Unilateral Trigeminal Sensory Neuropathy with Sjögren’s Syndrome with Liver and Renal Impairment
Round 1
Reviewer 1 Report
This is an interesting case of dry eye with trigeminal sensory neuropathy.
Line 62: 329 (106/ μL)
Trigeminal sensory neuropathy was a lack of objective evidence of nerve conduction study or somatosensory evoked potential. How do you confirm it rather than facial pain syndrome?
The diagnosis of primary biliary cirrhosis was related to Sjogren's syndrome, how to be confirmed?
The patient had anemia, abnormal liver function test. Metabolic impairment also can cause sensory neuropathy. Does it be confirmed higher lymphocyte or T-cell?
Author Response
We would like to thank the reviewers for their thorough and helpful comments. We have addressed all the reviewer’s comments and we believe these changes have improved the manuscript quality.
Line 62: 329 (106/ μL)
Trigeminal sensory neuropathy was a lack of objective evidence of nerve conduction study or somatosensory evoked potential. How do you confirm it rather than facial pain syndrome?
The following text has been included to address your concern: “It has been reported that hyperalgesia, allodynia, hypoesthesia, and hypoalgesia in the orofacial region precede Sjogren’s syndrome [8]. Somatosensory features might indicate clinically painful (gain of function; hyperalgesia, allodynia) or not painful (loss of function; hypoesthesia) signs of trigeminal nerve dysfunction. However, the results of a quantitative sensory tests (QST) protocol for the assessment of trigeminal sensory neuropathy due to Sjögren’s syndrome have not been reported to date. Here, we report a rare case of Sjögren’s syndrome in a patient presenting with unilateral trigeminal sensory neuropathy and primary bile cirrhosis.”
The diagnosis of primary biliary cirrhosis was related to Sjogren's syndrome, how to be confirmed?
She was diagnosed with primary biliary cirrhosis based on a liver biopsy and positive antimitochondrial antibody 20 years prior. At the same time, further laboratory tests showed positive anti-SSA and anti-SSB antibodies and a minor salivary gland biopsy resulted in a diagnosis of secondary Sjögren’s syndrome
The patient had anemia, abnormal liver function test. Metabolic impairment also can cause sensory neuropathy. Does it be confirmed higher lymphocyte or T-cell?
We added the following laboratory data but unfortunately did not order T-cell testing:
Lymp (20%), MCV (91.0 u3), MCH(31.3 pg), MCHC (34.4%).
From this result, we ruled out trigeminal sensory neuropathy due to megaloblastic anemia.
Reviewer 2 Report
My comments follow, in order of appearance not necessarily importance.
P1, L 28. “Initially, the cause of neuropathy was thought to be mainly vasculitis;” I agree but for completeness, do the authors have a citation for the statement?
P1, L 35 Because one of the interesting aspects of this case is the unilateral presentation of the trigeminal involvement, it seems worth emphasizing whether cranial nerve involvement is typically bilateral in patients with Sjogren’s syndrome.
P2, L 45. Dry “eye” or dry “eyes”? It seems unlikely that she would be experiencing a unilateral dry eye.
P2, L 49 Was the diagnosis of secondary Sjogren’s syndrome made 20 years ago or more recently? (I see in reading further in the discussion that the diagnosis of Sjogren’s was made 20 years ago. This should be clarified initially.)
P2, L 49 How long had the patient been treated with prednisone 10 mg daily? 20 years?
P3 L 72 The imaging results suggest that the left infraorbital nerve was not compressed, but Figure 2 draws attention to a soft tissue density identified by the yellow arrow. In the Figure, the caption is nonsensical: “CT x-ray showed mass were not observed.” The mass is presumably identified by the yellow arrow but the caption states “C indicates soft tissue density.” This is confusing. I assume that the final determination was that the soft tissue mass was not relevant to the clinical findings. Is this correct? This clearly needs clarification.
P3 L 76 Quantitative sensory testing (QST) is of interest but somewhat excessive for most clinicians. The presentation here is a mixture of methods (2.2 QST) and results (2.3 Z-score), representing a very confusing format that differs from other portions of the manuscript. Further confusing is the description of the results indicating that the pressure pain threshold (PPT) represented a gain of function without further explanation. Visual examination of Figure 3 suggests that only the mechanical detection threshold is substantially decreased, with a minor change in the PPT. Table 1 is similarly confusing. The purpose of data presentation is to simplify the interpretation of results, something the authors have not accomplished.
