Neuromuscular diseases
Myopathies and Neuropathies

Introduction

Disease s of muscle and nerve are summarized as neuromuscular disease s.

Myopathies are disease s of the muscle including

Ø      Muscular Dystrophies (MD),

Ø      Muscular inflammation (Myositis)

Ø      Metabolic disease s of the muscle (Metabolic Myopathies).

Neuromuscular Syndromes also consist of disease s of nerve cells and fibres including

Ø      Hereditary Motor and Sensory Neuropathies (HMSN),

Ø      Spinal Muscular Atrophies (SMA)

Ø      Amyotrophic Lateral Sclerosis )ALS). (www.amyotrophic-lateral-sclerosis.com)

Ø      Poliomyelitis and Postpolio-Syndromes

In case of disease s of the nerves the muscle shows symptoms as weakness and wasting.  

Following you will find an overview on Neuromuscular Disease s:

Ø      Schematic overview of Neuromuscular Disease s

Ø      Table: Neuromuscular Disease s

Ø      Neuromuscular Disease s: Occurrence and incidence

Ø      Neuromuscular Disease s: Signs and Symptoms

Ø      Neuromuscular Disease s: Therapy. 

Schematic overview: Neuromuscular disease s

The arrows indicate the affected structures of the disease.

Brain, spinal cord, nerve fibres and muscles are involved in voluntary movements. In the scheme above one nerve cell with its fiber represents a group of each in the area of the so-called motorcortex of the brain (Upper motor neuron (neuron = nerve cell)) and the spinal cord (Lower motor neuron). The fiber of the upper motor neuron connects with the lower motor neuron in the brain stem or spinal cord. The fibre of the lower motor neuron connects with the muscle. Fibers of the lower motor neurons and sensory nerve fibers form bundles in arms and legs as e.g. median or peroneal nerve. The link between nerve fiber and muscle is called neuromuscular junction. One single nerve fiber supplies (innervates) severel muscle fibers.  

Neuromuscular Disease s –

a tabulated overview (modified according to John Walton) 

This tabulated overview does not consider the recent findings in human genetics of the last years, but it gives a good systematic of the disease s and the affected structures.  

 1. Muscular Disease s (Myopathies)  

Muscular Dystrophies

Ø      Duchenne Muscular Dystrophy

Ø      Becker Muscular Dystrophy

Ø      Limb Girdle Muscular Dystrophies

Ø      Facio-scapulo-humeral Muscular Dystrophy

Ø      Emery-Dreifuss Muscular Dystrophy

Ø      others 

Myotonic Muscular Disease s

Ø      Myotonic Dystrophy (MD1)

Ø      Proximal myotonic myopathy (PROMM, MD2)

Ø      Myotonia congenita (Thomsen)

Ø      Myotonia congenita (Becker) 

Hereditary Metabolic Myopathies (Metabolic disease s of the muscle fibre itself)

Ø      Glycogen storage disease

Ø      Lipid storage myopathies

Ø      Mitochondrial myopathies  

Endocrine Myopathies (Metabolic disease s of endocrine glands)

Ø      Thyroid disease s

Ø      Cushing´s syndrome (hyperactivity of the cortex of the suprarenal gland)

Ø      other  

Congenital Myopathies

Inflammatory and Immune Myopathies

Ø      Auto-immune disease s

§         Polymyositis syndromes

§         Dermatomyositis

§         other

Ø      Myopathies caused by infection  

2. Disorders of the Junction of Nerve and Muscle (Neuromuscular Junction Syndromes)  

Ø      Myasthenia Gravis

Ø      Other Myasthenic Syndromes, e.g. Lambert-Eaton-Myasthenic-Syndrome (LEMS) 

3. Disorders of the Nerve fibers  

3.1. Spinal Muscular Atrophies and Motor Neuron Syndromes 

Ø      Poliomyelitis

Ø      Spinal Muscular Atrophies

o       SMA type I (Werdnig-Hoffmann (childhood-onset))

o       SMA type II (intermediate (childhood-onset))

o       SMA type III (Kugelberg-Welander Types II & III (juvinele or adult onset)

o       SMA type IV (adult-onset)

o       other adult forms

·        Peroneal type

·        Aran-Duchenne type

·        Vulpian-Bernhardt type

·        other

Ø      Amyotrophic Lateral Sklerosis 

3.2.  Polyneuropathies (Motor and Sensory Neuropathies)  

Ø      Hereditary Motor and Sensory Neuropathies (HMSN), Charcot-Marie-Tooth-Diesase CMT)

