseases of unknown etiology that result from degeneration of motor neurons in the spinal cord and occasionally in the brainstem.

Etiology and Pathology

The etiology is unknown. In most cases, the condition is inherited as an autosomal recessive trait, and rarely as an autosomal dominant condition, with linkage to chromosome 5. Major deletions of 5ql 1.2-13.3 have been described in severe infantile spinal muscular atrophy, unlike patients with mild disease who have smaller deletions. Genes for neuronal apoptosis inhibitory protein and the spinal muscular atrophy motor determining gene also map to 5ql3 and one or both of these genes may be implicated in spinomuscular atrophy.

The primary pathological process appears to be degeneration and atrophy of the anterior horn cells. However, chromatolytic changes with enhanced mitochondrial and oxidative activity in surviving neurons suggest that the primary change may be distal in the axons.

The muscle shows evidence of denervation atrophy with atrophic motor units surrounded by normal-appearing muscle fibers. However, histochemical studies show that the surrounding fibers are all of one histochemical fiber type, because of reinnervation of denervated fibers by sprouting collaterals from axons of surviving anterior horn cells. Other helpful findings include the presence of angular fibers and target or targetoid fibers.

Clinical Features

There are four clinical forms based on age and onset of signs and symptoms.

Infantile Form (Werdnig-Hoffman)

The condition is present at birth and the mother frequently reports diminution of the child's movements in utero in the later weeks of pregnancy. The infant is weak at birth and shows progressive muscular weakness and hypotonia (floppy infant). This produces a characteristic "frog" position when the baby is prone. The arm is abducted at the shoulder and flexed at the elbow, and the lower limbs are abducted and externally rotated at the hips and flexed at the knees. There is progressive weakness of respiratory muscles, paradoxical respirations leading to respiratory insufficiency, pneumonia, and death within 12 to 18 months.

Infantile muscular atrophy (Werding – Hoffman) is recognized by its onset in infancy, the presence of fibrillations and the rapidly fatal course.

Late Infantile Forms

These children have normal movements at birth but develop progressive muscle weakness and hypotonia within 2 months. The lower limbs are weaker than the upper limbs and the child is never able to stand or crawl. Fascicula-tions of the tongue occur in about 50 percent of cases. Death usually occurs within 2 years, but some children survive for several years.

Childhood Form

Children with this form of spinomuscular atrophy develop normally up to or beyond the first birthday and are able to stand and crawl. Many are able to walk for a short period of time, but progressive weakness, wasting, hypotonia, and hy-poreflexia, with proximal or distal preponderance, impose increasing restriction of activities. Fasciculations are unusual in limb muscles but may be present in the tongue. Focal or even diffuse muscle hypertrophy can occur due to hypertrophy of surviving motor units. There may be a fine asynchronous tremor of the outstretched hands due to the firing of large motor units; this results from reinnervation of denervated muscles by surviving nerve fibers. Voluntary contraction fas-ciculation, which disappear on relaxation, may be present. Palpation of the contracting muscle may yield a vibration-like sensation. Auscultation may reveal a low-pitched rumbling. Late changes include joint contractures and scoliosis. Severe scoliosis may lead to spinal cord compression and result in hyper-reflexia and extensor plantar responses. The combination of scoliosis and respiratory muscle involvement can produce severe respiratory insufficiency.

Adolescent Form (Familial Spinal Muscular Atrophy—Kugelberg-Welander Syndrome)

This is a more benign form of spinomuscular atrophy that is inherited as an autosomal dominant or autosomal recessive trait and begins at about 2 years of age. Wasting and weakness may be confined to the proximal limb-girdle musculature. There may be fas-ciculations in the limb-girdle muscles and the tongue, and some hypertrophy of muscles can occur. Both hy-poreflexia and hyperreflexia are reported. The disease is often confused with the limb-girdle type of muscular dystrophy but can be distinguished by muscle biopsy. This is the most benign form of generalized spinomuscular atrophy. The patient survives into adult life, at which time there is slowing or apparent arrest of the muscle weakness.

Focal forms of the disease present with:

1. Scapulohumeral distribution. This form is usually benign but may present as a rapidly progressive disease in adults, with death from respiratory failure within 3 years.

2. Scapuloperoneal distribution. This form also occurs in adolescents and adults. The atrophy involves muscles of the scapular and periscapular region and the anterior compartment of the leg.

3. Ocular and facial muscle involvement. This form occurs in children and adults and constitutes one of the conditions in the syndrome of "oculomy-opathy."

4. Bulbar involvement (Fazio-Londe disease). This rapidly progressive form of muscular atrophy involves bulbomotor neurons and begins in early childhood. The atrophy is most marked in the bulbar musculature with weakness and wasting of the extraocular facial and pharyngeal muscles. Death occurs from respiratory insufficiency and pneumonia.

Diagnostic Procedures

1. It is possible to produce fasciculations in suspected cases by intramuscular injection of 1 mg Prostigmin.

2. The EMG may show the presence of fasciculations and fibrillations.

3. Muscle biopsy with histochemistry is abnormal. The findings are outlined under etiology and pathology.

Treatment The infantile form of spinomuscular atrophy runs a rapid course, with death from respiratory failure 12 to 18 months after birth. Patients with the more chronic forms of the disease should receive:

1. Treatment directed toward maintaining ambulation as long as possible. This includes physical therapy, orthopedic consultation, bracing, and surgical procedures.

2. Prompt treatment of all respiratory tract infections that may lead to pneumonia, pulmonary insufficiency, and death.

3. The intelligence is not affected and patients benefit from an appropriate education.

Prognosis The life span is reduced in all forms of generalized spinomuscular atrophy, but a normal life span is possible in some patients, with focal forms of the disease.

Juvenile muscular atrophy (Kugelberg-Welander) may be suspected if fasciculations are seen in a patient who otherwise seems to have limb-girdle or facioscapulohumeral dystrophy because of proximal limb weakness. In some patients, however, fasciculations are not clinically visible and motor neuron disease is identified only by electromyography and muscle biopsy. This distinction is of some importance because, in general but not always, the prognosis of juvenile neurogenic disease is less serious.

Hereditary neuropathies

Peroneal muscular atrophy. Peroneal muscular atrophy (Charcot-Marie-Tooth syndrome) includes several genetic disorders of the peripheral nervous system that most severely affect the peroneal and other distal muscles of the legs.

Inheritance is usually autosomal dominant and, less frequently, autosomal recessive.

Foot deformities are frequent and may be the only apparent feature of the disease in mildly affected family members. Impairment of sensation in a stocking-and-glove distribution is usually present, though sensation is preserved in some families. Achilles reflexes are absent and other tendon reflexes may be diminished.

Clinical features. The pathologic changes are of three types. There are:

1. Demyelination of the peripheral nerve with axonal loss and some hypertrophy of the Schwann cells, producing hypertrophic neuropathic changes. In Type I Charcot-Marie-Tooth syndrome, symptoms begin in the first or second decade of life with foot-drop and a stoppage gait. Distal muscle atrophy produces a "stork leg" deformity; intrinsic hand muscle atrophy develops later. Distal tendon reflexes are diminished or absent and a stocking-and-glove sensory defect is present. Scoliosis and high pedal arches or club feet are common. Peripheral nerves are often palpably enlarged. Tremor is prominent in some patients; the clinical constellation of Charcot-Marie-Tooth syndrome with tremor is termed the Roussy-Levy syndrome.

2. Neuronal loss of anterior horn cells and posterior nerve root ganglion neurons in the lumbar and sacral segments (hereditary motor and sensory neuropathy, Type II). The first symptoms of peroneal muscular atrophy often appear in adult life, but foot deformities may be evident much earlier. The progression is slow with muscle weakness and wasting confined to the feet and sometimes involving the leg muscles. The involvement may be asymmetric. Atrophy and weakness of distal muscles, stocking-and-glove sensory impairment is minimal or absent, and depression of tendon reflexes in the lower limbs but normal in the arms. Deficits are usually less severe and nerves are not palpably enlarged.

3. Anterior horn cell involvement with secondary axonal loss and demyelination of motor fibers.

Examinations.

1. Lumbar puncture. CSF protein content is frequently elevated in Type I Charcot-Marie-Tooth syndrome, but is normal in Type II. The CSF is otherwise normal, as are blood and urine.

2. Nerve conduction velocities. Motor and sensory nerve velocities are very slow in the peripheral nerve demyelinating type but are normal or only slightly delayed in the other two types.

