Paraneoplastic Amyotrophic Lateral Sclerosis: Case Series and Literature Review

Paraneoplastic amyotrophic lateral sclerosis (ALS) is a rare and special type of ALS. The pathogenesis, clinical presentation, treatment and prognosis remain poorly understood. We herein presented three cases of paraneoplastic ALS. In case 1, we first reported an ALS patient with the positive serum antibodies against both Sry-like high mobility group box 1 (SOX1) and glutamic acid decarboxylase 65 (GAD65). However, immunotherapy did not improve his neurological symptoms. We also reported two ALS patients with renal clear cell carcinoma and chronic myelogenous leukemia. No positive paraneoplastic antibodies were detected in either the serum or the cerebrospinal fluid of the two patients, and their clinical symptoms progressed slowly after tumor treatment. The three cases enriched the existing case pool of this rare disorder. In addition, we have comprehensively reviewed the literature of paraneoplastic ALS. The clinical features, treatment effect and prognosis were summarized to broaden our understanding of paraneoplastic ALS.


Introduction
Amyotrophic lateral sclerosis (ALS) is a fatal and rare neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons of the brain and spinal cord [1][2][3]. Although ALS is not a classical phenotype of paraneoplastic neurological syndromes (PNS), PNS are one of a multitude of causes of ALS [4]. Although they are rare, the clinical situations that support the diagnosis of definite paraneoplastic ALS are: laboratory evidence of well-characterized onconeural antibodies or neurological improvement is observed after cancer treatment [4][5][6]. When onconeural antibodies are absent, if the onset is rapidly progressive or there are inflammatory findings in the CSF or brain/spine MRI, and cancer present within two years of diagnosis or neurological symptoms remained stable after tumor treatment, it supports the diagnosis of possible paraneoplastic ALS [4][5][6]. Paraneoplastic ALS generally has low incidence rates; hence, there are currently few case reports on the condition, and the description of the clinical characteristics of paraneoplastic ALS patients remains incomplete.
Therefore, this article aimed to raise the awareness on paraneoplastic ALS by reporting three cases and conducting a literature review.

Case Series
Case 1: A 50-year-old male was admitted to the hospital with 10 months of progressive weakness on the right upper limb, accompanied by slurred speech. He noticed atrophy of his right hand muscles and developed dysarthria seven months after onset. Neurological examination revealed marked fasciculation in his atrophic tongue and diminished bilateral gag reflexes. Muscle strength testing showed moderate weakness in the right limbs. Moreover, the deep tendon reflexes on the right upper limb were brisk, and the bilateral Babinski sign was positive. Sensory disturbance was absent. Brain and spine magnetic resonance imaging (MRI) were unremarkable. Electromyography (EMG) indicated low compound motor action potentials (CMAPs) in the bilateral median, ulnar and peroneal nerves, with normal motor nerve conduction velocities (MCV). Needle examination showed fibrillations, positive sharp waves and widespread polyphasic motor unit potentials in the genioglossus and tested muscles of the upper and lower limbs. Serum paraneoplastic panel examination tested positive for antibodies against Sry-like high mobility group box 1 (SOX1, titer 1:100) and glutamic acid decarboxylase 65 (GAD65, titer 1:32). However, whole-body PET-CT showed no tumors. He received intravenous immunoglobulin (IVIG, 0.4 g/kg/d) for 5 days and riluzole 50 mg twice daily. However, his symptoms did not improve and continued to deteriorate. He died of respiratory failure one year later.
Case 2: A 47-year-old male presented with a 13-month history of muscle weakness in the left lower limb. He had received partial resection of the right kidney due to a right renal clear cell carcinoma 11 months earlier, followed by diffuse muscle twitches and aggravated weakness of the left lower limb. Neurological examination revealed atrophy of the bilateral thenar muscles, diffuse muscles weakness, pathologically brisk limb reflexes and bilaterally positive Babinski signs. EMG showed extensively acute and chronic denervation (fibrillations and positive sharp waves, increased amplitude and duration of motor unit action potentials, and reduced recruitment pattern) in the bulbar, cervical and lumbosacral regions. Brain and spine MRI showed no obvious abnormality. The paraneoplastic antibodies (anti-Hu, -Yo, -Ri, -SOX1, -Titin, -Recoverin, -Ma2/Ta, -Ma1, -CV2, -amphiphysin, -GAD65, -Tr, -Zic4 and -PKCγ antibodies) in both serum and cerebrospinal fluid (CSF) were negative, and CSF analysis showed normal pressure (120 mmH 2 O), 1.00 × 10 6 /L nucleated cells and 536.6 mg/L protein. Subsequently, the patient was treated with 0.4 g/kg/d IVIG for 5 days, a tapering dose of oral prednisolone (initial dose: 60 mg per day) and 50 mg riluzole twice daily. His muscle strength in the upper limbs improved slightly, and his clinical symptoms were stable during one-year follow-up.
Case 3: A 50-year-old male presented with 2 years of progressive lower extremity weakness. He had been diagnosed with chronic myelogenous leukemia 18 months earlier and treated with imatinib 600 mg daily. One year earlier, he had noticed atrophy of the quadriceps femoris. On neurological examination, he had diffuse muscle weakness, amyotrophy and fasciculations in lower limbs, normal tendon reflex and bilaterally positive Babinski sign. EMG showed low CMAPs in all tested nerves of the upper and lower limbs, with normal MCV. Additionally, needle examination revealed spontaneous activity (fibrillations and positive sharp waves) and widespread chronic neurogenic suffering in multiple muscles of four regions (bulbar, cervical, thoracic and lumbar regions). Brain and spine MRI were unremarkable. Routine blood analysis suggested anemia (hemoglobin 98 g/L) and normal counts of red cells, white cells, lymphocytes and blood platelets.

