Amyotrophic lateral sclerosis (ALS) is a progressive and terminal neurodegenerative disorder involving cortico-motor neurons in the cerebral cortex, brainstem, and spinal cord. The wide spectrum of atypical presentations can frequently lead to expensive work-up and undue delay or failure in diagnosis of ALS in a substantial number of patients.1–3 Diagnosis of ALS based on El Escorial Diagnostic Criteria Revisited still remains a significant challenge.4 With improved understanding of pathophysiology and availability of newer treatment options, there is a need for development of diagnostic tests that can aid in early diagnosis of ALS.
A 60-year-old African-American man with past medical history of posttraumatic stress disorder (PTSD), gastroesophageal reflux disease, and hypertension presented in the Emergency Department (ED) with severe shortness of breath. His other complaints were repeated anxiety attacks, progressive weight loss, and generalized weakness over the past 8–9 months. At presentation, his hemogram, comprehensive metabolic panel, and electrolytes were within normal limits, except for serum bicarbonate level of 42 mmol/liter.
During the night of admission, he became increasingly lethargic and tachypneic, with alteration in mental status. An arterial blood gas analysis (ABG) on nasal oxygen (2 liter/min) revealed a pH of 7.13; pCO2: 145; pO2: 125; and HCO3: 48. The patient was started on a non-invasive positive pressure ventilation (NPPV/BiPAP) trial at 18 mmHg inspiratory pressure and 5 mmHg expiratory pressure, on which his FiO2 improved to 25%, with significant improvement in mentation. A repeat ABG on BiPAP showed pCO2: 80.4 and pO2: 34. BiPAP was discontinued, and a repeat ABG done 2 hours later at room air showed pCO2: 105 and pO2: 75.1, consistent with hypercarbic respiratory failure and CO2 narcosis.
Detailed history revealed that over 8–9 months, the patient had lost 90 pounds (documented decrease of BMI from 28 to 19.8), with little loss of appetite. The patient stated that very recently and occasionally, he had difficulty in swallowing. He also reported having anxiety attacks accompanied with shortness of breath and chest tightness. The patient had difficulty in identifying specific triggers for these episodes; but recollects that they occurred mostly to exertion, especially in the early morning, making it necessary for him to take several breaks during his morning ablutions. He felt that his shortness of breath has progressively worsened, making even everyday tasks difficult.
Physical examination revealed a thin, cachectic man, well-oriented in time, place, and person, with no clouding of consciousness or loss of memory. His oxygen saturation dropped from 98% to 86% with minimal exertion, like walking 10–20 steps. Cranial nerve examination revealed no abnormalities except tongue fasciculations. Examination of extremities revealed muscle wasting, with 3-to-4/5 asymmetric muscle power; power being less on the left side, with prominence of proximal weakness. Generalized atrophy, hypotonia, and fasciculations were present, most noticeably in dorsal inter ossei, right deltoid, pectoral, and quadriceps muscles. Also, pathologic hyperreflexia with spread of reflexes in upper extremities, 2–3 beats of bilateral ankle clonus, with down-going Babinski response were present. There were no sensory abnormalities to touch, pinprick, vibration, or proprioception, and the patient had normal coordination of movements. Examination of other systems did not reveal any significant abnormalities.
Old records from his primary-care physician, otolaryngologist, and psychiatrist showed an ED visit 8–9 months ago for weight loss. His only complaint at that time was a documented 50-pound weight loss; which was 90 pounds by the time we saw him 8–9 months later. The initial presentation of weight loss without any other symptoms or signs led to evaluation for occult malignancy and cancer cachexia, with repeated CAT scans of abdomen, pelvis, thorax, colonoscopy, and upper gastro-intestinal endoscopy, all of which were normal. Records of physical examination during this period done by multiple providers did not reveal any significant positive findings. In the meantime, the patient started complaining of occasional anxiety and panic attacks. Considering that he was a Vietnam veteran, his symptoms were attributed to PTSD, which was later changed to Anxiety Disorder and Mood Disorder, not otherwise specified. During this period, the patient was seen by multiple providers and underwent more investigations in a futile attempt to identify the cause of weight loss. We could not, however, find the records of his visit to a neurologist, although this would have added valuable information. His medications during this period were nifedipine, mirtazapine, omeprazole, and megestrol acetate.
