Werdnig-Hoffmann disease

Study objectives: To describe the clinical and respiratory course in infantile spinal muscular atrophy (SMA) type I, type II, and type III, and to evaluate the respiratory needs for these patients, using noninvasive or tracheostomy ventilation.

Design: Retrospective cohort study.

Methods: We report 33 patients with SMA true type I (onset before age 3 months), 35 patients with SMA intermediate type I (onset between 3 months and 6 months), 100 patients with SMA type II (onset between 6 months and 18 months), 12 patients with SMA type III (onset after age 18 months). We report the clinical symptoms, respiratory course, and respiratory management: respiratory physiotherapy, periodic hyperinsufflation, nasal nocturnal ventilation (NNV), and tracheostomy. Also, we measured the FVC over several years during childhood and adolescence.

Results: In patients with SMA true type I, 82% of patients died, one third of whom underwent tracheostomy. In patients with SMA intermediate type I, 43% needed NNV, 57% underwent tracheostomy, and 26% died. In patients with SMA type II, 38% needed NNV, 15% underwent tracheostomy, and 4% died. In patients with SMA type III, respiratory impairment was moderate and began during the second decade of life.

Conclusion: This data shows the progressively worsening course of restrictive respiratory insufficiency in patients with SMA, and the importance of early respiratory management to limit pulmonary complications and improve the quality of life for these patients.

Key words: children; FVC; nasal nocturnal ventilation; periodic hyperinsufflation; respiratory insufficiency; spinal muscular atrophy; tracheostomy

Abbreviations: FVC0[degrees] = FVC in supine position without brace; FVC90[degrees] = FVC in sitting position with brace; IPPV = intermittent positive pressure ventilation; NNV = nasal nocturnal ventilation; SMA = spinal muscular atrophy

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Spinal muscular atrophies (SMAs) are a group of autosomal recessive neuromuscular disorders involving motor neurons of the ventral horn of the spinal cord and motor nuclei from the brainstem. The degeneration of neurons leads to symmetrical muscle weakness with proximal muscles more affected, restrictive respiratory insufficiency, and absence of deep-tendon reflexes. The gene of SMA is called the survival motor neuron gene located at chromosome 5q13. Survival motor neuron gene abnormalities are present in > 95% of patients with SMA. (1,2)

Three forms of SMA are recognized, based on the age at onset: type I, called the acute form of Werdnig-Hoffmann disease, with onset of symptoms before age 6 months with severe hypotonia, diffuse muscle weakness, absence of reflexes, and inability to sit without support; type II, called the intermediate form of SMA, with onset of symptoms between 6 months and 18 months; type III, called the Kugelberg-Welander disease, with onset of symptoms after the age of walking. (3,4) For SMA type I with onset of symptoms before age 6 months, we distinguish between true type I for onset before the age of 3 months with floppy children never raising the head, and intermediate type I for onset between 3 months and 6 months with ability to raise the head. We report the cases of patients with SMA true type I, SMA intermediate type I, SMA type II, and SMA type III.

In patients with SMA, respiratory disability involves mainly intercostal muscles with relative sparing of the diaphragm. (5,6) The intercostal muscle weakness is responsible for a triangular chest deformity with falling ribs, and results in recurrent atelectasis and bronchopulmonary infections. The respiratory management consists of respiratory physiotherapy including assisted coughs, chest percussion therapy, periodic hyperinsufflation using preset pressure ventilators (intermittent positive pressure ventilation [IPPV]), and in some cases the use of nasal nocturnal ventilation (NNV) or ventilation by tracheostomy. (7-9) The purpose of this study is to evaluate the clinical and respiratory course in our SMA populations and to evaluate the respiratory needs for these patients using noninvasive or tracheostomy ventilation.

MATERIALS AND METHODS

We report the cases of patients with SMA true type I, intermediate type I, type II, and type III. Thirty-three patients had SMA true type I, 35 patients had SMA intermediate type I, 100 patients had SMA type II, and 12 patients had SMA type III. Diagnosis of SMA was confirmed by genetic study in all cases.

Patients were seen twice a year in our department for respiratory and orthopedic follow-up. They had all received the same respiratory and orthopedic management with braces since the age of 1 year. In all patients, we recorded the clinical symptoms, respiratory course, and respiratory management: respiratory physiotherapy, periodic hyperinsufflation (IPPV), NNV, and tracheostomy.