Discussion
Paraneoplastic ALS is a rare and non-classical form of PNS that can present as isolated or combined UMN/LMN syndrome and is challenging to distinguish from idiopathic ALS [7]. This article provides three cases, helping to broaden the understanding and enrich the existing case pool of this rare disorder.
We present the first case of paraneoplastic ALS associated with anti-SOX1 and anti-GAD65 antibodies. It has been indicated in previous reports that antibody against SOX1 is a paraneoplastic high-risk factor antibody that showed more than 70% frequency associated with cancer, and the most commonly associated cancer type with SOX1 is small cell lung cancer [6,22]. Lambert-Eaton myasthenic syndrome is the most frequent PNS found in patients positive for anti-SOX1-antibody [22,23]. Other neurological syndromes associated with anti-SOX1 antibodies have also been reported, including chronic axonal polyneuropathy, paraneoplastic limbic encephalitis and paraneoplastic cerebellar degeneration [22]; however, MND or ALS is being reported for the first time. Anti-GAD65 antibody is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy and paraneoplastic neurological syndrome [24]. It is also linked with tumors, such as small cell lung cancer, breast cancer and thymoma [24]. Although no tumor was found in case 1 during the one-year follow-up, two positive paraneoplastic antibodies indicated the possible diagnosis of paraneoplastic ALS [6]. The patient in case 1 did not had any improvement after IVIG treatment and progressively deteriorated. The effect of the paraneoplastic antibodies in ALS pathogenesis still needs further investigation.
No paraneoplastic antibodies were found in the latter two cases, but tumors were present. Generally, tumor occurrence had a strong temporal correlation with the incidence of ALS symptoms. According to the diagnostic criteria of possible PNS (a non-classical syndrome, no onconeural antibodies and cancer present within two years of diagnosis) [6], we considered these cases possible paraneoplastic ALS. Similar to previous literature reports, these patients benefited from tumor treatment and immunotherapy, and their symptoms progressed slowly.
Literature and the current findings indicate that the onset age of paraneoplastic ALS (definite and possible) ranges from 45 to 80 years, with an average of 61 years. There is no significant difference in gender distribution in paraneoplastic ALS. The most common tumor types are lung, breast, prostate and laryngeal. Notably, bulbar involvement was not frequent in patients with paraneoplastic ALS. For patients with onconeural antibodies, the most represented antibody was anti-Hu, followed by anti-Yo, anti-CV2, anti-Ri and anti-CRMP5. The common clinical manifestations include limb weakness, general fatigue, weight loss, bulbar dysfunction and muscle cramp. A few cases also experienced subacute depression, erectile dysfunction, anorexia and diaphragmatic paralysis. Sixty percent of the paraneoplastic ALS patients could achieve improvement or remained stable soon after cancer treatment and immunotherapy. For the progressively deteriorated patients after cancer treatment, it is hard to distinguish whether the ALS is tumor origin or is just coincidental with co-occurrent tumor. However, it is important to correctly identify ALS patients with paraneoplastic origin, as most of them can improve or at least stabilize following immunotherapy and tumor treatment.
This study reports the first paraneoplastic ALS case with anti-SOX1 and anti-GAD65 antibodies. The case series provides a better understanding of this unique type of ALS. We recommend increased attention to screening tumors and paraneoplastic antibodies in suspected ALS patients. When tumors or paraneoplastic antibodies are detected, then immunotherapy should be considered. Additionally, future studies should prioritize clinical research that explores the correlation between ALS and cancer.  Institutional Review Board Statement: Ethical review and approval were waived for this study, as they are not required for retrospective case studies at the researcher's institution.
Informed Consent Statement: Written informed consent was obtained from the patient to publish this paper.