Importance of early recognition of amyotrophic lateral sclerosis-like disorders in the Egyptian population

Heba Raafat; Radwa M Azmy; Reham Shamloul; Amr El Deeb

doi:10.4103/1110-1083.202381

ORIGINAL ARTICLE

Year : 2016 | Volume : 53 | Issue : 4 | Page : 219-224

Importance of early recognition of amyotrophic lateral sclerosis-like disorders in the Egyptian population

Heba Raafat MD ¹, Radwa M Azmy¹, Reham Shamloul², Amr El Deeb³
¹ Clinical Neurophysiology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
² Department of Neurology, Faculty of Medicine, Cairo University, Cairo, Egypt
³ Department of Tropical Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission	15-May-2016
Date of Acceptance	17-Jul-2016
Date of Web Publication	17-Mar-2017

Correspondence Address:
Heba Raafat
Clinical Neurophysiology Unit, Cairo University, Cairo, 11562
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1110-1083.202381

Abstract

Background
Early stages of amyotrophic lateral sclerosis (ALS)-like syndrome when only one limb is affected can be missed by physicians suggesting other unrelated disorders especially with evidenced concomitant pathology of the same limb, leading to diagnostic pitfalls and unnecessary procedures.
Objective
The aim of this study was to support the diagnosis of early stages of ALS-like disorders in clinically suspected patients by electrophysiological studies (EDX) including segments that may be clinically unaffected, and searching for the possible etiology.
Patients and methods
This study was conducted on 120 adult patients with unilateral limb symptoms associated with irrelevant imaging abnormalities. Diagnostic workup included history taking, general and neurological examination, and EDX using the El Escorial diagnostic criteria. Further investigations included laboratory studies and paraneoplastic and hormonal assays.
Results
Motor nerve conduction studies revealed reduced amplitude of compound muscle action potential in 62.5% of patients, borderline conduction velocities, normal distal latencies, conduction block in one case, and normal sensory nerve conduction studies. Electromyography of the cranial, cervical, lumbosacral, and dorsal segments showed acute denervation in 80% of patients and chronic denervation in all segments in 35% and in three body segments in 65% of patients. Laboratory investigations revealed 50.83% of patients with chronic hepatitis C, with significant statistical association between EDX and laboratory results, 30.83% with hyperthyroidism, 8.33% with paraneoplastic syndrome, one case with multifocal motor neuropathy with conduction block, one case with myasthenia gravis, and 8.3% with negative results.
Conclusion
ALS-like disorder should be investigated whenever ALS is suspected, and further laboratory workup might unveil a coexisting ‘possibly causative’ pathological condition.

Keywords: amyotrophic lateral sclerosis-like disorder, El escorial diagnostic criteria, electrophysiological studies

How to cite this article:
Raafat H, Azmy RM, Shamloul R, El Deeb A. Importance of early recognition of amyotrophic lateral sclerosis-like disorders in the Egyptian population. Egypt J Neurol Psychiatry Neurosurg 2016;53:219-24

How to cite this URL:
Raafat H, Azmy RM, Shamloul R, El Deeb A. Importance of early recognition of amyotrophic lateral sclerosis-like disorders in the Egyptian population. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2023 Sep 27];53:219-24. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/4/219/202381

Introduction

Motor neuron disease constitutes a heterogeneous group of disorders with amyotrophic lateral sclerosis (ALS) being one of its most severe and fatal diseases. In the early stages of the disease the picture can be misleading, making the diagnosis difficult. In addition, the first physicians consulted are usually general practitioners, orthopedics, neurosurgeons, or rheumatologists [1],[2].

Early stages with one-limb onset (monomelic amyotrophy) can be missed by many physicians suggesting other unrelated disorders, especially with evidenced concomitant pathology of the same, leading to diagnostic pitfalls and unnecessary procedures [3].

To verify the diagnosis of ALS, the El Escorial Criteria (EEC) was first established (1994) and revised (1999) to diagnose ALS [4],[5].