3. Nerve biopsy. Nerve biopsy is normal and should differentiate the three types of the disease.

Differential diagnosis. Peroneal muscular atrophy is considered when there is atrophy of the peroneal muscles, foot deformity, and a positive family history. Even if family history is reported to be negative, relatives should be examined because some affected individuals are asymptomatic, or deny mild symptoms.

1. Friedreich ataxia should be considered if distal neuropathy and a positive family history are accompanied by nystagmus, dysarthria, ataxia, or Babinski signs.

2. Familial amyloidosis may resemble peroneal muscular atrophy, and can be recognized by sural nerve biopsy.

3. Dejerine-Sottas syndrome also resembles peroneal muscular atrophy, but onset is earlier, nerve hypertrophy is more prominent, the elevation in CSF protein content is greater, and nerve conduction rates are slower than in Type I Charcot-Marie-Tooth syndrome.

4. The distal motor and sensory deficits in Refsum disease are associated with deafness, retinitis pigmentosa, scaly skin, and elevated serum phytanic acid.

5. Lipomas and other masses in the lumbosacral canal may cause neurogenic foot deformities and distal weakness, but sensory loss is in a radicular pattern, the arms are spared, and the family history is usually negative.

6. Myotonic muscular dystrophy may present with a similar pattern of distal atrophy and is a dominantly inherited disorder, but is distinguished from Charcot-Marie-Tooth syndrome by the presence of myotonia, cataracts, frontal balding, the absence of sensory abnormalities, and by the results of EMG studies.

Course and Treatment. The progression of disability is slow in Type I Charcot-Marie-Tooth syndrome and very slow in Type II. Death does not occur as a result of this syndrome and complete incapacitation is rare. There is no specific treatment. Braces for correction of the foot-drop and hand deformities can be helped ambulatory by splinting and orthopedic procedures.

Hereditary sensory neuropathy. These genetic disorders affect sensory fibers in peripheral nerve and sometimes autonomic fibers as well. Dominantly inherited, or Type I, hereditary sensory neuropathy causes progressive sensory loss beginning in the first or second decade. There is progressive loss of pain, thermal sensibility, light touch, and proprioception. Tendon reflexes are lost. Ulcerations may develop on the feet and fingers owing to unperceived injuries. The disorder is the result of a selective degeneration of sensory neurons in the dorsal root ganglia.

Other types of hereditary sensory neuropathy include an autosomal recessive form that resembles the dominantly inherited disorder, congenital sensory neuropathy with anhydrosis, hereditary sensory neuropathy with spastic paraparesis, and familial dysautonomia (Riley-Day syndrome). Familial dysautonomia is an autosomal recessive condition most common in Jews, and may be a result of an inherited defect in synthesis of nerve growth factor. It presents in infancy with lack of pain and temperature sensibilities, gastrointestinal dysfunction, poor regulation of blood pressure, and absence of fungiform papillae on the tongue.

Myotonic muscular dystrophy is distinguished from the cases of muscular dystrophy of relatively late onset by the distal weakness, myotonia, and the other characteristic features of the disease, i.e., cataracts, testicular atrophy and early baldness.

MUSCLE DISEASES ASSOCIATED WITH MYOTONIA

Myotonia is a sustained contraction of muscles that may be induced by voluntary contraction, percussion, or electrical stimulation. The primary failure of myotonia is a delayed relaxation due to increased excitability of muscle demonstrated on electromyography, which records discharges of repetitive action potentials following muscle contraction. Myotonia occurs in myotonia congenita, paramyotonia congenita, myotonic dystrophy, and hyperkalemic periodic paralysis.

Myotonia Congenita

Definition

Myotonia congenita is an hereditary condition characterized by myotonia, a condition of delayed relaxation following voluntary muscle contraction.

Etiology and Pathology

Myotonia congenita is caused by a genetically determined abnormality in the voltage gated chloride channel. This results in a blocking of membrane chloride conductance and action potentials can be triggered by a smaller than normal current, resulting in a train of impulses that are self-maintaining, following termination of the stimulating pulse.

Clinical Features

Myotonia congenita occurs in a mild form that is inherited as an autosomal dominant trait (Thomsen myotonia) or a more severe form (Becker myotonia) inherited as an autosomal recessive trait. Symptoms of myotonia first appear in infancy or childhood and consist of inability to relax a muscle following contraction. The symptoms tend to increase during childhood and adolescence but may lessen in severity in adult life. Myotonia occurs only in skeletal muscle, and the patient has difficulty initiating movement and making certain movements. Once repetitive movements are initiated, they can be continued without difficulty. Sudden movements may initiate a sustained contraction sufficient to throw the patient off balance. On grasping an object, the patient is often unable to release the object for as long as 60 s. Patients with myotonia congenita have a well-developed musculature and have been described as herculean in appearance. Percussion of an affected muscle produces percussion myotonia, a dimpling of the skin, and sustained contraction. Percussion may also be followed by local swelling of muscle, termed myedema.

Diagnostic Procedures

The diagnostic procedure of choice is electromyography. There is marked increased activity after insertion of the needle electrode. Traction or percussion of the muscle produces a series of prolonged potentials that persist when the patient is instructed to relax the contracted muscle. Contraction and relaxation of the muscle produces a typical sound on electromyographic examination, which has been termed the "dive bomber" effect.

Treatment

1. Mexiletine 150 mg ql2h, increasing to a maximum of 300 mg q8h, is the drug of choice to reduce myotonia. An electrocardiogram should be obtained before initiating therapy to exclude cardiac conduction abnormalities.

2. Phenytoin (Dilantin) beginning 100 mg ql2h and increasing the dose until the serum levels are within therapeutic range is also an effective treatment.

3. A number of other drugs known to be effective in myotonia include procainamide HC1 (Pro-nestyl) 50 mg/kg/day given in divided dosage four times a day and quinine 10 mg/kg/day in divided dosage. Quinine should always be followed by regular visual and audiometric tests because of the risk of optic or otic neuritis.

4. Intractable cases may respond to acetazol-amide (Diamox) 8 to 30 mg/kg/day in divided dosage.

cally relieved by acetazolamide. The clinical presentation resembles the Thomsen type of myotonia congenita, but the muscle stiffness is painful.

Sodium channel myotonias respond to mexiletine therapy and acetazolamide. Other medications such as phenytoin are less effective.

Chondrodystrophic Myotonia

This condition is inherited as an autosomal recessive trait and is characterized by myotonia, short stature, blepharospasm, muscle hypertrophy, and skeletal deformities. The affected infant presents with hip contractures or dislocation. This is followed by other joint contractures, progressive growth failure, and myotonia. There is a puckering of the mouth, blepharospasm, and small palpebral fissures. Intelligence is normal. Electromyographic findings are typically those of myotonia. Muscular atrophy can occur in older children. The myotonia responds to mexiletine or acetazolamide.

Sodium Channel Myotonias

The following conditions are related to sodium channel mutations.

1. Hyperkalemic periodic paralysis.

2. Paramyotonia congenita.

3. Myotonia fluctuans.

4. Myotonia permanens.

5. Acetazolamide-responsive myotonia.

Myotonia Fluctuans

This condition appears in adolescence and is characterized by the appearance of myotonia of delayed onset after exercise. The myotonia increases following potassium loading but is unaffected by cold.

Myotonia Permanens

Symptoms are similar to myotonia fluctuans, but the myotonia is permanent and more severe. There is continuous myotonic activity on electromyography and respiratory exchange may be affected by muscle stiffness.

Acetazolamide-Responsive Myotonia As suggested by its name, this form of myotonia is dramati-

Myotonic Dystrophy

Definition

Myotonic dystrophy is a multisystem disorder inherited as an autosomal dominant trait through a locus on chromosome 19.⁴⁹ The disease is characterized by progressive muscular weakness, myotonia, cataracts, cardiac abnormalities, hypogonadism, and frontal balding.

Etiology and Pathology

Myotonic dystrophy is the product of an expanded CTG repeat in the 3' untranslated region of a gene that encodes a protein kinase DM-PK on chromosome 19ql3.3. There is an expansion of the repeat sequence in myotonic dystrophy and a positive correlation between repeat size and clinical severity.⁵⁰ Protein kinases phosphorylate neurotransmitters to achieve a physiological response on specific target cells. Failure of protein kinase activity may cause ion channel dysfunction in myotonia. Expression is maximal in cardiac muscle in myotonic dystrophy but is also present in skeletal muscle and brain.

Affected muscles show evidence of fibronecro-sis and degeneration with areas of phagocytosis and increased endomesial connective tissue. Surviving fibers show loss of striations and a characteristic ring fiber has been described. Histochemical studies reveal that degeneration is confined to type 1 muscle fibers and that there may be some increase in the size of type 2 fibers.