P4 L 117 This paragraph includes the evaluation of the patient’s pain using a questionnaire that assesses pain-related limitations of daily function in patients with temporomandibular disorders. This is confusing because the patient is described to have facial and mucosal numbness but no mention of pain in the clinical presentation. The results include scores for various categories that will be meaningless to most readers (sensory, affective, evaluative, and miscellaneous), with a total pain rating index score of 7/78, equally meaningless. My interpretation is that the only scores contributing to the total score were “sensory = 5” and “miscellaneous = 2,” presumably indicating that this patient does not have pain, something that seemingly was clear from the onset.
P4 L124 In my experience, the sensory neuropathy of Sjogren’s syndrome is characterized by numbness and sometimes annoying tingling paresthesias, but it is not particularly painful, at least in the context of a painful small fiber neuropathy. Patients with Sjogren’s experience joint and muscle pain, and sometimes discomfort from swollen salivary glands or mucosal changes associated with dryness. If this patient was experiencing oral pain, the authors need to describe it in the case presentation. Discussing the results of seemingly irrelevant tests as little to the case report
P4 L133 The description of pain is further confused by their description of trigeminal sensory neuropathy, characterizing it as presenting with slowly progressive unilateral or bilateral facial numbness or paresthesia and “occasionally associated with pain.”
P4 L138 I agree that this patient would be considered rare because sensory impairment appeared in the unilateral face 20 years after the diagnosis of Sjogren’s syndrome. I guess the question is this: Was the facial numbness truly a manifestation of Sjogren’s or is there an unrelated second much gradually since 2 million does pretty good explanation associated with the unexplained soft tissue mass?
P4 L 140 I agree that the results of the somatosensory testing will be of interest to those who perform the studies. However, I do not see that it adds much to this clinical presentation.
P4 L 152 The discussion of the neuropathology of Sjogren’s ganglionitis is accurate.
P5 L 157 The discussion of neural sensory testing of orofacial pain is confusing because there is no indication that this patient had orofacial pain. The reader is left with the impression that the authors have a substantial interest in QST, and this case is being used to highlight that interest, despite it being an imperfect fit. The conclusion that a “simple sensory test should be performed during regular checkups of suspected patients” seems reasonable. However, I am confident that the probability of identifying clinical sensory loss due to a trigeminal sensory neuronopathy in an asymptomatic patient is highly unlikely.
P5 L182 The concluding sentence, “Furthermore, sensory testing of the trigeminal or spinal cord is important for differentiating disease affecting the PNS and CNS” is somewhat nonsensical and out of context.
Author Response
We would like to thank the reviewers for their thorough and helpful comments. We have addressed all the reviewer’s comments and we believe these changes have improved the manuscript quality.
P1, L 28. “Initially, the cause of neuropathy was thought to be mainly vasculitis;” I agree but for completeness, do the authors have a citation for the statement?
We have cited this statement as follows.
“Initially, the cause of neuropathy was thought to be mainly vasculitis [2];”
[2] Alexander, E.L.; Provost, T.T.; Stevens, M.B.; Alexander, G.E. Neurologic complications of primary Sjogren's syndrome. Medicine (Baltimore). 1982, 61: 247–257.
P1, L 35 Because one of the interesting aspects of this case is the unilateral presentation of the trigeminal involvement, it seems worth emphasizing whether cranial nerve involvement is typically bilateral in patients with Sjogren’s syndrome.
We added the following statement to address this.
In general, cranial nerve involvement is typically bilateral in patients with Sjogren’s syndrome.
P2, L 45. Dry “eye” or dry “eyes”? It seems unlikely that she would be experiencing a unilateral dry eye.
We changed dry eye to dry eyes.
P2, L 49 Was the diagnosis of secondary Sjogren’s syndrome made 20 years ago or more recently? (I see in reading further in the discussion that the diagnosis of Sjogren’s was made 20 years ago. This should be clarified initially.)
She was diagnosed with primary biliary cirrhosis based on a liver biopsy and positive antimitochondrial antibody 20 years prior. At the same time, further laboratory tests showed positive anti-SSA and anti-SSB antibodies and a minor salivary gland biopsy resulted in a diagnosis of secondary Sjögren’s syndrome.
P2, L 49 How long had the patient been treated with prednisone 10 mg daily? 20 years?
The patient had been treated with prednisone (10 mg) orally daily for a few years, after that ursodeoxycholic acid was administered to treat her primary biliary cirrhosis.
P3 L 72 The imaging results suggest that the left infraorbital nerve was not compressed, but Figure 2 draws attention to a soft tissue density identified by the yellow arrow. In the Figure, the caption is nonsensical: “CT x-ray showed mass were not observed.” The mass is presumably identified by the yellow arrow but the caption states “C indicates soft tissue density.” This is confusing. I assume that the final determination was that the soft tissue mass was not relevant to the clinical findings. Is this correct? This clearly needs clarification.
We clarified this, and added the following statement.
