J7ournal ofNeurology, Neurosurgery, and Psychiatry 1996;60:455-458

Motor neuron disease presenting as acuterespiratory failure: a clinical and pathologicalstudy

Robert Chen, Francois Grand'Maison, Michael J Strong, David A Ramsay,Charles F Bolton

AbstractRespiratory failure is rarely a presentingsymptom of motor neuron disease. Sevenpatients with motor neuron disease whopresented with acute respiratory failure ofunknown cause and required mechanicalventilation were studied. They all hadsymptoms and signs suggestive ofdiaphragmatic weakness. Respiratoryinvolvement seemed disproportionatelysevere, as six were ambulatory and onlythree noted limb weakness. Only one hadtongue weakness and none had swallowingdifficulty. Electrophysiological studiesshowed widespread denervation and, inparticular, diaphragmatic involvement toexplain the severe respiratory failure.Weaning from the ventilator was unsuc-cessful in all cases. The four patientsexamined at necropsy showed severe lossof anterior horns cells in the cervicalcord, with only minimal upper motorneuron involvement. Motor neuron dis-ease should be recognised as a cause ofacute respiratory failure, secondary todiaphragmatic paralysis from involve-ment ofphrenic motor neurons.

(7 Neurol Neurosurg Psychiatry 1996;60:455-458)

Keywords: respiratory failure, amyotrophic lateral scle-rosis, motor neuron disease

in severe hypercapnic respiratory failure. Hewas intubated in the emergency department.For 11 months previously he had had increas-ing shortness of breath on exertion, orthop-noea, difficulty climbing stairs, and a weightloss of 9 kg. Investigations for an underlyingmalignancy were negative.On examination he was on a ventilator but

able to communicate by writing. Cranial nerveexamination showed bifacial weakness, thetongue was moderately weak but withoutwasting or fasciculation. Motor examinationdisclosed fasciculations in the proximal mus-cles, mild wasting of the deltoids, intrinsicmuscles of the hands and feet, and diffusemild to moderate weakness in all limbs. Deeptendon reflexes were brisk and plantarresponses were flexor on the right and exten-sor on the left. Sensation was normal. Therewas indrawing of the abdomen with inspira-tion.

Blood gases before intubation, while on anoxygen rebreathing mask, showed pH 7-12,Pao, 133 mm Hg, Paco2 115 mm Hg, HCO341 mmol/l. A chest radiograph showed eleva-tion of both hemidiaphragms and atelectasis.Vital capacity was 700 ml and the maximuminspiratory pressure was -20 cm water (nor-mal > -50 cm water).He declined further ventilatory support and

died of hypercapnic respiratory failure threedays after extubation.

Department of ClinicalNeurological SciencesR ChenM J StrongC F BoltonDepartment ofPathology, UniversityofWestern Ontario,London, Ontario,CanadaD A RamsayDepartment ofNeurology, Universityof SherbrookeSherbrooke, Quebec,CanadaF Grand'MaisonCorrespondence to:Dr Charles F Bolton,Department of ClinicalNeurological Sciences,Victoria Hospital, 375 SouthStreet, London, Ontario,Canada N6A 4G5.

Received 14 August 1995and in revised form12 December 1995Accepted 15 December 1995

Although respiratory failure is common in theadvanced stages of motor neuron disease andis the major cause of mortality, it is rarely apresenting symptom. Early deterioration inrespiratory function is almost invariably grad-ual, with an accelerated decline during the 12to 15 months preceding death.1 2 Motor neu-ron disease presenting as acute respiratory fail-ure of unknown cause is rare.3-0 We reporthere the clinical features of seven suchpatients, with pathological findings in fourcases. The diagnostic and management diffi-culties are discussed.

MethodsCASE SERIESThe patients were seen at Victoria andUniversity Hospitals, London, Ontario, andCentre Hospitalier, Sherbrooke, Quebecbetween January 1991 and April 1995.