Clinical Features

The signs and symptoms appear at any time from birth to age 40 years. Hydrops fetalis has been reported in congenital myotonic dystrophy in a newborn infant who presented with hypertonia, edema, pleural effusion, and respiratory distress. Weakness tends to be nonprogressive in the congenital form of myotonic dystrophy but is slowly progressive in the noncongenital type of the disease. Myotonia is usually the first symptom and affects the hand with later involvement of other muscles, particularly those of the lower limbs. Muscle wasting also affects the hands first then spreads to the facial muscles, muscles of mastication, the sternocleidomastoids, the flexors and extensors of the forearm, the quadriceps, and the dorsiflexors of the feet. The facial appearance is characteristic, with bilateral ptosis and wasting, which has been termed "hatchet face."

Patients with myotonic dystrophy usually have involvement of other organ systems. These include:

1. Cardiac abnormalities. Prolapsed mitral valve and atrial flutter⁵⁴ sometimes occur in the early stages of the disease. More advanced cases with severe cardiac fibrosis suffer cardiac arrhythmias. Syncopal attacks may occur. Subclinical cardiac involvement is not uncommon and may be responsible for sudden death in some cases.⁵⁵

The number of CTG repeats in the myotonic dystrophy gene appears to be a significant predictor of cardiac dysfunction in myotonic dystrophy.

2. Brain involvement. Neuropsychological testing indicates functional impairment in the majority of patients with myotonic dystrophy. Mental retardation occurs in about 70 percent of cases of congenital myotonic dystrophy but is rarely severe. Progressive dementia occurs in 75 percent of adults with noncongenital disease. Magnetic resonance imaging (MRI) shows cerebral atrophy and areas of increased signal intensity in the white matter in most adults with myotonic dystrophy. However, there is no correlation between the extent of white matter changes and neuropsychological impairment.

3. Ophthalmic abnormalities. Subcapsular lens opacities, which enlarge and eventually impair vision, are present in most patients.

4. Endocrine abnormalities. Primary gonadal failure and gonadal atrophy occur in both sexes. Impotence, loss of libido, and testicular atrophy occur in the male. Mild diabetes mellitus may be present in both sexes.

5. Skin and skeletal abnormalities. Frontal balding occurs at an early stage in the male. A high-arched palate may be present.

6. Smooth muscle abnormalities. There is impairment of mobility in the gastrointestinal tract, with dilatation of the colon in advanced cases.

7. Respiratory abnormalities. Respiratory insufficiency, which has been associated with neuronal loss in the medulla, resulting in hypoventilation is a feature in the late stages of the disease when there is an increased risk of aspiration pneumonia.

8. Hearing loss. There is a high incidence of sensorineural hearing loss in myotonic dystrophy.

9. Peripheral neuropathy of axonal type is responsible for the areflexia, distal sensory impairment, and fasciculations seen in some cases.

Children born to mothers with myotonic dystrophy may present with congenital myotonic dystrophy in the neonatal period. This condition is characterized by hypotonia, facial diplegia, dysphagia, mental retardation, a high-arched palate, and tented lips. Myotonia develops later in the course of this condition.

Diagnostic Procedures

1. DNA analysis using a DNA probe allows direct identification of the myotonic dystrophy mutation in DNA extracted from peripheral blood lymphocytes. Southern blot analysis can be used to detect abnormally large DNA fragments with expanded gene repeats. The polymerase chain reaction will detect small expansions of the unstable DNA sequence. DNA testing can also be used for prenatal diagnosis of myotonic dystrophy, as well as detection of carriers.

2. The effect of temperature change. Myotonia may be difficult to demonstrate in some cases. Submersion of the hands in cold water for several minutes may facilitate the appearance of myotonia.

3. The electromyogram is characteristic with an increase in insertional activity and typical myotonic discharges following voluntary contraction of muscle.

4. Cardiac involvement affects predominantly the conduction system in the heart. Atrial fibrillation, atrial flutter, a prolonged PR interval, and various conduction defects may be present.

5. Slit lamp examination reveals the characteristic lens opacities.

6. Serum tests. There are abnormally low levels of IgG, an abnormal glucose tolerance test, and low follicle-stimulating hormone levels in most cases.

7. The MRI and computed tomography (CT) scans and chest and skull x-rays. Thickening of the calvarium and enlargement of the frontal sinuses are often present on skull x-rays. Microcephaly, calcification of the basal ganglia, and cerebral atrophy may be demonstrated by CT scan. The MRI shows the presence of increased signal intensity in the white matter.

8. Pure tone screening and impedance audiometry will detect sensorineural hearing loss.

9. The diagnosis can be established by a muscle biopsy, which shows characteristic findings of a dystrophic process.

Treatment

1. The relief of myotonia is discussed under myotonia congenita. The calcium channel blocking agent, nifedipine, which has no effect on cardiac conduction, decreases myotonia in doses of 10 to 20 mg q8h.

2. In the latter stages, when the risk of aspiration pneumonia increases, respiratory infection should be treated with appropriate antibiotics, postural drainage, and chest percussion.

3. Muscle weakness can be severe in those with marked expansion of CTG repeats. These patients need supportive care, including splinting and use of an electric cart or wheelchair.

4. Cardiac involvement is often the main complication. Patients require regular evaluation of cardiac function and appropriate treatment for arrhythmias.

5. Preoperative and postoperative care and intraoperative monitoring are requred to avoid complications of anesthesia, which carry increased morbidity and may be lethal in myotonic dystrophy.

6. Pregnancy and delivery carry a high risk of complications in mothers with myotonic dystrophy and their offspring. Consequently, mothers should be monitored for increased muscle weakness involving respiratory muscles, reduced fetal movements and hydramnios, and prolonged, often ineffective labor. There is also an increase of spontaneous abortion earlier in pregnancy.

Obstetric complications include retained placenta, placenta previa, and neonatal death.

Prognosis

Myotonic dystrophy is a chronic condition with progressive deterioration in most cases. In noncongenital forms of the disease, death occurs between ages 40 and 60 years due to cardiac or respiratory dysfunction.

In congenital muscular dystrophy, there is a 25 percent chance of death before 18 months of age, and a 50 percent chance of survival until the mid-thirties.

Proximal Myotonic Myopathy

This rare variant of myotonic dystrophy is inherited as an autosomal dominant trait in which there is no abnormal enlargement of the CTG repeat in the gene for myotonic dystrophy.

Clinical Features

Symptoms are present in adults with complaints of stiffness in the thigh muscles followed by a more generalized myalgia, which can be severe in the thighs. Cataracts can occur at an early stage, and grip myotonia is prominent in most cases. Muscle weakness is often delayed and fluctuates in intensity. Electromyography is abnormal and demonstrates myotonic discharges. The condition is probably compatible with a normal life span because severe cardiac involvement has not been demonstrated.

Treatment Supportive. There is no specific treatment for these conditions.

Benign Congenital Myopathies

The benign congenital myopathies are a heterogenous group of rare disorders. Most congenital myopathies are mild, slowly progressive or nonprogressive, infantile or adolescent conditions associated with specific structural alterations in muscle fiber.

Nemaline myopathy usually presents at birth or in infancy, but symptoms may be delayed until adolescence or adult life. The condition is inherited as an autosomal dominant or recessive trait and presents with generalized muscle hypotonia and weakness from birth or infancy, high-arched palate, long face, pigeon chest, scoliosis, and pes cavus. The severity varies from mild weakness to wheelchair dependency or even use of a mechanical ventilator.

Central core disease is a mild myopathy inherited as an autosomal dominant trait, presenting in infants. The condition is nonprogressive, with proximal muscle weakness and pes cavus. Type I muscle fibers contain central cores of myofilaments lacking mitochondria.

Myotubular myopathy presents as a severe myopathy in infancy, with hypotonia, respiratory failure, and death. Milder cases can occur with survival and these patients present with hypotonia, muscle weakness, delayed psychomotor development, and mental retardation. Muscle biopsies show small myotube-like fibers with central nuclei dispersed between normal-sized fibers.

Vacuolated myopathy is a rare condition of juvenile onset, slow progression, and predominantly proximal muscle weakness. Muscle biopsy shows vacuolated muscle fibers, which probably represent superficial muscle fiber injury associated with sarcolemmal invagination, the result of deposition of complement membrane attack complex on the damaged cell surface membrane.

Diagnostic Procedures

The diagnosis may be established by a muscle biopsy, which indicates a myopathic process. In many cases, a definitive diagnosis requires electron microscopy.