§         HMSN Type I (CMT I)

§         HMSN Type II (CMT II )

Ø      other Hereditary Polyneuropathies

Ø      Guillain-Barré-Syndrome (GBS)

Ø      other Polyneuropathies 

Neuromuscular disease s - Occurrence and incidence  

Neuromuscular disease s are rare compared with other disease s. Three or four persons in 100.000 inhabitants live for example with the muscle dystrophy of Duchenne type which is the most often form of muscle dystrophy. About three to eight persons in 100.000 inhabitants are suffering from Amyotrophic Lateral Sclerosis. SMA type III is seen about 0,3 in 100.000 persons and inflammation of muscle (myositis) 0,5 in 100.000. Hence many physicians and therapists are not common with these disease s. 

Neuromuscular disease s - Signs and symptoms

The main symptoms of most neuromuscular disease s are weakness in different extention and early exhaustion as well as muscular atrophy (wasting of muscles). Some disease s present with muscle pain and cramps. In case of involvement of nerve fibers (polyneuropathies, see table, 3.2) additional disturbances of the sensory system may occur, especially in the feet.  

Muscular dystrophy

Muscular dystrophies present with paralysis, often pronounced in muscle groups near the trunk. In case of Duchenne or Becker muscular dystrophy weakness starts in muscles of the hip. According to the course of the individual disease paralysis can be more or less progressive and spread to other muscle groups. For example Duchenne muscle dystrophy starts in childhood and is rapidly progressive while Becker muscle dystrophy or Limb girdle muscle dystrophy get apparent in juvenile or adult persons with slow progression. Facioscapulohumeral muscular dystrophy is slowly progressive and affects particular facial and shoulder muscles. 

The affected muscle groups are wasting, but nevertheless they can look strong and well built, especially the calves. We call it pseudohypertrophy. Here muscle fibers are replaced by connective and fatty tissue. Pseudohypertrophy is not only found in primary muscle disease but also in Spinal Muscular Atrophy and even HMSN.

Daily stress of the muscles, especially abnormal and overtrain exercise often leads to pain of the apparatus of locomotion. Weakened muscles have to work harder, to fulfil their task, e.g. to maintain posture. Subsequently muscles get tense and cramps may occur. Joints are stressed by unphysiological movements caused by weakened muscles resulting in pain as well. Pain again leads to a higher grade of tension of the muscles, consequently  unfavourable posture and subsequently more pain occurs, a vicious cycle.

The affection of heart muscle fibers in some Muscular Dystrophies is called Cardiomyopathy. There is to be paid attention on cardiac irregularity, disordered action of the heart and reduced exercise tolerance. Respiratory failure may occur in some Muscle Dystrophies as well. 

Myotonic Dystrophy (Curschmann, Steinert, Batten)

Myotonic disease s are characterised by a special disturbance of movements. Voluntary movements can be done only slowly and viscous, extremities seem to be stiff. That is why in Myotonia Congenita (Thomsen or Becker) movements may be severely disabled. In Myotonic Dystrophy (Curschmann, Steinert, Batten) movements especially of the hands are concerned, but in most times in a mild dimension. In Myotonic Dystrophy weakness of muscles may occur, especially in the hand and lower leg. Heart, eyes, pancreas and other organs can be concerned by this multi-system-disease as well.  

Metabolic Myopathies

Metabolic Myopathies are caused by a disturbance of energy supply in the muscle fiber. Carbohydrates and fatty acids are taken up into the muscle fibre and are stored. In case of the disease these stored carbohydrates and lipids cannot be used as energy supply. According to the different disease s there are weakness of the muscles groups near the trunk,  reduced efficiency of staying power or muscle pain dependent on amount of exercise. The extent of the symptoms varies from slight impairment to death in early childhood. 

Immune Myopathies (Myositis)

Myositis represents an inconsistent group of muscle disease s. It concerns a disorder of the body defence, so-called autoimmune-disease. The body defence recognizes own structures, e.g. parts of the muscle, as unknown and fights against them. In Polymyositis  this results in weakness especially of the muscles near the trunk, that means muscles of the shoulders and hips. The symptoms may progress over weeks and months. Sometimes pain of the muscles is reported, too. If inflammatory alterations of the skin occur in addition, Dermatomyositis is supposed. In case of the appearance of further symptoms like pain of the joints or impairment of the circulation of blood flow investigations on connective tissue disease s like Sclerodermia, Lupus erythematosus and others have to be done. As an autoimmune-disorder myositis often can be treated well. 