CT X-ray showing that masses were not observed in the left maxillary sinus (a, b, and c). b indicates soft tissue density. A sagittal section (d; yellow arrow) shows an apical periodontitis-like image at the maxillary left first molar, suggesting that it was not relevant to the clinical findings.
P3 L 76 Quantitative sensory testing (QST) is of interest but somewhat excessive for most clinicians. The presentation here is a mixture of methods (2.2 QST) and results (2.3 Z-score), representing a very confusing format that differs from other portions of the manuscript.
The QST protocol of the German Research Network on Neuropathic Pain was performed [3]. Abnormal patient QST parameters showed thermal sensory limen (TSL = 32.6 ℃), cold pain threshold (CPT = 0 ℃), mechanical pain threshold (MDT = 1.63 g), and pressure pain threshold (PPT = 1.2 kPa). Of these, TSL, CPT, MDT, and PPT at the trigeminal region indicated a loss of function. In contrast, all parameters were within the normal limits in the forearm.
Further confusing is the description of the results indicating that the pressure pain threshold (PPT) represented a gain of function without further explanation. Visual examination of Figure 3 suggests that only the mechanical detection threshold is substantially decreased, with a minor change in the PPT. Table 1 is similarly confusing. The purpose of data presentation is to simplify the interpretation of results, something the authors have not accomplished.
QST data showed both PPT in the control and patient as follows: pressure pain threshold in control (PPT = 0.4±0.3 kPa); pressure pain threshold in the patient (PPT = 1.2 kPa).
Obviously, the PPT in the patient was higher than that in controls.
Therefore, we recalculated the Z-score, which resulted in a loss of function (PPT= −3.30).
P4 L 117 This paragraph includes the evaluation of the patient’s pain using a questionnaire that assesses pain-related limitations of daily function in patients with temporomandibular disorders. This is confusing because the patient is described to have facial and mucosal numbness but no mention of pain in the clinical presentation. The results include scores for various categories that will be meaningless to most readers (sensory, affective, evaluative, and miscellaneous), with a total pain rating index score of 7/78, equally meaningless. My interpretation is that the only scores contributing to the total score were “sensory = 5” and “miscellaneous = 2,” presumably indicating that this patient does not have pain, something that seemingly was clear from the onset.
P4 L124 In my experience, the sensory neuropathy of Sjogren’s syndrome is characterized by numbness and sometimes annoying tingling paresthesias, but it is not particularly painful, at least in the context of a painful small fiber neuropathy. Patients with Sjogren’s experience joint and muscle pain, and sometimes discomfort from swollen salivary glands or mucosal changes associated with dryness. If this patient was experiencing oral pain, the authors need to describe it in the case presentation. Discussing the results of seemingly irrelevant tests as little to the case report
As the reviewer suggested, the patient absolutely complained of numbness but not pain. An assessment of psychophysical quality of pain using the JMPQ would be unclear to the readers. Thus, we removed this part and information relevant to the JMPQ.
P4 L133 The description of pain is further confused by their description of trigeminal sensory neuropathy, characterizing it as presenting with slowly progressive unilateral or bilateral facial numbness or paresthesia and “occasionally associated with pain.”
We mentioned this earlier; since this patient did not have pain, we corrected this as follows.
“Trigeminal sensory neuropathy is characterized by slowly progressing bilateral facial numbness and occasionally paresthesia”
P4 L138 I agree that this patient would be considered rare because sensory impairment appeared in the unilateral face 20 years after the diagnosis of Sjogren’s syndrome. I guess the question is this: Was the facial numbness truly a manifestation of Sjogren’s or is there an unrelated second much gradually since 2 million does pretty good explanation associated with the unexplained soft tissue mass?
From the perspective of facial numbness, differential diagnoses include herpes zoster, HIV infection, osteomyelitis, neurological diseases such as multiple sclerosis, malignant lymphoma, cerebral infarction, space-occupying lesions (acoustic nerve tumors, epithelioma), jawbone tumors, megaloblastic anemia, and metastatic tumors. Neurologists ruled out central nervous neuropathy using MRI and other methods, and we ruled out peripheral nerve neuropathy. The diagnosis of possible unilateral trigeminal sensory neuropathy with Sjögren’s syndrome and primary biliary cirrhosis was made.
However, it is undeniable that Sjogren’s syndrome and numbness might occur independently, and thus, the title was modified as follows.
“A possible case of unilateral trigeminal sensory neuropathy with Sjögren's syndrome and primary biliary cirrhosis”
P4 L 140 I agree that the results of the somatosensory testing will be of interest to those who perform the studies. However, I do not see that it adds much to this clinical presentation.
We changed the Z score to absolute data, which might be of more interest to readers.