Prognosis In the majority of cases, the congenital myopathies are slowly progressive conditions; in some cases, the process appears to become arrested in adolescence or adult life. Other cases show a slow deterioration requiring the eventual use of a wheelchair. There is an increased risk of respiratory infection, which may be fatal unless treated promptly.

Muscle Carnitine Deficiency

This condition is a proximal myopathy with onset in childhood and exhibiting a slowly progressive course. Cardiac muscle involvement and myoglobinuria occur in some cases. Muscle biopsy shows a severe vacuolar myopathy affecting type 1 fibers, with vacuoles staining positive for lipid. The condition results from impaired carnitine transport into muscle; serum carnitine levels are normal or occasionally low, but muscle carnitine content is reduced.

Zidovudine (AZT) therapy may induce a similar myopathy by depletion of mitochondrial DNA, reduced muscle carnitine levels, and lipid storage in muscle fibers.

A systemic form of carnitine deficiency can result from many inborn errors of metabolism. All are associated with deficiency in free carnitine resulting in the limited entry of low-chain fatty acids into mitochondria. Affected children have recurrent attacks of encephalopathy resembling Reye syndrome and later development of myopathy, hepatomegaly, and cardiomyopathy.

DISORDERS CHARACTERIZED BY STIFFNESS AND SPASMS

Stiff-Person Syndrome (Stiff-Man Syndrome)

Definition

The stiff-person syndrome is a rare disorder characterized by persistent muscle contraction, spasms, and muscle cramps, which disappear during sleep.

Etiology and Pathology

The condition is believed to be the result of an autoimmune reaction where antibodies are directed against glutamic acid decarboxylase (GAD), an intracellular enzyme in y-aminobutyric acid (GABA)-containing neurons. This leads to destruction of these neurons, with a lack of inhibitory influence by the GABA motor neuron system, resulting in continuous motor neuron activity and clinical rigidity.

Clinical Features

The patient initially experiences muscle aches and pains followed by stiffness of the muscles of the trunk, limbs, and neck. Voluntary movements are slowed. Emotional or sensory stimuli may exacerbate the stiffness and produce painful spasms. On examination, the muscles are contracted and the patient is unable to relax them. The disorder is progressive and eventually results in considerable disability. Misdiagnosis of a psychogenic movement disorder is not unusual.

A congenital form of the disorder has been reported. In these cases, stiffness is present at birth and gradually resolves, so that by age 3, the tone is almost normal. Later, in adolescence or adulthood, the stiffness reappears in a milder form.

Diagnostic Procedures

Electromyography reveals persistent contractions of muscle fibers and bursts of motor unit potentials during spasm.

Treatment

The stiffness and spasm improve with diazepam (Valium) 20 to 200 mg/day, or clonazepam, or valproic acid. Baclofen (Lioresal), which reduces spasticity by activating GABA-b receptors in the dorsal horn of the spinal cord, reduces muscle contractions and spasms. The use of the baclofen pump is a most effective form of therapy, but pump failure may be associated with acute autonomic disturbances, a life-threatening situation.

Acquired Neuromyotonia (Isaac Syndrome)

Neuromyotonia is a syndrome associated with a known neuropathic process such as a hereditary neuropathy or an acquired disorder, with or without an associated neuropathy. The syndrome is characterized by myokymia (muscle twitching at rest), cramping of muscle often induced by muscle contraction, impaired muscle relaxation, muscle weakness, increased sweating, and an elevated CK level. Neuromyotonia is believed to be an autoimmune disease where antibodies are directed against potassium channels in motor neurons proximal to the terminal branches.⁸³ Electromyography reveals neuromyotonic discharges characterized by bursts of motor unit action potentials firing at 150 to 300 Hz for several seconds, or occasionally, myokymic discharges of motor unit action potentials recurring regularly at rates up to 60 Hz. Motor nerve conduction studies may demonstrate a peripheral neuropathy in some cases.

Most patients show excellent response to phenytoin or carbamazepine. Refractory patients should be treated with plasmapheresis.⁸⁵

FAMILIAL PERIODIC PARALYSIS

There are three types of familial periodic paralysis, all of which are inherited as an autosomal dominant trait.

Hypokalemic Periodic Paralysis

Definition Hypokalemic periodic paralysis is an inherited condition of episodic muscle paralysis associated with hypokalemia.

Etiology and Pathology

Familial hypokalemic periodic paralysis has been linked to a mutation in chromosome lq31-32. This area is the site of the gene for the alpha_: subunit of the skeletal muscle, DHP-sensitive calcium channel. Mutation in this gene modifies the function of the DHP receptor by altering calcium channel current in hypokalemic periodic paralysis.

Muscle biopsy shows the presence of vacuoles, containing glycogen, in muscle fibers, which are present during an attack, and which may decrease in number immediately after an attack. Other features include tubular aggregates derived from sarcoplasmic reticulum, variations in fiber size, and increased internal nuclei.

Clinical Features

Hypokalemic periodic paralysis is more common in men and occurs predominantly during the teens and twenties. Attacks begin at night and the patient awakens with weakness of all skeletal muscles except those involved in respiration and speech. However, there are reports of respiratory involvement and some deaths from respiratory failure, but this is a rare complication. Involved muscles are firm and tender to palpation. The neurological examination is normal, with sparing of muscles supplied by cranial nerves and those involved in respiration and speech. The attacks last from several hours to days. Several factors have been reported to precipitate attacks. These include large meals with a high carbohydrate content; exertion; trauma; heavy alcohol ingestion; upper respiratory tract infection; cold weather; and administration of insulin, thyroid hormone, steroids, epinephrine, thiazides, or licorice. Permanent muscle weakness of the proximal musculature, but spreading later to a more diffuse involvement, can occur.

Diagnostic Procedures

1. The movement of potassium, sodium chloride, phosphate, ions, and water into the muscle fibers during an attack is reflected in decreased serum potassium level below 3.5 mEq/L.

2. Urinary excretion of potassium and sodium is decreased.

3. Electromyography shows decreased amplitude, number, and duration of motor unit potentials or electrical silence during periods of paralysis. Muscle fiber velocity is reduced between attacks.

4. Provocative tests to induce hypokalemia, using glucose and insulin, require close monitoring by electrocardiography because hypokalemia may induce cardiac arrhythmia. A 10-min bicycle exercise test is a safer alternative. Patients with hypokalemic periodic paralysis experience a minimal increase in serum potassium levels 10 and 30 min after exercise, compared to a control population where the increase is significant.

5. Corticotropin 80 to 100 IU intravenously can be used in suspected periodic paralysis of either hypo- or hyperkalemic type. Corticotropin will induce an attack of paralysis with appropriate changes in serum potassium concentration in each condition.

Treatment

1. Attacks may be terminated by oral or parenteral administration of potassium and may be prevented by oral administration of potassium 130 mEq/day.

2. Acetazolamide 125 mg q.o.d., increasing by increments to achieve an optimum dosage, to a maximum of 500 mg ql2h orally, is the drug of choice to prevent attacks.

3. Spironolactone 100 mg daily or bid is effective in reducing the number of attacks.

4. Other drugs that may be of benefit include the carbonic anhydrase inhibitor dichlorphenamide, the calcium channel blocking agent, verapamil, or lithium.

5. Predisposing factor should be avoided.

Secondary Hypokalemic Periodic Paralysis

A number of disorders with associated hypokalemia may develop symptoms of periodic paralysis resembling hypokalemic paralysis. This syndrome occurs in thyrotoxic periodic paralysis, which is seen predominantly in men of Asian extraction and is rare in the United States. Other conditions include renal diseases associated with loss of potassium such as renal acidosis types 1 and 2, acute tubular necrosis, and a nephrotic syndrome. Chronic gastrointestinal potassium loss can also cause periodic paralysis in patients with emesis and diarrhea, nasogastric suctioning, fistulae, and malabsorption in celiac disease, tropic sprue and Salmonella enteritis. Other causes include primary hyperaldosteronism, excess licorice ingestion, laxative abuse, and barium toxicity.

Diagnostic Procedures

Primary hypokalemic periodic paralysis and thyrotoxic periodic paralysis may be distinguished from nonthyrotoxic secondary hypokalemic periodic paralysis by a prolonged exercise test.

Treatment

Intravenous propranolol may terminate an attack in patients with thyrotoxic periodic paralysis, who fail to respond to potassium therapy. The underlying cause of secondary hypokalemic periodical paralysis should be identified and treated.

Hyperkalemic Periodic Paralysis

Definition Hyperkalemic periodic paralysis is a condition inherited as an autosomal dominant trait, where periodic paralysis is associated with elevation of serum potassium levels.

