Medical Care
No proven, effective treatment of Kennedy disease (KD) is available. However, the androgen-dependent nature of the disease is the rationale for use of anti-androgens, which have been shown to improve some aspects of the disease manifestations in patients.
The following is the summary of the relevant clinical trials performed in this area:
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Leuprorelin acetate is a luteinizing hormone-releasing hormone agonist. A phase 2, randomized, placebo-controlled trial of leuprorelin acetate in 50 patients with spinal and bulbar muscular atrophy for 48 weeks appeared to show some benefit based on cricopharyngeal opening duration (videofluorography) and reduced mutant AR accumulation (scrotal skin biopsy). [76] In an editorial on this trial, Fishbeck and Bryan cautioned on the results with respect to using cricopharyngeal opening duration as a surrogate marker. [77] A 48-week trial may also be too short given the chronicity of the disease.
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From August 2006-March 2008, the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was performed as a 48-week, randomized, double-blind trial with 204 patients. The authors concluded that treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, but leuprorelin was well tolerated. [78] While disease duration might influence the efficacy of leuprorelin, more clinical trials with sensitive outcome measures should be done. A 48-week trial may be too short given the chronicity of the disease.
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In an another randomized, placebo-controlled trial using dutasteride (a 5alpha-reductase inhibitor) to inactivate testosterone no change was seen in the progression of muscle weakness or swallowing dysfunction in patients with Kennedy disease. [79]
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In a review by Fishbeck, androgen-reducing strategies did not help control symptoms of KD. [80]
Other emerging therapeutic strategies tested in animal models include decreasing expanded polyglutamine androgen receptor expression, increasing degradation of the polyglutamine-expanded protein using heat shock protein 70, leading to misfolding of the mutant protein and elimination via the ubiquitin-proteasome system and autophagy mediated abnormal protein degradation. Improving mitochondrial function and providing trophic support to motor neurons and peripheral tissues using coenzyme Q10, idebenone, and growth factors have also been proposed. [81]
In an open trial using oral beta 2 agonist (clenbuterol), Querin et al found significant improvement in 6-minute walking distance and forced vital capacity at 12 months in 20 patients of KD (Class IV evidence). However, no difference in the Medical Council of Research (MRC) scores was noted preintervention and postintervention. Clenbuterol was well tolerated, except elevation of CK level and hand tremor in 2 subjects. The authors postulated an anaboliceffect of clenbuterol in preventing disease progression and recommended considering a trial with more widely available beta 2 agonist salbutamol in the future. [82]
Overall management of KD is directed at maintaining maximal function in the presence of this slowly progressive disease.
The severity and progression of illness should be monitored. Given the ongoing, slowly progressive weakness, assessing the patient's strength and tolerance to exertion, along with any compromise in activities of daily living or occupation, is important. Such periodic assessments allow for thoughtful, proactive management to minimize the patient's risk for falls, to optimize their mobility, and to provide for appropriate assistive devices as the disability increases.
Certification for disabled parking should be made when appropriate.
Surgical Care
Some patients with marked dysphagia may require a gastrostomy tube. With respect to the other procedures, Okamoto et al (2004) advocate the use of spinal epidural anesthesia in appropriate settings, such as internal urethrotomy. [83]
Consultations
Depending on degree of weakness, input from the physical therapist or physiatrist may be useful in optimizing the patient's abilities. If clinically significant dysphagia occurs, appropriate evaluation of their swallowing (eg, video radiographic swallow study) is indicated. This evaluation may need to be repeated to ascertain the need for and timing of gastrostomy-tube placement.
Diet
No special diet is needed in most cases, unless symptomatic dysphagia occurs.