EEC was criticized as being fairly rigid and it allows diagnosis only relatively late in the course of the disease. Many ALS/EMG experts were not satisfied with the EEC and suggested the Awaji criteria (2008). The Awaji criteria modified the EEC toward better attention to EMG findings, especially the clinically unaffected regions, increasing the diagnostic sensitivity [6].

The Awaji criteria focused more on electrophysiological studies and changed the clinically probable laboratory-supported degree of EEC into probable. Active denervation in the Awaji criteria includes fasciculations, not only fibrillation potentials and positive sharp waves. It also discussed the role of transcranial magnetic stimulation in detecting subclinical upper motor neuron lesions, which is possible in early stages of the disease [6].

Once ALS is suspected on clinical and electrophysiological bases, further investigations should be carried out to search for possible ALS-like disorders that occur more frequently than ALS and give the picture of ALS but are potentially treatable [7].

ALS-like disorders include multifocal motor neuropathy with conduction block, hyperthyroidism, paraneoplastic syndrome, mostly Lambert–Eaton myasthenic syndrome and lymphoma, viral infection such as HIV, human T-cell leukemic virus, and myasthenia gravis [8].

The aim of this study was to support the diagnosis of early stages of ALS-like disorders in clinically suspected patients by means of electrophysiological studies (EDX) including segments that may be clinically unaffected, and search for the possible etiology.

Patients and methods

After approval by local review board this study was conducted on 120 adult Egyptian patients over a period of 9 months who presented with weakness with or without atrophy related to only one limb, with irrelevant imaging abnormalities.
The following patients were referred to the Clinical Neurophysiology Unit of El Kasr Al Aini Hospital from the Orthopedic, Rheumatology, and Neurosurgery Departments of El Kasr Al Aini Hospital with suspicion of other unrelated conditions, evidenced with some abnormal imaging results.
1. Patients with mild disc protrusions on cervical or lumbosacral MRI not correlated with the wasting of proximal or distal muscles of the same limb.
2. Patients with unilateral foot drop suspecting sciatic or peroneal nerve injury or compression.
3. Patients with old mild brachial plexopathy presenting with recent wasting in the same limb.
4. Patients with suspected femoral neuropathy with wasted quadriceps muscle.

Diagnostic workout

The battery of assessments performed on our patients included thorough clinical evaluation, careful history taking, and general and neurological examination as per the standard neurological sheet of the Neurology Department, Cairo University, with special emphasis on subtle neurologic deficit due to a corticospinal tract lesion that may be detected using ancillary maneuvers such as the pronator drift (Barrés sign), the digiti quinti sign, the leg or knee-dropping test, and other tests for fine motor control.
Extensive electrophysiological studies as mentioned below were conducted using a Nihon Kohden, Corporation, Tokyo, Japan (Neuropack M1) apparatus.
1. Nerve conduction studies (NCS) including motor NCS and sensory NCS on the nerves of the upper and lower limbs to exclude motor neuropathy or other disorders of the peripheral nerve, neuromuscular junction, and muscle that may mimic ALS. Stimulus duration was 0.2 ms, at a rate of 1 Hz.
2. EMG examination using a concentric needle electrode guided by the Awaji criteria for diagnosis once anterior horn cell affection was suspected upon the appearance of active denervation and detection of chronic denervation by EMG examination of the symptomatizing limb. The examination included cranial, cervical, lumbosacral, and thoracic segments. Apparatus settings were as follows: sweep duration 20 ms/division, display sensitivity ranging from 20 mV/division at rest to 200 to 1 mV/division on activation, and filter setting 1 to 10 kHz.
3. Inching techniques for both median and ulnar nerves to exclude multifocal motor neuropathy with conduction block.
4. Repetitive supramaximal stimulation at 3 Hz, at rest and after exercise.
Further investigations were suggested by the clinical/EMG results:
1. Laboratory studies such as complete blood count, thyroid function tests, and evaluation of anticholinesterase antibodies (when suspected).
2. Paraneoplastic assay.
3. Virological screening.
4. Imaging studies (brain and cervical MRI).
5. Cerebrospinal fluid analysis (when suspected).
Patients’ data were stored, analyzed and tabulated. Electrodiagnostic results were compared with cervical and lumbosacral MRI findings and further laboratory investigations using the χ²-test. All statistical calculations were made using SPSS (Statistical Package for the Social Sciences; IBM Inc., Chicago, Illinois, USA).