During noninvasive ventilation (IPPV, NNV), the use of an abdominal belt was necessary because of paradoxical breathing with thoracoabdominal asynchrony. This allowed better ventilation of upper pulmonary areas. IPPV was used for 20 min, two or three times a day, in all patients except when there were severe swallowing problems. The pressure of ventilators ranged between 15 cm [H.sub.2]O and 25 cm [H.sub.2]O to obtain a good thoracic and alveolar expansion. NNV was used when there was a severe restrictive respiratory insufficiency with hypercapnia or repeated bronchitis. Volume and frequency were regulated in order to obtain a right pulmonary expansion, and blood gas PC[O.sub.2] between 30 mm Hg and 40 mm Hg. NNV was contraindicated when there was salivary stasis with swallowing problems and/or marked pulmonary congestion. Tracheostomy was performed when the patient had frequent pulmonary congestion leading in invasive ventilation several times during the same year.

The FVC measurement required a spirograph with the patient in supine position without brace (FVC0[degrees]) and in sitting position with brace (FVC90[degrees]). The measurement of FVC corresponds to the volume between deep inspiration and deep expiration. Afterwards, the percentage of the predicted normal FVC is calculated according to the formula: percentage = measured capacity in milliliters x 100/theoretical capacity. Expected capacity depends on age, sex, and height of the patient.

The course of FVC has been measured over several years during childhood, adolescence, and until adult age lot some patients. Results are given as mean [+ or -] SD.

RESULTS

In Table 1, we report the percentages of patients who needed IPPV, NNV, tracheostomy, and gastrostomy with age of onset for each treatment in SMA true type I, intermediate type I, type II, and type III. We report also the mortality rate for patients with each type of SMA.

For patients with SMA true type I, swallowing difficulties were present. Patients were not able to swallow correctly and had false passages of saliva and food. Respiratory episodes of pulmonary congestion, aspiration pneumonia, and atelectasis were frequent. Twenty-seven of the 33 children (82%) died. The six living children underwent tracheostomy, and are now between 8 years and 17 years of age. Concerning the 11 patients who underwent tracheostomy in this group, 5 patients (45%) died at the ages of 19 months, 24 months, 46 months, 8 years, and 10.5 years, respectively (mean age, 5 years). Causes of death were respiratory distress, bulbar disorders with salivary swallowing difficulties with false passages, respiratory infections, or sudden death for all patients with or without tracheostomy.

For patients with SMA intermediate type I, 20 of 35 children (57%) needed tracheostomy. While 10 of these patients (50%) underwent primary tracheostomy, the others had NNV 2.4 [+ or -] 2.6 years before tracheostomy. A child who needed tracheostomy at the age of 3 years for recurrent atelectasis could be decannulated at the age of 18 years and continued with nasal ventilation with 19% of FVC0[degrees].

Nine of 85 children (26%) with SMA intermediate type I died; 3 of them underwent tracheostomy. The reasons for these deaths were not always known. They occurred more frequently at home during sleep, and were regarded as sudden death by bulbar disorders.

The course of FVC0[degrees] and FVC90[degrees] of patients without tracheostomy and of patients with tracheostomy in relation to age is reported in Figure 1. The number of patients with known FVC according to age is reported in Table 2. The mean FVC at the age of IPPV onset, NNV onset, and tracheostomy are known in several cases. At the age of IPPV onset, the mean FVC0[degrees] was 54 [+ or -] 30% (n = 6). At the age of NNV onset, the mean FVC0[degrees] was 30 [+ or -] 12% (n = 11). At the age of tracheostomy, the mean FVC0[degrees] was 30 [+ or -] 15% (n = 12).

[FIGURE 1 OMITTED]

For patients with SMA type II, 65% had onset of symptoms between 6 months and 9 months inclusive, 26% between 9 months and 12 months inclusive, and 9% between 12 months and 18 months. Support walking was acquired in 20% of patients. The period of walking varied from the age of 13 months to 12 years, and all of these children have since lost the ability to walk with support. The age of walking loss occurred before 3 years for 11 patients (55%), between 3 years and 5 years for 3 children (15%), and between 6 years and 12 years for 6 children (30%). None of them had ever been able to walk alone.