Etiology and Pathology

The disease has been linked to allelic defects in a gene that encodes for the alpha subunit of the tetrodotoxin-sensitive skeletal muscle sodium channel, localized to chromosome 17q23 1-25.3.¹⁰° There is non-inactivation of this channel during an episode of paralysis, with influx of sodium resulting in sustained membrane depolarization.

Muscle biopsy may be normal or may show some nonspecific features, such as large variation in fiber size and central nuclei, increased subsarcolemmal glycogen and the presence of vacuoles in some cases.

Clinical Features

Attacks begin in childhood and occur during the day, usually while resting after exercise. Each attack may be preceded by a sensation of heaviness and stiffness in the muscles and paresthesias in the face and extremities. Episodes usually last 1 h. In addition to exercise, paralysis can be precipitated by exposure to cold, hunger, administration of potassium, emotional stress, and pregnancy. Attacks may be prevented by eating a carbohydrate after exercise.

Muscle weakness affects the lower extremities predominantly, but upper extremity and neck muscles can be involved. Mild myotonia can be experienced during muscle weakness. Permanent muscle weakness is an occasional complication. Cardiac arrhythmias have been reported in a few cases.

Diagnostic Procedures

1. Serum potassium levels are increased during an attack, but normal potassium levels have been recorded in some cases, giving rise to so-called normokalemic periodic paralysis.

2. Serum sodium levels decrease as sodium enters muscle fibers.

3. Urinary potassium increases during an attack, resulting in a drop in serum potassium levels and recovery.

4. Electromyography may reveal electrical silence during paralysis or fibrillations, positive sharp waves, and myotonic discharges during paresis. Motor unit potentials are decreased in number and duration.

5. Provocative test with administration of 2 to 10 g potassium chloride will induce an attack within 1 to 2 h. Electrocardiographic monitoring should be performed to detect any abnormalities related to hyperkalemia.

Treatment

Attacks can be prevented by thiazide diuretics—hydrochlorothiazide 25 to 75 mg/day. Acetazolamide, albuterol, and metaproterenol are also effective.

Paramyotonia Congenita

Definition

This is a familial condition characterized by muscle stiffness induced by exposure to cold or by exercise, followed by muscle weakness. The condition is inherited as an autosomal dominant trait.

Etiology and Pathology

Paramyotonia congenita, like hyperkalemic periodic paralysis, is the product of a defect in the skeletal muscle sodium channel. Linkage has been established between paramyotonia congenita and the gene encoding the alpha subunit of the muscle sodium channel localized to chromosome 17q20 231-225.3.

Muscle biopsy may be normal or show nonspecific changes.

Clinical Features

The symptoms are present at birth. Babies develop mask-like facies on exposure to a cold environment. This is followed by paradoxical muscle stiffness that increases with exercise. Attacks of weakness are delayed until adolescence and often last several hours or days. The weakness has an upper limb predominance; respiratory muscle involvement is rare. Symptoms can be more severe during pregnancy. Permanent weakness does not occur.

Diagnostic Procedures

1. Muscle cooling results in symptoms of weakness and reduced compound muscle potentials on electromyography.

2. Electromyography demonstrates myotonic discharges at room temperature, enhanced by cooling, but myotonic discharges may decrease or disappear with the onset of paralysis.¹⁰³

Treatment

1. Avoid exposure to a cold environment, which can precipitate an attack.

2. Mexiletine, a cardiac antiarrhythmic drug, is effective in reducing both myotonia and weakness.

Diseases of the Basal Ganglia

Progressive Supranuclear Palsy

Definition

Progressive supranuclear palsy (PSP) is a chronic progressive brain disease characterized by supranuclear ophthalmoplegia affecting chiefly vertical gaze, pseudobulbar palsy, prominent neck dystonia, behavioral and cognitive disturbances, parkinsonism, axial dystonia, gait disturbances, impaired equilibrium and falls.

Etiology and Pathology

The etiology is unknown, but the condition may be related to exposure to an exogenous toxin.

The brain shows evidence of atrophy. There is decreased pigment in the substantia nigra and locus ceruleus and loss of neurons in the basal ganglia, brainstem and cerebellum. Neurofibrillary tangles are present in the cerebral cortex, caudate nucleus, puta-men, globus pallidus, subthalamic nucleus, brainstem, and cerebellum.

Clinical Features

The prevalence of PSP is 1.4 cases per 100,000, with an annual incidence of 3 to 4 per million. The disease is usually sporadic, but familial cases have been described, suggesting an autosomal dominant trait. The symptoms begin in the early sixties and are seen in all ethnic groups. Sur vival following the onset of overt symptoms is from 6 to 9 years. Early symptoms consist of bradykinesis and supranuclear gaze palsy, with voluntary down gaze less than 15°, impaired optokinetic nystagmus, stimulus downward, and horizontal square wave jerks. This is followed by the development of rigidity affecting the axilla muscles more than the limb muscles, in the lower limbs more than the upper limbs. Parkinsonian features, including paucity of blinking and a fixed facial expression, occur early in the course of the disease. Progressive dysarthria, increased reflexes, and extensor plantar responses are constant features. The head and neck are held in extension, and there are frequent falls in a patient with a relatively well-preserved gait. Torticollis, blepharospasm, and stuttering speech have been described. The dementia associated with PSP is often mild, with cognitive slowing, but almost all patients suffer from apathy and disinhibition occurs in about one-third of cases.⁶⁹ Eventually the patient becomes bedridden and dies from intercurrent infection.

Diagnostic Procedures

The diagnosis depends largely on clinical presentation and the characteristic progression of the disease.

The MRI scan shows diffuse brain atrophy, including cerebellar atrophy, atrophy of the midbrain, a widening of the posterior third ventricle, and increased signal intensity in the periaqueductal region in the T2-weighted images.

Differential Diagnosis

In the early stages of PSP, the condition is frequently misdiagnosed as Parkinson disease. Other conditions that might be considered include multisystem atrophy, including striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy.

Treatment

Carbidopa-levodopa therapy may produce some improvement in the early stages of the disease and at relatively high doses. Levodopa content up to 1500 mg 24 h can be used without producing adverse effects. Amitriptyline beginning at 10 mg q.h.s. and increased by 10 mg q5d, up to 100 mg q.h.s., is of established benefit. Amantadine and selegiline may produce temporary improvement.

Multiple System Atrophy

Multiple system atrophy (MSA) is a sporadic, progressive adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. MSA encompasses conditions described previously under the heading of striatonigral degeneration (SND), sporadic olivopontocerebellar atrophy (OPCA), and Shy-Drager syndrome (SDS), presenting with any combination of extrapyramidal corticospinal cerebellar and autonomic signs and symptoms.

Etiology and Pathology

The etiology is unknown. Pathological changes consist of neuronal loss and gliosis in the striatal, nigral, and olivopontocerebellar systems, with the presence of oligodendroglial and neuronal intracytoplasmic and intranuclear argyrophilic inclusions containing accumulations of tubular structures.

Clinical Features

Initial symptoms consist of parkinsonism (SND type), or cerebellar ataxia (OPCA type), or autonomic dysfunction (SDS).

Parkinsonism consisting of akinesia and rigidity is an early feature of SND, accompanied by a jerky irregular tremor in some cases. Cerebellar signs with intention tremor or heal-to-shin ataxia occur in the early stages of OPCA, with later development of postural instability and gait ataxia.

Autonomic failure is a feature of SND and OPCA or SDS and may be the presenting symptom or develop later in the course of the disease. Symptoms consist of impotence, mild-to-moderate postural hypotension, urinary incontinence or retention, and syncopal episodes. Corticospinal tract involvement, with increased tendon reflexes and extensor plantar responses, are usual, but spasticity and lower limb weakness are uncommon.

Many patients develop nystagmus, saccadic eye movements, and dysarthria, which can be severe in some cases. Upward, downward, or horizontal gaze may be limited. Respiratory stridor is a later feature, and stimulus-sensitive myoclonus occurs in about one-third of cases. Sensory changes are minor, with some impairment of vibration and position sense in the toes.

Patients presenting with prominent autonomic dysfunction and labeled SDS ultimately develop parkinsonism or cerebellar dysfunction, or both. Consequently, SDS is probably a variant of MSA, with later development of the features of SND or OPCA.

Diagnostic Procedures

An MRI scan may show brainstem and cerebellar atrophy in the later stages of OPCA.

Treatment

Parkinsonism responds to lev-odopa preparations in about one-third of cases. Response to dopamine agonists is poor.