Myasthenia gravis

Myasthenia gravis presents a special form of muscle weakness. Dependent on stress the power of the muscle deteriorates fast, after a sufficient rest these muscles can be used again. Characteristically muscles for moving eyes and lifting eyelids are concerned. Muscles groups near the trunk, particular muscles of the shoulder and neck are often involved, too. Failure of respiratory muscles may occur. Myasthenia gravis is caused by a disorder of the body defence (autoimmune disease). Mostly symptoms can be improved by immune-suppressive medicine or sometimes by surgical removal of thyme.  

Spinal Muscular Atrophies

Wasting and weakness seen in Spinal muscular atrophies look similar to those of Muscular Dystrophies. It is caused by the disease of nerve cells in spinal cord, whose fibers reach muscles of the trunk, arms and legs. As a result of destruction of these cells some muscles fibres are not innervated any longer. Consequently muscles get weak and waste, that means they atrophy. Muscles near the trunk are often affected. Sometimes the disease already exists  at birth and progresses rapidly like Werdnig-HoffmannType (SMA I). Other courses occur in childhood, adolescence or adult with lower progression like Kugelberg-Welander Type. 

Poliomyelitis and Postpolio Syndrome

Poliomyelitis is a disease of the nerve cell of the lower motor neuron in the spinal cord. This nerve cell is damaged by a virus during acute paralytic poliomyelitis. Nowadays this disease almost completely is eliminated. Furthermore we see the consecutive symptoms especially of the polio epidemics in the early sixties. There is a full or partial recovery of the muscle weakness. Residual muscle weakness may lead to an abnormal stress of the locomotor system. Degenerative joint disease (arthrosis) and disease s of the vertebral column may occur in consequence.

Characteristically the so-called Postpolio-Syndrome presents with appearance and/or slow progress of muscle weakness after decades. Especially those muscle groups are concerned, which primarily have been considerably weakened and recovered well. At first patients frequently report a decrease of staying power and exercise tolerance and in the course of the disease a slow increase of paralysis. Further rapid exhaustion, disturbed sleep and other symptoms are told.

Motor and Sensory Neuropathies

Motor and Sensory Neuropathies affect nerve fibers, the longest nerve fibers run the greatest risk to fall ill. According to this symptoms are initially found in the muscles of the lower leg and foot and sometimes of the hand. Especially dorsiflexion of the feet is concerned. In addition disturbances of sensory system (hypoesthesia) of the feet may occur, but are usually of small intensity. Even within a family the extent of the symptoms varies.

One type (HMSN I) is characterized by slowed nerve conduction velocity. Type II presents with normal conduction velocity. Genetics showed us, that these two types are caused by several different gene disease s. 

Neuromuscular disease s: diagnosis

In the history of illness the beginning of the functional disorder, the course and appearance of similar impairment in other members of the family are of special interest.

Physical examination has to detect further disease s like joint disease s, enlargement of organs, pulmonary function, and so on. The specific neurological examination investigates function of nerves and muscles and their coordination. Concerning paralysis the maximum degree and form of the muscular weakness are determined exactly. By these first investigations a narrowing of the diagnosis of the muscular disorder often is possible.

An better differentiation can be done by so-called neurophysiological investigations, especially nerve conduction studies (electroneurography) and electromyography. By electroneurography the conduction of the nerve and the function of the nerve fibers are determined. Nerves are stimulated by an electric impulse. By electromyography electrical activities of the muscle are measured. Usually with these investigations it can be found out whether the nerve fibers or the muscle itself are damaged.

Laboratory investigations may give important clues for diagnosis. Creatine Kinase (CK) is an enzyme in the muscle fibre. In case of muscle disease or damage but even in cases of spinal muscular atrophy there are found more or less elevated levels in blood. Other enzymes and products of metabolism (e.g. aldolase, pyruvate, ammoniac, lactate) and certain antibodies (proteins of immune system), hormons (thryoid gland, adrenal gland as well as parameters of routine blood and urine examination complete the laboratory search depending on the supposed illness.

In the last decades imaging techniques like ultrasound and magnetic resonance imaging (MRI) were develop, they may give supplementary information about the affected muscle groups without stressing the patient. Unfortunately these methods do not give very much evidence in search for diagnosis.