Results

The ages of the patients ranged from 25 to 60 years, with a mean of 41±12 years. The study showed that 66 (55%) patients were male and 54 (45%) were female.

The presenting symptoms of all studied patients were in the form of muscle twitches observed in the symptomatizing limb in 40 patients (33.3%), muscle wasting in 76 patients (63.3%), distal unilateral lower-limb weakness in 54 (45%) patients, distal unilateral upper-limb weakness in 48 patients (40%), proximal unilateral lower-limb weakness in seven patients (5.83%), and proximal unilateral upper-limb weakness in six patients (5%), as shown in [Table 1].

Table 1 Various presenting symptoms of all studied patients

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Careful neurological examination confirmed exaggerated reflexes in the symptomatic limb in 72 of the studies patients (60%) and retained reflexes in 48 patients (40%), also in the symptomatizing limb, normal cranial examination, sensory, sphincteric, and coordination in all the studies patients, shown in [Table 2].

Table 2 Results of neurological examination of all patients

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NCS revealed small compound muscle action potential (CMAP) in 75 patients (62.5%) and absent CMAP amplitude of motor nerves in 45 patients (37.5%), borderline motor nerve conduction velocities in 65 patients (54.17%) and normal motor nerve conduction velocities in 55 patients (45.83%), normal distal latencies in all the studied patients (100%), conduction block in one case (0.83%), and normal sensory conduction studies in all cases (100%). All nerve conduction results are presented in [Table 3].

Table 3 Nerve conduction results in the studied patients

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EMG examination of the cervical, craniobulbar, lumbosacral, and thoracic regions showed evidence of active denervation at rest in the form of fasciculations, fibrillation potentials, or positive sharp waves in 96 patients (80%). On mild volitional activity 42 patients (35%) showed evidence of chronic denervation in all four regions examined. Chronic denervation was in the form of long duration, and large amplitude motor unit potential with evident polyphasicity. Seventy-eight patients (65%) showed chronic denervation in three regions, as presented in [Table 4].

Table 4 EMG examination results of the four examined regions

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Further laboratory investigations with EMG examination results revealed 61 cases with chronic hepatitis C (50.83%), 37 cases with hyperthyroidism (30.83%), 10 cases with paraneoplastic syndrome (8.33%), one case with myasthenia gravis (0.83%), and another case (0.83%) with multifocal motor neuropathy with conduction block. However, 10 patients (8.33%) showed negative laboratory investigations with no suggestive etiology of the ALS-like disorder, as shown in [Table 5]. Those 10 patients with negative laboratory results were suggested to have typical ALS according to clinical and electrophysiological results as shown in [Table 2],[Table 3],[Table 4]. When comparing the electrophysiological results with the existing cervical or lumbosacral MRI reports there was no statistical significance (P>0.05), denoting disagreement between EMG results and imaging results. However, on comparing the EMG and NCS results with the positive chronic hepatitis C laboratory results, a statistically significant association (P<0.05) was found between chronic hepatitis C and clinical/electrophysiological evidence of ALS.

Table 5 Full investigation results of all examined patients

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Discussion

A diagnosis of ALS is devastating, carrying with it the expectation of decline in health as well as death in a few years. Other viable alternative possibilities should be excluded to avoid misdiagnosis [3].

Clinical electrophysiological studies have proven useful in helping to establish a diagnosis by eliminating possible disease mimics and providing evidence of subclinical abnormalities in different body segments [9].