Case 1

A 69 year old man collapsed at home and was

CASES 2 TO 7The table summarises the clinical features. Innone of these patients was a neuromusculardisorder suspected before their presentation tothe emergency department as acute respiratoryfailure, although all had respiratory symptomssuch as dyspnoea or orthopnoea for variableperiods (table). Blood gases before intubationall showed severe hypercapnia. Although allthe patients were ventilated, they were alertand usually able to communicate by writing.Motor examination showed mild or moderatewasting and weakness in the limb muscles inall patients. Fasciculations were present inpatients 1 and 7. Phrenic nerve conductionstudies invariably showed very reducedresponses. Needle EMG showed widespreaddenervation in all patients, most severe in thediaphragm.

PATHOLOGICAL FINDINGSNecropsy examinations were performed inpatients 1, 2, 3, and 7. The gross appearancesof the cerebral cortex, cerebellum, and brain-stem were normal, except for mild diffuse

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Clinical features

Precipitat-Other ingfactor

Duration of symptoms Mobility at for acute Deep DiaphragmsAge respiratory at presen- presen- respiratory tendon Plantar Abdominal on chest

Patient Sex symptoms tation tation failure reflexes response paradox radiograph Diagnosis Outcome

1 69M 11 months Leg Ambula- Atelectasis Brisk Right Present Elevated ALS Died,weakness tory flexor, left respiratory11 months extensor failure

2 55F 5 weeks Hand Ambula- Atelectasis, Reduced Flexor Present Not PMA Died,weakness tory COPD to absent elevated respiratory15 months failure

3 70M 3 weeks None Ambula- Pulmonary Normal Flexor Absent Not PMA Died,tory infection, elevated unrelated

COPD condition4 77F 2 weeks Leg Non- Pulmonary Reduced Flexor Present Not PMA Died,

weakness ambula- infection, elevated respiratory12 months tory COPD failure

5 68M 12 months None Ambula- None Brisk Right Present Not ALS Alive, ontory identified flexor, left elevated home

extensor ventilator6 48F 3 months None Ambula- None Reduced Flexor Present Not PMA Died,

tory identified to absent elevated respiratoryfailure

7 72M 2 months None Ambula- None Brisk Extensor Present Not ALS Died,tory identified elevated respiratory

failure

ALS = amyotrophic lateral sclerosis; COPD = chronic obstructive pulmonary disease; PMA = progressive muscular atrophy.t..s>b.*A -3 4

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(A) Loss of anterior horn cells-patient 1. Photomicrograph from the cervical anterior hornshowing an area devoid of motor neurons (bottom and right), background gliosis andresidual anterior horn cells (top and left), one of which is degenerating (arrow);haematoxylin, eosin, solochrome; bar = 50,m. (B) Nerve root axonal swelling-patient 1.An axonal swelling is shown in this photomicrograph from the anterolateralfuniculus;haematoxylin, eosin, solochrome; bar = 10 um.

atrophy in patient 7. The anterior spinal nerveroots seemed normal in patient 1, but wereatrophic in patients 2, 3, and 7. In all patients,microscopic examination of the motor cortexwas normal. Cranial motor neurons were gen-erally well preserved, although a few Buninabodies were found in patient 1 and mild neu-ronal loss was seen in the nuclei ambiguus andthe hypoglossal nuclei in patient 7.Microscopic examination of the spinal cord allshowed pronounced loss of anterior horn cells,scattered axonal swellings, and gliosis (figure).There was no obvious predilection for the cer-vical cord in patients 1 and 2. In patient 3, theupper cervical segments seemed moreinvolved than the lower cervical, thoracic, andlumbar segments. In patient 7, there wassevere involvement of the cervical cord butonly minimal changes in the thoracic and lum-bar segments. In the corticospinal tracts mildloss of myelinated fibres occurred and a fewmacrophages were found in patients 1, 2, and3, but there were no detectable changes inpatient 7.