Muscle and nerve biopsies allow the investigator to look on the altered structures. The stained biopsies give good information about primary muscle or nerve disease s in light microscopy. Electron microscopy is often an integral part of investigation of biopsies. Biochemical investiagations of the specimen can indicate specific metabolic disease s. In chronic disease s usually a muscle with moderate, but not severe weakness is selected for biopsy. In acute disease a muscle with severe or moderate weakness is chosen. MRI can be used to select pathological muscle site in difficult cases. Muscles that were site of EMG, injections, or trauma have to be avoided. Frequently deltoid,  biceps or quadriceps muscle are taken. If a nerve biopsy is necessary the suralis nerve is selected, it is a pure sensory nerve.

Supplementary investigations provide hints for the involvement of further organs like electrocardiogram (ECG) and ultrasound of heart or abdomen.

Molecular analysis and genetic testing are of increasing importance. Parts of chromosomes are investigated to get a definitive diagnosis. It allows a genetic counseling of the patient´s familiy. With the dramatically expanding knowledge of the primary biochemical defect for hundreds of disorders hope is growing that in some time the pathological process can be slowed or halted. Since there is a high number of gene defects the clinical diagnosis has to be made before a precise moleculargenetic diagnostic can be done. Only in some cases molecular diagnostics can be done primarily, e.g. in boys with typical history and neurological findings of Duchenne muscle dystrophy.  

Neuromuscular disease s - Therapy  

Improvement and maintenance of function and independence are the main subjects of therapy and rehabilitation. Therapy is most effective by an interdisciplinary team consisting of physicians, nursing staff, physiotherapists, occupational therapists, logopedics, dietists, social workers and psychologists.

A better understanding of the molecular process of many neuromuscular disease s improved diagnostic accuracy. There is a reasonable prospect that this may be the base for specific therapies, e.g. medication. Gene therapy might be a successful option in distant future, but a break through is not to be seen today.

Neuromuscular disease s – Medication

Riluzole is a medication improving the course of amyotrophic lateral sclerosis. A mean extension of life duration of some months was documented in a well controlled study. It seems to be especially effective in patients with initial signs of dysarthria and dysphagia. In a recent retrospective study as well as in an open prospective study patients showed an increase of life duration of 21 or 12 months. It is recommended to prescribe this medication as early as possible in the course of the disease.   

In Duchenne type muscle dystrophy corticoid medication can prolong duration of walking ability. Side effects as e.g. osteoporosis  and gain of weight are tried to be reduced by choosing special preparations like deflazacort.   

Creatine is important in muscle energy metabolism. The mouse model of motor neuron disease showed an effectiveness of Creatine on survival of motor neurons. These results could not be reproduced in man. Some athletes use it to get a better strength of their muscles. So patients with different neuromuscular disease s tried it as well with the same purpose. Some of them noticed a subjective improvement. The substance is to be taken with much fluid (2 litres per day), but not with coffee. In the first ten days of intake twice a day 4 g are recommended, then twice a day 2 g. Uptake of this substance into the muscle fibre is an active process. The activity of this process gets downregulated when there is much creatine circulating in the blood. So after three months of intake an interruption for one month is necessary. Then one has to start with a loading dose for ten days again. Before taking creatine one should consult the general practitioner wether there are any contraindications, especially in case of preexisting renal disease.  

Tocopherol (Vitamin E) is an antioxidative substance. It reduces the effect of metabolic products of oxygen (radicals) in cells. Even with high doses of 1000 mg per day a gain of life duration could not be noticed in Amyotrophic Lateral Sclerosis, but the progression from less severe to more severe stages seemed to be slowed. In other neuromuscular disease s no benefit has been shown up to now.

In myositis, myasthenia gravis and other autoimmune disease s corticoids and immune suppressants are used to stabilize the condition. 

Nerve growth factors were examined without success on course of neuromuscular disease s or presented intolerable side effects. Antiviral medications and hormones did not show any reliable effect. 

In facio-scapulo-humeral muscle dystrophy some effect of albuterol has been shown, the result of further studies has to be expected. 

Neuromuscular disease s – Surgical procedures

In some neuromuscular disease s surgical procedures have shown to improve function. E.g. boys with Duchenne type muscle dystrophy can walk for a longer time after release of contractures of several muscles, as Rideau reported. A good influence on respiration may result, as well. Foot deformation or straightening up the spine in case of severe scoliosis may be further indications for surgical intervention. Persons with severe weakness of shoulder muscles in facio-scapulo-humeral muscle dystrophy may have a benefit from surgical fixation of their shoulder blade to the trunk. 