Orthostatic hypotension often responds to head uptilt at night, elastic support stockings, or an elastic leotard and an increased salt intake. When syncope is a feature, additional treatment is indicated.

Prognosis

Life expectancy is reduced to a considerable degree. The mean survival time is approximately 10 years.

Olivopontocerebellar Atrophy

Definition The OPCAs are a group of inherited degenerative disorders characterized by a predominant involvement of the brainstem and cerebellum.

Etiology and Pathology

The disorders may be inherited as an autosomal dominant or autosomal recessive trait and have in common neuronal degeneration and gliosis in the cerebellum, brainstem, spinal cerebellar tract, and dorsal columns. Histopatholog-ical changes typical of MSA have been described in some cases, indicating a close relationship between inherited OPCA and MSA. However, the inclusion bodies of MSA are usually absent in inherited OPCA.

Clinical Features

One of the characteristics of olivopontocerebellar degeneration is the wide variety of presenting symptoms. Affected members of the same family may present with a totally different clinical picture. Eventually, however, the affected members of the family will develop ataxia, nystagmus, intention tremor, and titubation of the head. There may be generalized rigidity and parkinsonian features in some cases. The speech becomes severely dysarthria The tendon reflexes may be hyperactive or hypoactive, and there is a bilateral extensor plantar response. Some patients develop signs of dementia as a late feature of the disease. Others have prominent autonomic symptoms, with incontinence and orthostatic hypotension and can be regarded as a form of multiple system disease. Sleep disorders, including hyposom-nia, rapid eye movement sleep without atonia, and sleep apnea are present in some cases.

Diagnostic Procedures

Magnetic resonance imaging and CT scanning may show atrophy of the brainstem and atrophy of the cerebellum with enlargement of the fourth ventricle, ambiens, and pre-pontine cisterns.

Treatment Treatment is symptomatic. Sleep apnea may respond to trazodone 50 mg q.h.s.

Prognosis There is typically a relentless progression of the disease with death occurring from intercurrent infection approximately 20 years after the development of initial symptoms.

Familial Spinocerebellar Ataxias

The autosomal dominant spinal cerebellar ataxias (SCAs) are a heterogeneous group of multisystem neurodegenerative diseases that have been mapped to five chromosomes.

The clinical features, pathological changes, and gene location are listed in Table 14-4.

Families diagnosed with SCA-3 may be examples of Machado-Joseph disease, exhibiting the type 2 phenotype.

Treatment

No therapeutic measures are available to treat these diseases. Patients require aids to maintain ambulation and prevent falling.

Table 14-4

Familial spinocerebellar ataxias

Type	Clinical features	Pathology	Gene location
SCA-I	Ataxia, optic atrophy, ophthalmoplegia, corticospinal tract involvement, extrapyramidal features	Neuronal loss, Purkinje cells, pontine nuclei, inferior olivary nuclei	6p23-24
SCA-2	Ataxia, slow saccades, ophthalmoplegia, peripheral neuropathy	Neuronal loss, Purkinje cells, inferior olivary nuclei, substantia nigra, degeneration of posterior columns of spinocerebellar tracts	12q23-24
SCA-3	Ataxia, nystagmus, corticospinal tract involvement, dystonia, hyporeflexic tendon reflexes ankles	Neuronal loss, molecular layer cerebellum, pontine nuclei	14q24-q32
SCA-4	Ataxia, sensory axonal neuropathy, corticospinal tract involvement	Unknown	16q24ter
SCA-5	Benign ataxic course, later appearance of corticospinal tract involvement	Unknown	11
SCA-7	Ataxia, macular dystrophy, retinal degeneration	Unknown	3p14-21.1
Machado-Joseph disease Type 1, early onset	Ataxia, ophthalmoplegia Plus dystonia corticospinal tract involvement	Lost neurons, substantia nigra, subthalamic nuclei, pontine nuclei, dentate nuclei,	14q32.1
Type 2, onset middle age Type 3, onset fifth decade	Corticospinal tract involvement Amotrophy	anterior horn cells, posterior root ganglia, degeneration, Clarke's column, spinocerebellar tract
Dentatorubropallidoluysian atrophy	Ataxia, choreoathetosis, myoclonus, epilepsy, dementia	Lost neurons, dentate nucleus, red nucleus, globus pallidus, subthalamic nucleus, Purkinje cells, brainstem tegmentum, corticospinal tracts	12p12ter

Friedreich's Ataxia

Definition

Friedreich's ataxia is a degenerative disease of childhood and early adult life that primarily involves the long tracts of the spinal cord. The disease is inherited as an autosomal recessive trait in which the Friedreich's ataxia gene has been mapped to the proximal long arm of chromosome 9 (9ql3-q21). This mutation consists of an unstable expression of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function. Larger GAA expansions correlate with earlier age of onset and shorter time to loss of ambulation.

Pathological changes consist of atrophy with demyelination involving the posterior columns and the spinocerebellar, and corticospinal tracts of the spinal cord. The areas of degeneration show a loss of axons and myelin with secondary gliosis. The degenerative changes begin in the neurons of the dorsal root ganglia and are followed by a dying back of axons of large myelinated fibers in the peripheral nerve and in the posterior columns of the spinal cord. Similar neuronal changes eventually involve the nucleus gracilis and cuneatus, with degenerative changes in the medial lemniscus. The dorsal and ventral spinocerebellar tracts are similarly involved. The corticospinal tract shows demyelination with increased involvement in a caudal direction. Loss of Purkinje cells in the cerebellum and degeneration of the dentate nucleus with axonal loss and demyelination of the superior cerebellar peduncle also occur.

Cardiac hypertrophy and diffuse myocardial fibrosis with degeneration of cardiac muscle cells are an invariable finding.

Clinical Features

The first symptoms of ataxia and easy fatigability develop before 10 years of age in about half the cases, and the majority have well-established signs before the age of 20. The ataxia is progressive, beginning in the lower limbs and gradually involving the trunk and upper limbs. Cranial nerve examination reveals reduced visual acuity in some cases, horizontal nystagmus, saccadic pursuit eye movements, hearing loss, dysarthria, and dysphagia. The motor system shows wasting of muscles and weakness of all four limbs. Rapid alternating movements are slowed, with overflinging and past pointing on finger-to-nose testing and bilateral intention tremor. The gait is wide based due to a combination of posterior column dysfunction, spasticity, and cerebellar ataxia. Involvement is symmetrical in most cases, but some asymmetry is not unusual. Sensation is abnormal, with preservation of touch but impairment of temperature, vibration, and position sense in hands and feet. Tendon reflexes are depressed or absent, but there is a bilateral extensor plantar response. Early onset ataxia with cardiomyopathy and retained reflexes has been described.^83d The fully developed syndrome is characterized by a mild degree of dementia. Optic atrophy with visual failure is not unusual and many patients have a progressive hearing loss. Speech is slow, staccato, and explosive in more developed cases but may eventually become unintelligible in the later stages of the disease.

Examination of the spine shows scoliosis in the majority but not all cases and there is deformity of the feet with pes cavus and extension of the metacarpophalangeal joints and flexion of the interphalangeal joints in about 90 percent of patients.

Cardiomyopathy occurs in about two-thirds of the cases and electrocardiographic (ECG) abnormalities can occur early in the disease and are present in most cases. Death from congestive heart failure or cardiac arrhythmia is common.

Diagnostic Procedures

1. Clinical diabetes mellitus due to insulin-resistant B cell deficiency and type 1 diabetes are present in about 20 percent of cases.

2. Serum bilirubin levels are frequently elevated.

3. Pulmonary function tests show progressive impairment due to progressive kyphoscoliosis.

4. The ECG is abnormal and many patients have obstructive hypertrophic cardiomyopathy.

5. The EEG shows mild nonspecific abnormalities in most cases.

6. Motor nerve conduction velocities are normal, but sensory conduction velocities are prolonged or absent in the lower limbs.

7. Somatosensory evoked potentials recorded after peroneal nerve stimulation are abnormal, indicating spinal cord involvement.

Differential Diagnosis

1. Other forms of spinal cerebellar degeneration. The characteristic finding of moderately rapid progression and cardiac involvement differentiate Friedreich's ataxia from other spinocerebellar degenerations.

2. Congenital abnormalities. The Arnold-Chiari malformation, platybasia, and odontoid compression can be excluded by MRI studies.

3. Arteriovenous (AV) malformation of the spinal cord. Increased tone and hyperreflexia occur only below the level of the malformation. There are progressive urgency of micturition and a sensory level. The AV malformation can be demonstrated by MRI scanning.