On the 15 children who underwent tracheostomy, 6 children (40%) underwent primary tracheostomy The reasons for tracheostomy were frequent respiratory distress and recurrent atelectasis requiring mechanical ventilation. Two children underwent tracheostomy in a perioperative period (spinal arthrodesis). One of these children, who needed tracheostomy at the age of 13 years, was decannulated at the age of 19 years and continued with NNV with 20% of FVC0[degrees] at 19 years of age.

Figure 2 reports the percentages of FVC0[degrees] and FVC90[degrees] for children with SMA type II with and without tracheostomy. The number of patients with known FVC according to age is reported in Table 3. Note that one of the patients with SMA type II, who did not need tracheostomy, had 12% of FVC0[degrees] at the age of 54 years. At the age of IPPV onset, the mean FVC0[degrees] was 66 [+ or -] 26% (n = 43). At the age of NNV onset, the mean FVC0[degrees] was 30 [+ or -] 11% (n = 34). At the age of tracheostomy, the mean FVC0[degrees] was 27 [+ or -] 11% (n = 11).

[FIGURE 2 OMITTED]

For patients with SMA type III, clinical symptoms occurred after the age of 18 months. Symptoms were characterized by walking weakness with falls. Six of the 12 patients (50%) have lost the ability to walk. The age of walking loss varied from the age of 7 to 14 years, with a mean age of 10 years. The first clinical symptoms occurred from the age of 18 months, after the onset of walking, to the age of 6 years, with a mean age of 2.5 years.

Four of the 12 patients (33%) needed IPPV, while the others did not need any respiratory aid. The respiratory course of patients showed a moderate impairment. The percentages of FVC0[degrees] and FVC90[degrees] were > 100% until the age of 11 years. At the age of 13 years (five patients), the mean FVC0[degrees] was 99.5% and FVC90[degrees] was 97.5%. At the age of 15 years (five patients), the mean FVC0[degrees] was 94% and FVC90[degrees] was 90%. At the age of 17 years (three patients), the mean FVC0[degrees] and FVC90[degrees] were 79%.

DISCUSSION

Few studies concerning respiratory function in patients with SMA have been reported in the literature. (6-18) Our work is a retrospective study. The patients were followed up in the same unit with the same strategy. For patients with SMA type I, we distinguished SMA true type I with onset of symptoms before 3 months and SMA intermediate type I with onset between 3 months and 6 months because our management is different for these two types.

For patients with SMA true type I, the onset of clinical symptoms varies from birth to the age of 3 months, and is expressed by neonatal hypotonia, swallowing difficulties, respiratory insufficiency, and absence of deep-tendon reflexes. Eighty-two percent of patients with SMA true type I died at a mean age of 18 months. NNV is not indicated in true type I SMA because of severe bulbar disorders. One third of our patients underwent tracheostomy, and some patients underwent gastrostomy. Concerning patients with tracheostomy, 45% died at the mean age of 5 years; the others are completely dependent, and without verbal communication.

The reasons for death are respiratory insufficiency and bulbar symptoms responsible for false passage of saliva, increasing pulmonary congestion, and aspiration pneumonia. Sudden death without clear explanation occurs in SMA type I. Bulbar dysfunction could be responsible for central apneas, but these sudden deaths occur even in patients with ventilation support by tracheostomy. Cardiac arrhythmia could be a reason for death by vagal hypertonia and severe bradycardia, although cardiac features are not classical symptoms in SMA. However, abnormalities such as palpitations, ST-segment abnormalities, and couplets are described in the literature. (19) Right ventricular signs are also reported, as well as dilated cardiomyopathy. (20-22)

At present, the management of patients with SMA tree type I consists of noninvasive therapy without tracheostomy or gastrostomy. Actually, the death rate remains high in spite of tracheostomy. More importantly, the motor handicap is very serious because the patient is further limited by diminished mobility of the fingers causing a decreased self-sufficiency, complete respiratory dependence, and facial paralysis allowing no verbal communication and ophthalmoplegia.

According to our definition, the age of onset for patients with SMA intermediate type I varies between 3 months and 6 months (with the child acquiring the ability, to raise the head). Management is different for intermediate type I patients, as the pathology is less severe. In fact, patients maintain mobility of the limbs, and can thus drive an electric wheel-chair and communicate normally.