The present study included 120 patients aged 25–60 years (mean of 41±12 years), of whom 55% were male, which is consistent with the NINDS fact sheet [10]. Authors reported an increase in incidence after age 40, including the elderly population [11]. According to NINDS, men are affected more often than women. Other studies reported a male/female ratio of ∼1.5 [12].

In this retrograde study, patients presented with unilateral weakness or wasting. NCS was performed primarily in the symptomatic extremity, showing findings irrelevant to the suspected diagnosis; thus, examination was further extended, covering the four extremities, following the protocol of Preston and Shapiro [13].

Motor NCS showed reduction in CMAP amplitudes, reflecting axonal loss, but not a distinction between lesions at the motor neuron, nerve root, plexus, or peripheral nerve. No prolongation of distal latencies was encountered. The decrease in conduction velocity was less than 75% of the lower limit of normal, ruling out demyelination. Authors recommended that NCS of a patient with suspected ALS should include testing of at least one motor nerve and one sensory nerve in an upper and lower extremity on the most symptomatic side [9]. On sensory NCS, sensory nerves were typically not affected in any of our patients. Sensory nerve action potential abnormalities should raise the possibility of other diagnoses.

Conduction block was diagnosed in one of our cases, in the form of a drop in the CMAP area and amplitude greater than 50% between proximal and distal stimulation sites according to Preston and Shapiro [13]. Conduction block of motor nerves in areas not associated with entrapment, with sparing of sensory nerves, suggests multifocal motor neuropathy with conduction block [14].

Following the Awaji modifications, the four body segments (cervical, cranial, lumbosacral, and thoracic) were examined by EMG in this present study. The role of needle EMG in ALS is to establish evidence of ongoing degeneration and chronic compensatory reinnervation, with spread within an initial body segment and to other body segments. In the present study, EMG examination detected acute denervation in the form of fibrillation potentials, positive sharp waves, and fasciculation potentials in 80% of the cases, with chronic reinnervation in the voluntary motor unit potential (MUPs) in three and four body segments in 65 and 35% of cases, respectively [6].

The exact etiology of ALS is unknown [15]. The ALS Multidisciplinary Clinic at Massachusetts General Hospital looks for evidence of other diseases whose symptoms are similar to early signs of ALS, including thyroid and parathyroid disease, vitamin B₁₂ deficiency, HIV, hepatitis, autoimmune diseases, and some types of cancer [16].

We investigated all our patients to detect a possible underlying triggering factor. Studies supported the hypothesis of viruses causing ALS-like disorder through neuronal infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease [17]. Authors hypothesized selective vulnerability of motor neurons to certain viruses [15]. Clinical evidence suggests that ALS may be associated with HIV infection, in addition to poliomyelitis virus as well as enterovirus, whose RNA sequences have been detected in the spinal cord of patients with ALS [18].

Virological screening revealed 50.83% of patients to have hepatitis C, in agreement with a study that reported a case with a 9-year history of hepatitis C presenting with an ALS-like picture [18]. Could hepatitis C be a major triggering factor in Egypt, having the highest prevalence of hepatitis C virus infection in the world, estimated nationally at 14.7%, with no evidence of a statistically significant decline in hepatitis C virus prevalence over time [19]. There was statistical significance (P<0.05) between chronic hepatitis C and clinical/electrophysiological evidence of ALS. One of our patients who proved to have hepatitis C experienced marked clinical improvement on receiving treatment for hepatitis C, which raises hopes for possible reversibility of ALS-like symptoms in hepatic patients [19]. Supporting our theory of the viral role in ALS, which in our country proved to be the hepatitis C virus, some authors reported sustained complete recovery of cases presenting with a rapidly progressive ALS-like syndrome, who were found to be HIV positive, on antiretroviral treatment [20].