4. Syphilis. Syphilitic pachymeningitis is rare. The condition is associated with a CSF pleocytosis and increased protein content. The serological test for syphilis is positive.

5. Subacute combined degeneration can cause confusion if it occurs before overt signs of pernicious anemia. Serum vitamin B₁₂ levels are depressed.

6. Spinal cord tumors tend to cause pain, particularly nerve root pain. There is progressive spasticity below the level of the lesion and progressive urgency of micturition. Examination shows a sensory level. The diagnosis can be established by MRI scanning.

7. Multiple sclerosis. The spinal cord form of multiple sclerosis can cause some confusion with Friedreich's ataxia. There tends to be a relapsing and remitting course in multiple sclerosis, with bladder involvement and patchy sensory loss. Visual evoked potentials and auditory evoked potentials may be abnormal in multiple sclerosis. The CSF may show an elevated protein, increased gamma globulin content, and the presence of oligoclonal bands in the CSF, which are not present in the serum. An MRI scan of the brain is usually abnormal.

8. Vitamin E deficiency is a condition closely resembling Friedreich's ataxia. Serum vitamin E levels are normal in Friedreich's ataxia.

Treatment The treatment is symptomatic. Cardiac and pulmonary complications should receive prompt attention in advanced cases because they are frequently fatal.

Prognosis The disease runs a progressive course and most patients are unable to walk 5 years after the appearance of symptoms. Death occurs 10 to 20 years after onset from pulmonary or cardiac complications.

Familial Spastic Paraplegia

Definition This is a slowly progressive spastic paraparesis, without involvement of other cerebrospinal or cerebellar systems.

Etiology and Pathology

The condition is inherited as an autosomal dominant or autosomal recessive trait but occasionally appears to be a sex-linked recessive trait and occurs more frequently in males.

In some cases, the disease may represent a forme fruste of an inherited spinocerebellar degeneration.

Clinical Features

The first symptoms begin in the first two decades of life, although a rare form with later onset has been described. There is a slowly progressive spastic paraparesis evolving to spastic paraplegia, with increasing weakness and spasticity of the lower limbs, increasing tendon reflexes and extensor plantar responses.

Treatment

It is important to rule out compressive conditions of the spinal cord, particularly cervical spondylosis in all cases. Because the condition is slowly progressive, most cases are not associated with the reduction of a normal life span.

There is no definitive treatment for this condition. The use of a baclofen pump should be considered in those with advanced disease and severe spasticity.

Familial Episodic Ataxia

This uncommon condition is characterized by episodic ataxia, which occurs in two distinct forms, familial episodic ataxia with interictal myokymia (EA1) and familial episodic ataxia with interictal nystagmus (EA2). In EA1, the result of a genetic defect located on chromosome 12pl3, the attacks are brief, lasting no more than several minutes. EA2, the result of a genetic defect on chromosome 19p, is characterized by longer episodes of ataxia of several hours' duration. In EA2, symptoms vary from pure ataxia to signs suggesting involvement of the cerebellum, brainstem, and cerebral cortex, and some individuals exhibit a progressive ataxia indistinguishable from dominantly inherited spinal cerebellar ataxia. About 50 percent of patients with EA2 experience basilar migraine or hemiplegic migraine, the latter linked to a genetic defect on chromosome 19 in the same region as EA2. Both EA1 and EA2 respond to acetazolamide therapy.

HEREDITARY DISEASES OF WHITE MATTER

The Leukodystrophies

The leukodystrophies are a rare group of genetically determined conditions characterized by metabolic defects in the formation or breakdown of myelin (Table 14-5). Metachromatic leukodystrophies are the most frequently encountered in this group of rare metabolic disorders.

Metachromatic Leukodystrophy

Definition

Metachromatic leukodystrophy is characterized by a degeneration of myelin in the central and peripheral nervous systems due to lack of the enzyme arylsulfatase A. The condition is transmitted as an autosomal recessive trait and the mutated gene is located on chromosome 22.

Etiology and Pathology

There is a disturbance of the sphingolipid metabolism in which galac-tosyl-3-sulfate ceramide (sulfatide) is metabolized. The decreased activity of arylsulfatase A in metachromatic leukodystrophy leads to accumulation of sulfatide in the central and peripheral nervous systems.

The brain is normal in size and weight. The white matter is firm and brownish in appearance, with occasional cavitation. Microscopic abnormalities include loss of myelin sheaths, axonal degeneration, loss of oligodendrocytes, and accumulation of lipid lying free within macrophages and neurons. The peripheral nerves show myelin degeneration and axonal loss, with accumulation of lipid. Lipid deposits are also present in the Kupffer cells of the liver and the renal tubules. The ganglion cells of the retina are heavily involved.

Clinical Features

There are three clinical forms of metachromatic leukodystrophy:

Late Infantile Form

This form has its onset at 12 to 18 months of age, with progressive weakness of the lower limbs. The gait is abnormal because of spasticity and ataxia or hypotonia due to peripheral neuropathy. There is progressive visual loss and optic atrophy. Occasionally, macular degeneration and a "cherry-red spot" appearance occur. Progressive dementia, loss of speech, ataxia, spasticity and tremors are seen. Seizures occur in about 50 percent of cases. The condition progresses to severe dementia, blindness, and spastic tetraplegia, with decerebration in the terminal stages. Death occurs 2 to 10 years after onset.

Table 14-5

Disorders of sphingomyelin metabolism

Disease	Inheritance	Enzyme deficiency	Metabolite that accumulates
Metachromatic leukodystrophy	Autosomal recessive	Sulfatidase	Sulfatide
Globoid cell leukodystrophy (Krabbe)	Autosomal recessive	Galactocerebroside-β-galactosidase	Galactocerebroside
GM1 gangliosidoses (generalized)	Autosomal recessive	Ganglioside GM^ /3-galactosidase	Ganglioside GM1
Tay-Sachs disease (infantile)	Autosomal recessive	Hexosaminidase A	Ganglioside GM2
Tay-Sachs disease (juvenile)	Autosomal recessive	Hexosaminidase B	Ganglioside GM2
Tay-Sachs disease (Sandhoff-Jatzkewitz)	Autosomal recessive	Hexosaminidase A, B	Ganglioside GM2
Fabry disease	X-linked recessive	Ceramidetrihexoside-α-galactosidase	Ceramidetrihexoside
Gaucher disease	Autosomal recessive	Glycocerebroside β-galactosidase	Glucocerebroside
Niemann-Pick disease	Autosomal recessive	Sphingomyelinase	Sphingomyelin

Juvenile Form

In this form, symptoms do not appear until 5 to 10 years of age. The initial symptoms consist of a declining performance in school, behavioral changes, and gait disturbance. Older children show cognitive decline and abnormal behavior before the gait is affected. The early symptoms are followed by progressive spasticity, rigidity, and ataxia with a somewhat slower progression than the late infantile form of the disease. Peripheral neuropathy may develop but is usually mild. Seizures occur in 80 percent of patients. Life expectancy is 3 to 15 years from time of onset.

Adult Form

Symptoms begin in the early twenties with mental deterioration and behavior abnormalities, followed by ataxia. The disease is slowly progressive, with the development of dementia and polyneuropathy progressing to death after several years. Psychiatric illness with psychosis, personality change, emotional lability, abnormal behavior, and dementia occur in the late teens. Neurological find ings are similar to the younger onset types but evolve slowly. The course is prolonged, with eventually profound dementia, but survival into the fifth or sixth decades is possible. An adult pseudodeficiency of arylsulfatase A, with progressive neurological and psychiatric symptoms, has been described, in which arylsulfatase A levels are low, but there is no accumulation of sulfatides in the nervous system or in other organs.

Diagnostic Procedures

1. Metachromatic bodies can be seen in frozen sections of the sural nerve after biopsy.

2. Metachromatic bodies or abnormal urinary lipids can be demonstrated in the urine.

3. A deficiency of arylsulfatase A can be demonstrated in the urine and leukocytes and in cultured skin fibroblasts.

4. Visual, brainstem, auditory, and somatosensory evoked responses are abnormally prolonged or absent.

5. Peripheral nerve conduction velocities are slowed to less than 30 m/s.

6. The MRI scan shows cortical atrophy, ventricular enlargement, and abnormal signal intensity in the periventricular white matter on T2-weighted images. CT scanning shows scattered areas of decreased attenuation in the central white matter or decreased white matter attenuation near the frontal and occipital horns.