The curves of the FVC course according to age show a progressive and regular decrease of FVC, with percentages of FVC0[degrees] higher than FVC90[degrees] as the diaphragmatic muscle is less affected than the intercostal muscles. In fact, in patients with SMA, respiratory disability involves mainly intercostal muscles, with a relative sparing of the diaphragm. (5-6) The mean values of FVC90[degrees] and FVC0[degrees] for patients with tracheostomy are lower than those for patients without tracheostomy (Fig 1).

NNV was necessary for 43% of patients. Tracheostomy was frequently necessary since it was performed on 57% of patients, half of whom underwent primary tracheostomy. Mean values of FVC at the age of NNV onset and at the age of tracheostomy are similar, approximately 30%. This means that risks of pulmonary complications and acute respiratory insufficiency are increased for patients whose FVC reaches only 30% of expected values. The choice between NNV and tracheostomy does not depend on the FVC but the degree of pulmonary congestion and swallowing problems.

It seems that there is no real efficacy of NNV in SMA intermediate type I with high frequency of tracheostomy. This is due to the frequency of bulbar disorders associated with ineffective cough in patients with this type of SMA. False passages of saliva with swallowing disturbances increase pulmonary congestion and the risk of aspiration pneumonia. Therefore, the risk of respiratory distress requiring invasive ventilation is increased.

The mortality rate is high (26% of our intermediate type I patients), and three who died underwent tracheostomy. The reasons for death are not always clear, but death occurred more often at home. The clinical history is sudden death probably by false passage due to swallowing disturbances, cardiac rhythm abnormalities, or central apnea. It would be of interest to carry out cardiac Holter monitoring in patients with SMA intermediate type I in order to eliminate vagal hypertonia or cardiac arrhythmia that could promote sudden death. Polysomnographic recording with respiratory parameters (overnight P[O.sub.2], PC[O.sub.2], rib cage movements, nasal air flow) and sleep staging could also be useful in order to study the hypothesis of central apneas in SMA type I.

Twenty percent of patients with SMA type II acquired the ability to walk with support. All patients later lost that ability, half of them before the age of 3 years. The respiratory function shows a restrictive pulmonary insufficiency with a slow and progressive decrease of respiratory capacity from childhood to adulthood, without stabilization. Percentages of FVC0[degrees] are higher than percentages of FVC90[degrees], because intercostal muscles are more affected than the diaphragmatic muscle (Fig 2). NNV was necessary for 38% of patients. Tracheostomy was rarely necessary for patients with SMA type II (15% of our patients), and in these cases, it was justified because of recurrent respiratory congestion and atelectasis requiring invasive ventilation. Like patients with SMA intermediate type I, the mean FVC at the age of NNV onset and at the age of tracheostomy are similar, approximately 30%. Unlike SMA intermediate type I, our patients with type II SMA do not have bulbar disorders with swallowing disturbances and risk of false passage. They often just need treatment for gastroesophageal reflux. Thus, respiratory distress requiring mechanical ventilation and need for tracheostomy are less frequent.

It is interesting to note that a child with type II SMA who needed tracheostomy at the age of 13 years was decannulated at the age of 19 years followed by NNV (20% of FVC0[degrees]). One patient with type II SMA, with 12% of FVC0[degrees] at the age of 54 years, never needed tracheostomy. One patient with intermediate type I SMA who needed tracheostomy at the age of 3 years for recurrent atelectasis was decannulated at the age of 18 years and continued with NNV (19% of FVC0[degrees]). Another patient with intermediate type I SMA, who never needed tracheostomy, had 12% of FVC0[degrees] at 21 years. Thus, the value of FVC seems to be just a marker of risk for pulmonary complications. It is not an indication for tracheostomy. Regular chest percussion, assisted coughs, IPPV, and NNV limit the risk of pulmonary congestion and atelectasis and make it possible to avoid tracheostomy for these patients. Respiratory management is associated with concurrent orthopedic management. All patients with type II SMA have scoliosis. They need orthesis, which limits the course of the spinal scoliosis. Subsequently, during the second decade of life, they need surgical spinal stabilization.