Thyroid function tests showed that 30.83% of our patients had hyperthyroidism, although some authors stated that the hormone level in ALS patients was not different from that of controls despite the hypothesis of coexistence of ALS with autoimmunological disorders, including thyroid diseases [21],[22].

Paraneoplastic assay in the present study showed positive results in 8.33% of our cases in agreement with studies that linked ALS-like syndromes to lymphoma and breast cancer, although they were considered extremely rare [23],[24].

Conclusion

An ALS-like disorder should be thoroughly investigated whenever ALS is suspected on clinical and electrophysiological basis, especially in early stages, using extensive laboratory workup, to unveil any potentially treatable pathological etiology that may lead to regression of symptoms and possible recovery unlike the fatal ALS disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Dengler R. Diagnostic criteria of amyotrophic lateral sclerosis. Rom J Neurol 2010; 9:165–171.
2.	Turner MR, Talbot K. Mimics and chameleons in motor neuron disease. Pract Neurol 2013; 13:153–164.
3.	Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O. Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch Neurol 2000; 57:109–113.
4.	Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial ‘Clinical limits of amyotrophic lateral sclerosis’ workshop contributors. J Neurol Sci 1994; 124:96–107.
5.	Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Disease. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord, 2000 1:293–299.
6.	De Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008; 119:497–503.
7.	Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol 2000; 57:1171–1176.
8.	Wood-Allum C, Shaw PJ. Motor neuron disease: a practical update on diagnosis and management. Clin Med (Lond) 2010; 10:252–258.
9.	Duleep A, Shefner J. Electrodiagnosis of motor neuron disease. Phys Med Rehabil Clin N Am 2013; 24:139–151.
10.	National Institute of Neurological Disorders and Stroke. Motor Neuron Diseases Fact Sheet, NINDS. Publication date March 2012. NIH Publication No. 12–5371
11.	Belzil VV, Langlais JS, Daoud H, Dion PA, Brais B, Rouleau GA. Novel FUS deletion in a patient with juvenile amyotrophic lateral sclerosis. Arch Neurol 2012; 69:653–656.
12.	Ragonese P, Cellura E, Aridon P, D’amelio M, Spataro R, Taiello AC et al. Incidence of amyotrophic lateral sclerosis in Sicily: a population based study. Amyotroph Lateral Scler 2012; 13:284–287.
13.	Preston D, Shapiro B. Electromyography and neuromuscular disorders. Philadelphia (Pennsylvania): Elsevier; 2005. 40–43.
14.	Kimura J. Physiology of ALS and related diseases. In: Kimura J, Kaji R. Multifocal motor neuropathy and conduction block. Amsterdam: Elsevier Science; 1997. 57–72.
15.	Jubelt B, Berger JR. Does viral disease underlie ALS? Lessons from the AIDS pandemic. Neurology, 2001; 57:945–946.
16.	William S, Atassi N, Bali T et al. The amyotrophic lateral sclerosis (ALS) multidisciplinary clinic. Boston: Massachusetts General Hospital; 2005.
17.	Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology 2001; 57:995–1001.
18.	Akhvlediani T, Kvirkvelia N, Shakarishvili R, Tsertsvadze T. ALS-like syndrome in the patient with chronic hepatitis C. Georgian Med News 2009; (172–173):70–72.
19.	Mohamoud YA, Mumtaz GR, Riome S, Miller D, Abu-Raddad LJ. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis 2013; 13:288.
20.	MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 2001; 57:1094–1097.
21.	Iłzecka J, Stelmasiak Z. Thyroid function in patients with amyotrophic lateral sclerosis. Ann Univ Mariae Curie Sklodowska Med 2003; 58:343–347.
22.	Turner MR, Talbot K. Mimics and chameleons in motor neurone disease. Pract Neurol 2013; 13:153–164.
23.	Younger DS, Rowland LP, Latov N, Hays AP, Lange DJ, Sherman W et al. Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis. Ann Neurol 1991; 29:78–86.
24.	Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol 1997; 41:722–730.