7. The CSF protein is elevated in 90 percent of patients, sometimes greater than 2000 mg/dL.

8. The diagnosis should be confirmed by leukocytic genomic DNA analysis.

9. Prenatal diagnosis is possible by demonstrating lack of arylsulfatase A in the amniotic fluid.

Treatment A bone marrow transplant may slow the progression of the disease in some patients with the infantile form of the disease, but treatment is usually symptomatic.

Globoid Cell Leukodystrophy

Definition

Globoid cell leukodystrophy is a rare demyelinating disorder of the central and peripheral nervous systems in which there is a deficiency of the lysosomal enzyme galactosylceramide-P-galacto-side. The disorder is inherited as an autosomal recessive trait that maps to chromosome 14q31.

Etiology and Pathology

The deficiency of the enzyme leads to an abnormal accumulation of galactosyl sphingosine, which is cytotoxic to oligodendrocytes resulting in impaired myelin formation in the brain (see Table 14-5). The brain is small and there is a diffuse loss of myelin. Microscopic examination shows the presence of multinucleated histiocyte (globoid) cells in the white matter. The globoid cells contain galactosyl sphingosine. The cortex remains remarkably normal in appearance, despite isolation from subcortical centers and loss of interhemispheric connections.

Clinical Features

Globoid cell leukodystrophy usually occurs in the infantile form. Rare juvenile and adult variants have been described. In the infantile form, there is loss of ability to sit, hold up the head, and reach other developmental milestones. Hyperirritability, hyperesthesia, and episodic fever occur. There are gradual development of optic atrophy, deafness, and progression to hypotonic or spastic quadriparesis. Seizures may occur. Terminal decere-bration and death occur within a year of onset.

Diagnostic Procedures

1. There is diminished activity of the enzyme galac-tosylceramide-3-galactosides in leukocytes or cultured fibroblasts.

2. The MRI scan shows areas of increased signal intensity in T2-weighted images in the white matter of the cerebral hemispheres and cerebellum and occasionally in the thalamus and posterior limb of the internal capsule and corona radiata.

3. The CT scan will show areas of low attenuation in the white matter in similar areas.

4. Nerve conduction velocities are slowed.

5. The CSF protein may be elevated.

6. Antenatal diagnosis can be made by amniocentesis and demonstration of deficient galactosylceramide-β-galactoside in cultured amniotic fluid cells.

Treatment Treatment is symptomatic.

Adrenoleukodystrophy

Definition

Adrenoleukodystrophy is a sex-linked recessive disorder owing to a mutation of a gene located in Xq28 that encodes a peroxisomal transporter protein of unknown function. The disorder is characterized by degeneration of myelin and adrenal insufficiency.

Etiology and Pathology

The etiology is unknown. There is accumulation of very long chain fatty acids, particularly hexacosanoate in the tissues. There is symmetrical demyelination of the cerebrum, brainstem, cerebellum and spinal cord. Microscopic examination shows sudanophilic lipids within macrophages lying in the perivascular spaces of the white matter. The adrenal glands are atrophic and contain balloon cells with eccentric nuclei.

Clinical Features The disease presents in three forms:

Diagnostic Procedures

1. Elevated plasma concentrations of long chain fatty acids can be demonstrated in some, but not all, cases of adrenoleukodystrophy.

2. An MRI scan shows diffuse areas of increased signal intensity in the white matter cerebrum and spinal cord. They appear as areas of decreased attenuation in the CT scan.

3. An EMG and nerve conduction studies are compatible with a primary axonal degeneration in peripheral nerves.¹²⁴

4. The EEG shows symmetrical slowing that increases as the disease progresses.

5. The corticotropin infusion test is abnormal, indicating primary adrenal insufficiency.

6. The CSF protein content may be elevated.

7. Adrenocortical biopsy will reveal the characteristic balloon cells and establish the diagnosis.

Cerebral Form

This is the most common phenotype, occurring in 45 percent of cases and presenting in boys aged 5 to 12 years. There is progressive failure of academic achievement in school, followed by progressive deterioration of vision. Ataxia and spasticity develop, and seizures may occur. There is deterioration to decorticate and decerebrate states. Death occurs 1 to 4 years after onset.

Adrenomyeloneuropathy

Some 35 percent of cases of adrenoleukodystrophy present as adrenomyeloneuropathy, which occurs in young adults and involves the spinal cord and peripheral nerves. Symptoms consist of progressive spastic paraparesis, peripheral sensory loss compatible with a peripheral neuropathy, and impaired function of the adrenal cortex and testes.¹²³

Leukodystrophy with Diffuse Rosenthal Fiber Formation (Alexander Disease)

Definition Leukodystrophy with diffuse Rosenthal fiber formation is a sex-linked recessive disorder characterized by demyelination and progressive deterioration.

Etiology and Pathology

The etiology is unknown. Rosenthal fibers are inclusion bodies within the astrocytes in which stress protein inclusions consisting of a-B-crystallin and small heat shock protein, HSP-27, are formed as part of a chronic stress response to an unknown stimulus. The brain is normal in size or enlarged. There is diffuse demyelination, occasionally accompanied by cavitation, with proliferation of astrocytes containing granular eosinophilic deposits within astrocytic processes and cell bodies.

Clinical Features There are three clinical forms of presentation of this disorder.

Infantile Onset

This form occurs in boys and is characterized by progressive psychomotor retardation, spasticity, megalocephaly, and seizures at approximately 6 months of age. Death occurs by age 3.

Juvenile Onset

This form of the disorder occurs equally in boys and girls; it begins in late childhood and is characterized by progressive paresis, bulbar signs, and hyperreflexia. The patient dies in the late teens.

Adult Onset

The adult-onset form may resemble multiple sclerosis¹³⁰ presenting with a remittent course with ataxia, nystagmus, and spastic paraparesis or quadriparesis.

Sensory symptoms are not significant in any of the clinical presentations.

Diagnostic Procedures

The diagnosis is established by brain biopsy or autopsy, with demonstration of a profusion of refractile Rosenthal fibers within astrocytes.

Treatment Treatment is symptomatic.

Spongy Degeneration (Canavan)

Spongy degeneration is an autosomal recessive disorder that occurs predominantly in Ashkenazi Jewish families and is characterized by demyelination and progressive deterioration, caused by the deficiency of aspartoacy-clase (ASPA). The human ASPA gene has been localized to chromosome 17.

Clinical Features

The etiology is unknown. There is progressive megalencephaly spasticity and developmental delay. The disease runs a progressively deteriorating course with death in childhood.

Diagnostic Procedures

1. There are high levels of JV-acetylaspartic acid in the urine, serum, and CSF and absence of ASPA activity in fibroblasts.

2. The MRI and CT scans show findings compatible with leukodystrophy.

3. DNA analysis of amniotic cells is probably a reliable method for prenatal diagnosis.

4. Screening for the mutation is warranted among Ashkenazi Jewish couples.

Students’ practical Study Program.

Step I: Aim: to determine the clinical diagnosis. It is necessary:

1. To examine the patient (history, somatic-neurological state).

2. To use the results of the laboratory investigation (general and biochemical blood and urine analyses, EEG, craniography, tomography).

3. Make the differential diagnosis using the algorithm.

Step II. To prescribe treatment. It is necessary to use a principle of the pathogenic correction:

1. treatment of myodysthrophias:

a) diet;

b) drugs – protein remedies, amino acids, vitamins, macroerges, biostimulators, spasmolytics, ganglioblocators, anticholinesterase drugs, CAMP-regulators;

c) physiotherapeutic methods – electrophoresis, massage, remedial gymnastics, mineral wax (ozocerite), bathes;

d) provide facilities in health reports.

2. treatment of Thomson’s myotonia:

a) diet;

b) drugs – quinine in the dose of 0,3 to 0,6 gm 3 times a day, calcium, corticosteroids, corynfar, finlepsin, mekselitin;

c) phonophoresis, faradizations, massage.

3. treatment of myasthenia:

a) drugs – anticholinesterase remedies (Prostigmin, Mestinon), kalium salts, glucocorticoids, anabolic hormones, immunosuppressive therapy;

b) surgical treatment: thymectomia;

c) X-ray treatment;

d) the treatment of the crisis is in the “Drug therapy of the urgent neurological clinical cases”.

4. treatment of paroxysmal myoplegia:

a) if there is a type of hypokaliemia: cilium chloride, verospirone, amyloride, diet rich of cilium.

b) if there is a type of hyperkaliemia: hypothiazide, calcium, gluconate, insulin with glucose and kalium free diet.

Step III. Aim: medical genetic consultation and prevention. Taking on account a heredity type ans gene’s penetration to estimate a probability of a sick child birth.