SMA type III is the least severe form of SMA. However, the course of the pathology shows a progressive worsening of patients' motility. Fifty percent of our patients have lost the ability to walk. It is important, however, to note that the number of patients with SMA type III in our study is small, since we report only 12 cases. Respiratory function is preserved until the age of 13 years with a mean FVC a bit lower than 100%. Subsequently, FVC decreases progressively with a mean value of 79% at the age of 17 years. The course during adulthood is not reported here.

SMA has been described by some authors (15,16) as a slowly progressive disease. Steffensen et al (16) reported a slow decline of FVC percentage (1.1%/yr) in 13 patients with SMA type II followed up > 5 years. Carter et al (15) reported 45 individuals with SMA types II and III evaluated prospectively over a 10-year period. Pulmonary function was severely impaired in SMA type II (mean FVC was 54 [+ or -] 26% at a mean age of 17 [+ or -] 14 years). Forty-one percent of patients had severe restrictive lung disease, and 17% had moderate restrictive lung disease. Twenty-one percent required mechanical ventilatory assistance. The SMA type III population had much better pulmonary function. Mean FVC was 84 [+ or -] 22% at a mean age of 40 [+ or -] 20 years, with 39% showing a restrictive pattern and 60% of these being mild in severity. The authors also described nonspecific ECG abnormalities in SMA type II and III patients. However, these were not associated with any cardiovascular complications. (15) Distefano et al, (21) in a retrospective study of 43 patients (37 SMA type I, 6 SMA type II), found ECG signs of right ventricular overload probably provoked by pulmonary hypertension due to respiratory abnormalities in 37.3% of the patients. The authors underline the importance of correct respiratory assistance to prevent the onset of cardiologic alterations. (21) For Manzur et al, (18) patients whose FVC ranges between 20% and 50% of that predicted for height are at increased risk of pulmonary complications. Those with FVC < 20% are at particularly increased risk of requiring nocturnal ventilation. (18)

CONCLUSION

Our data support the fact that SMA is a slowly progressive disease. We show the progressively worsening course of restrictive respiratory insufficiency in all SMA types. The measurements of FVC show a progressive decrease of values during childhood and adolescence.

Management of SMA type I is controversial because of the severity of physical disability. In our experience, we distinguished patients with SMA true type I and intermediate type I. In fact, because of the prognosis, our management is different for these two populations at the present time. For patients with SMA true type I, the management consists of noninvasive therapy, involving neither tracheostomy nor gastrostomy since the prognosis for these patients is poor. In contrast, management is different for intermediate type I patients, as the pathology is less severe. The management of these patients is similar to that of patients with SMA type II, and the symptoms of these two patient groups are very similar in adulthood. This management consists of early and regular chest percussion, assisted coughs, IPPV, and NNV. These therapies are essential to limit pulmonary congestion and atelectasis, and to limit the risk of respiratory distress requiring mechanical ventilation and, subsequently, tracheostomy. The risk of pulmonary complications increases as FVC decreases. In our experience, patients with intermediate type I and type II SMA whose FVC reaches 30% of expected values are at increased risk for pulmonary complications.

Nevertheless, NNV must be tried but seems to be poorly efficacious in intermediate type I SMA, with a high frequency of tracheostomy occurring at almost the same period of onset of NNV. The frequency of respiratory distress in intermediate type I SMA patients is increased not only due to respiratory muscle weakness evaluated by FVC, but also by swallowing difficulties and saliva false passages with risk of bronchopulmonary infections. Mortality in patients with SMA seems to be more correlated with bulbar disorders than with restrictive respiratory insufficiency.

In type II SMA patients, the necessity for tracheostomy is uncommon; there is less severe bulbar dysfunction. Chest physiotherapy in association with IPPV and NNV are often sufficient to limit the risks of pulmonary complications, and so allow a better quality of life for these patients with SMA, limiting hospitalizations for severe respiratory distress and decreasing the need of tracheostomy. Nevertheless, this management strategy cannot prevent the progressive course of the disease.

* From the Department of Pediatric Neurology, Hopital Raymond Poincare, Garches, France.

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Manuscript received May 14, 2003; revision accepted March 17, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Christine Ioos, MD, Department of Pediatric Neurology, Hopital Raymond Poincare, 104, Boulevard Raymond Poincare, 92380 Garches, France 78-83; e-mail: christine.ioos@rpc.ap-hop-paris.fr

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