Morphometric analysis of the spinal cordwas performed in patient 7. The segments C5to T2, T6, and L3 were analysed. Ten ,umthick sections were cut from each segment atfour levels separated by 100 um and stainedwith cresyl violet. The grey matter from eachsection and its anterior horn cells were drawnon paper with a camera lucida. Each drawingof the anterior horn was divided in theparasagittal plane into medial, intermediate,and lateral thirds and the anterior horn cells ineach third were counted. There was a 30% to43% decrease in the number of anterior horncells in the C5 to T2 segments compared witha control patient without neurological disease(Mann-Whitney U test: P < 0-0001). How-ever, there seems to be no difference in theinvolvement of the medial neurons comparedwith the lateral neurons in the cervical seg-ments.

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Motor neuron disease presenting as acute respiratory failure: a clinical and pathological study

DiscussionCLINICAL FEATURESAll of our patients developed hypercapnic res-piratory failure requiring assisted ventilation,before the diagnosis of motor neuron disease.Although they were previously seen byinternists or neurologists, their clinical find-ings were subtle and were overlooked by theexamining physicians. In all cases the respira-tory failure was initially attributed to othercauses, such as pneumonia, exacerbation ofchronic obstructive pulmonary disease, heartfailure, or sleep apnoea.

Twelve patients with motor neuron diseasepresenting as acute respiratory failure havebeen reported in detail3-10 and two in abstractform."1 There are other reports of motor neu-ron disease with dyspnoea as a presentingSyMptoM.4i712-44 All our patients had symp-toms and signs of diaphragmatic weakness.They complained of dyspnoea, sometimesassociated with orthopnoea. Examinationinvariably showed poor chest expansion.Paradoxical indrawing of the abdomen duringinspiration is a useful sign of bilateraldiaphragmatic weakness and was present in sixof our seven patients. In all patients there waslimb involvement with a variable combinationof wasting, weakness, and fasciculation.Pulmonary function tests typically showed arestrictive pattern and blood gas analysisinvariably showed hypercapnia. Elevation ofthe diaphragm on chest radiography was pre-sent in only one of our seven patients.Electrophysiological results were important inclearly establishing diffuse anterior horn celldisease, and in particular, involvement of thediaphragm, to explain the severe respiratoryfailure.

Although the main cause of respiratory fail-ure in all our patients was diaphragmaticweakness, other factors often contribute to theacute decompensation. In patients 1 and 2there was atelectasis, a complication ofretained secretions due to respiratory muscleweakness. In patients 3 and 4, acute respira-tory failure seemed to be precipitated by minorpulmonary infections and mild chronicobstructive pulmonary disease, which mayhave decreased respiratory reserve.

Diaphragmatic weakness in our patientsseemed to be disproportionately severe com-pared with limb involvement. Six of our sevenpatients were walking at the time of presenta-tion, and patient 5 continued to walk one yearlater. Four of our patients did not complain ofany limb weakness. Only one (patient 1) hadmild tongue weakness and none had swallow-ing difficulty.

Three of our patients (1, 5, and 7) had amy-otrophic lateral sclerosis and four (2, 3, 4, and6) had progressive muscular atrophy, withonly lower motor neuron signs. Of the 12reported patients,3-10 seven can be classified asamyotrophic lateral sclerosis and five as pro-gressive muscular atrophy. As progressivemuscular atrophy represents less than 10% ofcases of motor neuron disease,15 its representa-tion may be increased among this group ofpatients.

PATHOLOGICAL FEATURESAll four patients showed severe anterior horncell loss in the spinal cord. With normalmicroscopy of the motor cortex and corre-spondingly only slight or no loss of myelinatedaxons from the corticospinal tract, uppermotor neuron involvement in these patientswas mild or non-existent. This supports ourconclusion based on clinical and electrophysio-logical studies that respiratory failure is due todegeneration of phrenic motor neurons, ratherthan upper motor neuron involvement.

Although one report described selectiveinvolvement of the phrenic nuclei'1 located inthe ventromedial cell column of C3 to C5, wedid not find such predilection in our fourpatients, even with morphometric analysis inpatient 7. However, the cervical cord wasseverely involved in all of our patients. Ourfindings were similar to those for three otherpatients reported.36 Given the clinical andelectrophysiological features of our patients, itis likely that the phrenic motor neurons weremore severely involved than motor neurons oflimb muscles. The reason for the failure toshow this pathologically is unclear. Somephrenic motor neurons may be involvedbut have not yet progressed to neuronalloss. Also, microscopy may be less sensitivethan clinical examination and electrophysiol-ogy in detecting small but clinically significantdifferences.