Neuromuscular disease s - Physiotherapy

Weakness of muscles is the cause of most of the problems in neuromuscular disease s. Patients should train with low to moderate intensity, not aiming an increase of strength but stabilisation of present functions. According to the actual condition and the course of the individual disease an increase of stamina and function may be aimed. Too intensive training can result in further weakness, especially in rapid progressive disease s. Patients should be advised not to train until exhaustion. They should learn to recognize warning signs like marked weakness and muscle pain, especially continuing 24 to 48 hours after training or enhanced cramps. A sore muscle is not a sign for effective training but for overtraining exercise. Therefore physiotherapists should change the trained muscle groups rapidly during a treatment unit.

In addition training with low to moderate aerobic exercise, e.g. walking, swimming and training with an ergometer, always dependent on the individual disease and condition can be done. So staying power and performance of the cardiovascular system may be maintained.

Shortening of muscles is a frequent problem. Especially in muscle dystrophies it can result in contractures meaning a reduced range of motion of joints. This condition has to be recognized and moderate stretching has to be done. Wheelchair dependency is another factor of risk for this problem. Here particularly fixed flexion of hip and knee muscles may occur. Attention has to be paid on stability of trunk being another considerable problem in a couple of neuromuscular disease s.  Back pain or even scoliosis can be the consequence.

In individual cases orthotic devices can lead to better movement function. E.g. an ankle-foot orthosis can help walking without stumbling in case of weakness of foot elevators.

In the course of some disease s muscles of respiration may be involved. First symptoms might be sleep disturbances, morning headache and dyspnea on exertion. In the last fifteen years increasing knowledge in therapy of this condition was gained. Pulmonary function has to be be trained by physiotherapy, as well. If this is not sufficient patients should be offered nasal ventilation, at first mainly used in the night.

Further aspects of physiotherapy are massage, thermotherapy, balneotherapy and electrotherapy. Their main issue is pain reduction and relaxation of tense muscles due to unphysiological use. 

Neuromuscular disease s – Occupational Therapy

Occupational therapy has a similar approach to neuromuscular disease s as physiotherapy.  The main focus lies on arm function and trunk control. A domain of occupational therapy is providing patients with assistive devices to support independence in daily living. When properly selected and designed, they can maintain independence and often increase safety, speed and acceptance. Simple assistive devices such as grab bars, reachers or sliding boards can help with gross positioning and activities. Clamp-On Raised Toilet Seat and safety frame may support  toilet use. 

Neuromuscular disease s – Logopaedics

Disease s of speaking and swallowing are the main subjects of logopaedia. Some disease s may present with these disturbences in different degrees. The disorder of speaking due to muscular problems is called dysarthria. Patients have to train and learn techniques to be better understandable. If this is impossible in very severe cases, they have to be encouraged to write down the message or have to be provided with an electronic communicator.

Swallowing problems need identifying early to minimize the risk of aspiration-related infections developing and malnutrition or dehydration. Management of dysphagia is an important clinical province of logopaedics. Their strategies for dysphagia treatment involve modification of either eating behavior, modifying the consistency of food and drinks, or postural adjustment. They also teach swallow techniques (facilitation and maneuvers). If all other methods fail and the patient is not getting sufficient nutrition and hydration, a percutaneous gastrostomy tube (PEG), also known as a feeding tube, may be necessary. The decision to get a PEG is highly personal. Patients are understandably reluctant to undergo an invasive procedure that bypasses the normal eating process, yet some are ultimately relieved after the surgery and find they get some of their strength back after receiving adequate nutrition again. 

Neuromuscular disease s – Psychology

Patients may suffer from depressive disturbences. Coping with the disease or problems of social integration may be reasons. Patients have to be informed about the course of the individual disease in an adequate way. Sometimes it may be helpful to give psychological support. Only with a constructive attitude patients can deal with the disease in the best way. Antidepressants can help to handle with the depression, as well.

The family/partner of the patient also may need psychological support. In many regions support groups for patients with neuromuscular disease s do important work. The groups provide a platform for patients and their partners to discuss any relevant or personal issues, and professionals working in this particular field are often featured speakers. 

Neuromuscular disease s – Inpatient Rehabilitation

The Klinik Hoher Meissner provides a qualified rehabilitation treatment program that helps patients maintain the highest possible level of functioning. Following an evaluation, the treatment team teaches individuals to improve movement and funciton and to develop ways to compensate for any loss of function. Led by a specialized physician the team includes nurses, physical, occupational and speech therapists, psychologists, dieticians and social workers. Together with the patient the team works out an appropriate treatment plan. The aim of our inpatient rehabilitation is a lasting improvement of functions and abilities.

The opportunity to live together with the patient in our clinic is used by the spouses quite often. The patient can concentrate on the therapies without labour, housework or other stressing factors of home.

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