After reviewing old records, CAT scans, and endoscopy report, and considering the presence of both upper and lower motor neuron weakness, we considered ALS, manifesting as upper motor-neuron disease with bulbar signs and symptoms as the diagnosis. Even though the diagnosis of ALS seems established from the clinical picture, we analyzed serum levels of Vitamin B12, folate, TSH, anti-HIV antibody titers, and heavy metals, which were normal. ECG revealed sinus tachycardia with nonspecific T-wave changes in V1–V3. Echocardiogram showed borderline diffuse hypokineses with preserved ejection fraction. A CAT scan (pulmonary embolism protocol) performed revealed only mild emphysema. Given the history of severe weight loss, we were concerned about underlying neoplastic process and paraneoplastic syndrome. Although considered unlikely, to rule out underlying neoplastic process, we did CAT scans of the head, cervical spine, chest, abdomen, and pelvis, none of which revealed any abnormal mass.
Muscle biopsy done from right deltoid and quadriceps ruled out myositis and showed a modest number of scattered atrophic angular shaped fibers with small- and large-group atrophy, along with regenerating fibers, further sealing the diagnosis of ALS. Electromyography and nerve-conduction velocity studies of sensory and motor conduction showed multiple isolated radiculopathies and polyphasic motor unit potentials in cervical, thoracic, and lumbosacral levels. A dysphagia study conducted did not reveal any abnormalities.
Together, these investigations were consistent with early ALS, and the ALS multidisciplinary team took over further management of the patient.
The diagnosis of ALS is based on the presence of symptoms, signs, or laboratory evidence consistent with progressive upper and lower motor-neuron dysfunction, with no alternative explanation. There is no widely accepted diagnostic test for ALS. Neuro-imaging and other lab tests are used to exclude other diseases, while electro-diagnostic tests are used to support the diagnosis. Classic presentations of ALS include asymmetric weakness of extremities (60%–80%), bulbar symptoms (20%), respiratory muscle weakness (1%–3%), generalized weakness in limbs and bulbar muscles (1%–9%), axial onset with head drop or truncal-extension weakness, muscle atrophy, fasciculations, and cramps.5–7 Although diagnostic criteria for ALS were revised in 2000, lack of a sensitive diagnostic test is a major obstacle to early diagnosis of these patients.4,8,9
Weight loss is usually a late manifestation and has never been noted as initial complaint. The etiology of weight loss in ALS is multifactorial: impaired nutrition due to dyspnea while eating, dysphagia, weakness in extremities, difficulty with mastication; and hypermetabolic state have been proposed.10–12 Decreased dietary intake and weight loss can exacerbate catabolism and atrophy of respiratory muscles and weaken the immune system, forming a vicious cycle. Weight loss and BMI ≤18.5 kg/m2 has been associated with shortened survival and is a negative prognostic indicator.11,13 The quality of life of ALS patients is strongly related to respiratory muscle function, with the frequency of apneas and hypopneas making it a criterion for hospice eligibility.14,15 Our patient exhibited classic signs of nocturnal hypoventilation, such as fear of sleeping, daytime hypersomnolence, early-morning headaches, fatigue, and impaired cognition. It is interesting that our patient had relatively well-preserved muscle power in all extremities (3-to-4/5), even though he had already lost 90 pounds and had severe hypercapneic respiratory failure.
Even though ALS is known for its atypical presentations, severe weight loss as isolated presenting complaint has never been reported in the literature. In our patient, progressive severe weight loss was the only complaint for months, before development of classic neurologic signs, making diagnosis of ALS difficult. This unique clinical presentation highlights the challenges involved in early diagnosis of atypical cases of ALS.