OUTCOMENone of our seven patients was successfullyweaned from the ventilator. Six died, fourafter having declined further respiratory sup-port and one from an unrelated condition(small bowel perforation). Patient 5 is alivebut dependent on a home ventilator. Amongthe cases reported, only one became indepen-dent of a ventilator,4 six required nocturnalventilatory support,479 two remained fullydependent on a ventilator, and three died onfull ventilation.3 6 10 Thus, weaning from theventilator is difficult for these patients.However, a reasonable quality of life can bemaintained in some patients with ventilatorysupport.

ETHICAL ISSUESAll our patients presented challenging ethicalissues. As their neuromuscular disorder waspreviously undiagnosed, the question of lifesupport had not been discussed and yet theyhad been precipitated into lifetime depen-dency on a ventilator. As they had normalcognitive functions and were able to commu-nicate, we discussed the diagnosis and progno-sis with the patients and their families in afrank and compassionate manner. Thepatients were given ample time to considertheir options. Four of our patients chose todiscontinue ventilatory support. We offeredlong term ventilation, which can greatlyimprove the quality of life in selected caseswith motor neuron disease,5 13 especially thosewith respiratory muscle weakness withoutsevere bulbar involvement.5 Patient 5 in ourseries is such an example. However, long

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mitment from the patient and family.

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2 Braun SR. Respiratory system in amyotrophic lateral scle-rosis. Neurol Clin 1987;5:9-31.

3 Parhad IM, Clark AW, Barron KD, Staunton SB. Dia-phragmatic paralysis in motor neuron disease. Neurology1978;28: 18-22.

4 Hill R, Martin J, Hakim A. Acute respiratory failure inmotor neuron disease. Arch Neurol 1983;40:30-2.

5 Howard RS, Wiles CM, Loh L. Respiratory complicationsand their management in motor neuron disease. Brain1989;112:1155-70.

6 Fromm GB, Wisdom PJ, Block AJ. Amyotrophic lateralsclerosis presenting with respiratory failure. Diaphrag-matic paralysis and dependence on mechanical ventila-tion in two patients. Chest 1977;71:612-4.

7 Nightingale S, Bates D, Bateman DE, Hudgson P, EllisDA, Gibson GJ. Enigmatic dyspnoea: An unusual pre-sentation of motor-neuron disease. Lancet 1982;i:933-5.

8 Daras M, Spiro AJ, Swerdlow M. Respiratory failure inamyotrophic lateral sclerosis. New York State J7ournal ofMedicine 1984;84:570-2.

9 Al-Shaikh B, Kinnear W, Higenbottam TW, Smith HS,Shneerson JM, Wilkinson I. Motor neurone disease pre-senting as respiratory failure. BMJ 1986;292:1325-6.

10 Meyrignac C, Poirier J, Degos JD. Amyotrophic lateralsclerosis presenting with respiratory insufficiency as theprimary complaint. Clinicopathological study of a case.Eur Neurol 1985;24: 115-20.

11 Hostetler J, Ludwin S, Saly V, Zochodne D. Motor neurondisease presenting as ventilator dependency [abstract].Can I Neurol Sci 1992;19:280-1.

12 Paul GR, Appenzeller 0. Dyspnea as the presenting symp-tom in amyotrophic lateral sclerosis. Dis Chest 1962;42:558-62.

13 Sivak ED, Streib EW. Management of hypoventilation inmotor neuron disease presenting with respiratory insuffi-ciency. Ann Neurol 1980;7:188-91.

14 Miller DR, Mulder DW, Fowler WS, Olsen AM. Exer-tional dyspnea: A primary complaint in unusual cases ofprogressive muscular atrophy and amyotrophic lateralsclerosis. Ann Intern Med 1957;46:119-25.

15 Caroscio JT, Mulvihill MN, Sterling R, Abrams B.Amyotrophic lateral sclerosis. Neurol Clin 1987;5:1-8.

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