Activity
The patient's activity level depends on their condition. Aerobic exercise in the form of a formal training program was not found to be of benefit. [84] A clinical trial using exercise in 50 subjects with KD at the National Institutes of Health for 12 weeks showed no significant difference in muscle function overall, but most low-functioning patients improved. [85]
A trial examining the efficacy of exercise in Kennedy disease found that low-functioning men with KD may respond better to functional exercise rather than stretching. Overall, however, functional exercise had no significant effect on total Adult Myopathy Assessment Tool (AMAT) scores or on mobility, strength, balance, and quality of life. [85]
Findings from a small Japanese study suggested that the head lift exercise may improve swallowing dysfunction, particularly tongue pressure, in patients with Kennedy disease. [86]
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Note wasting in the thighs and shoulders. The arms hang down and are rotated internally so that the thumbs point toward the patient (ie, simian posture) rather than forward, as in a healthy individual. This observation strongly suggests weakness in shoulder girdle muscles.
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Prominence of breast tissue consistent with gynecomastia in Kennedy disease.
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The forehead of this patient with Kennedy disease is smooth, in fact, too smooth for a man this age. The smoothness is particularly noticeable when the patient tries to perform upgaze, when wrinkling of the forehead due to contraction of the frontalis is expected.
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Photographs show asymmetry at rest due to facial weakness, which is enhanced when the muscles are activated by pursing the lips.
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Note the scalloping of the borders of the tongue, which strongly suggests wasting. In addition, the marked wasting of the large group of glossal muscles on each side has caused them to separate and form a midline furrow.
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Motor-unit action potentials recorded from the biceps brachii in a patient with Kennedy disease. Upper tracing shows 2 action potentials discharging during low-to-moderate effort. In a healthy person, additional discharges are expected. (Calibration is 1 mV per division on the vertical axis and 10 ms per division on the horizontal axis.) Potential on the left is approximately 1.2 mV and 26 ms. It is moderately increased in amplitude, almost twice the upper limit in duration, and shows marked irregularity or serrations (ie, turns) in the main component. Potential to the right is markedly increased in amplitude (approximately 3.3 mV), and its duration is at least 30 ms but cannot be measured on this tracing because it extends off to the right and qualifies as a giant motor-unit action potential. Bottom tracing shows the same 2 potentials at standard setting used to view motor-unit action potentials (0.1 mV per vertical division), which emphasizes their large size and complexity (ie, increased number of changes in polarity of the waveform).
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Recording of motor-unit action potentials from the pectoralis muscle in a patient with Kennedy disease. Calibration is 1 mV per division on the vertical axis and 10 ms per division on the horizontal axis. The patient's level of effort in activation is high. Therefore, the number of motor unit action potentials clearly is reduced, and the individual potentials observed are enlarged, consistent with a chronic neurogenic process.
Tables
Disease
|
Differentiating Characteristics or Tests
|
ALS |
Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness [58] |
Spinal muscular atrophy |
See Table 2 below |
Fascioscapulohumeral muscular dystrophy |
Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker |
Myasthenia gravis - Adult acquired form |
Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive |
Oculopharyngeal muscular dystrophy |
Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker |
Hexosaminidase A deficiency |
Rectal biopsy, enzyme assay |
Sandhoff disease |
Rectal biopsy, enzyme assay |
Syphilis (neurovascular form) |
Positive serology |
Lead neuropathy |
Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels |
Motor neuron disease with macroglobulinemia |
Monoclonal gammopathy [59] |
Autosomal dominant cerebellar ataxia type I |
Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA |
Polymyositis |
Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy |
Cervical spondylosis |
Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion |
Facial onset sensory and motor neuropathy (FOSMN syndrome) [60, 61] |
Slow progressing, trigeminal-onset sensory loss that may spread to upper limbs and torso, associated with lower motor syndrome with prominent bulbar involvement |
Pattern
|
Characteristics*
|
Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease) |
Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant |
Scapuloperoneal hereditary motor neuropathy |
Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared |
Fascioscapulohumeral hereditary motor neuropathy |
Autosomal dominant, pattern of weakness as described |
Hereditary motor neuronopathy with oculopharyngeal involvement |
Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia |
Hereditary proximal motor neuropathy |
Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared |
Hereditary distal motor neuropathy |
Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) [62] |
*In none of these diseases are results of test for the KD marker positive, and associated endocrinopathy or sensory nerve conduction abnormality should be absent. |
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