Patients with Sjögren’s syndrome and primary biliary cirrhosis showed an extensive increase in the MDT (1.63 g), TSL (32.6 ℃), CPT (0 ℃), and PPT (1.2 kPa) on the affected side.
P4 L 152 The discussion of the neuropathology of Sjogren’s ganglionitis is accurate.
P5 L 157 The discussion of neural sensory testing of orofacial pain is confusing because there is no indication that this patient had orofacial pain. The reader is left with the impression that the authors have a substantial interest in QST, and this case is being used to highlight that interest, despite it being an imperfect fit. The conclusion that a “simple sensory test should be performed during regular checkups of suspected patients” seems reasonable. However, I am confident that the probability of identifying clinical sensory loss due to a trigeminal sensory neuronopathy in an asymptomatic patient is highly unlikely.
We added the following sentences to address this:
simple sensory testing might be helpful in identifying trigeminal neuropathy during regular checkups of suspected patients, especially when complaining of abnormal sensation.
In the previous discussion, we removed neural sensory testing of orofacial pain and the relationship between the MPQ and QST.
Regarding neurosensory testing of orofacial pain, Svensson et al. developed a rapid and simple chairside protocol that can be used by general primary providers [15]. In this study, the most prominent abnormal findings were MDT, CPT, and TSL (including heat pain threshold); therefore, these should be tested. These tests can be performed as follows. In the spatula thermal test, a metal spatula is cooled in a refrigerator to 5 ºC, heated in a water bath to 40 ºC, and then applied to the affected area and contralateral unaffected area to test for sensitivity to cold and hot stimuli. For the cotton swab test, light pressure can be applied to the affected area and contralateral unaffected area with a cotton swab to test for sensitivity to low-intensity, non-painful mechanical stimuli. As observed in our case, trigeminal sensory impairment might develop after the diagnosis of Sjögren’s syndrome; therefore, it is important for the primary care provider to perform a simple sensory test. Moreover, performing a QST on both the face and forearm can distinguish between disorders of the peripheral nervous systems (PNS)and central nervous systems (CNS).
The MPQ and QST can be used to evaluate different functions of the peripheral and central nervous systems [16]. QST measures the function of the peripheral nervous system and part of the central nervous system. In contrast, the MPQ reflects psycho-physical functions, including memory, affect, and cognition. The sensory category showed the highest score in our patient. Her category scores were sensory (5/42), affective (0/14), evaluative (0/5), and miscellaneous (2/17). Based on the QST and her sub-ective symptoms, the JMPQ sensory or miscellaneous symptoms (including terms such as cool and cold) and QST results (MDT or CPT) might be related.
P5 L182 The concluding sentence, “Furthermore, sensory testing of the trigeminal or spinal cord is important for differentiating disease affecting the PNS and CNS” is somewhat nonsensical and out of context.
As the reviewer suggested, the sentence “Furthermore, sensory testing of the trigeminal or spinal cord is important for differentiating disease affecting the PNS and CNS” is wrong. MRI might be important for differentiating diseases affecting the PNS and CNS. Thus, we removed this sentence.
Round 2
Reviewer 1 Report
This study is a lack of confirming study about TN. Primary biliary cirrhosis was diagnosed 20 years ago.
Line 51 ASL:51 means AST? eGFR:49 was meant sicca syndrome induced renal impairment?
Liver and renal impairment seem to be better for the title.
Author Response
We would like to thank the reviewers for their thorough and helpful comments. We have addressed responses to all the reviewer’s comments and we believe these changes have improved the manuscript quality.
This study is a lack of confirming study about TN. Primary biliary cirrhosis was diagnosed 20 years ago.
Based on QST testing, thermal and mechanical QST showed elevations of TSL, CPT, MDT, and PPT, and hypoalgesia was marked, suggesting not painful trigeminal neuropathy. The diagnosis of possible unilateral trigeminal sensory neuropathy with Sjögren’s syndrome was made.
Line 51 ASL:51 means AST? eGFR:49 was meant sicca syndrome induced renal impairment?
Liver and renal impairment seem to be better for the title.
The title was modified as follows.
Unilateral trigeminal sensory neuropathy with Sjögren’s syndrome with liver and renal impairment
Abstract
Liver and renal involvement is a rare event during Sjögren’s syndrome. Sjögren’s syndrome is characterized by the progressive immune-mediated destruction of epithelial tissues of the salivary and lacrimal glands.
Discussion
The exact frequency of Sjögren’s syndrome and renal impairment is unclear, but kidney disease occurs in 5% of patients with primary Sjögren’s syndrome [14]. There are many patterns of tubular interstitial nephritis. In addition, it also causes renal tub-ular acidosis, resulting in a decrease in the urinary concentration. Symptoms vary from asymptomatic to electrolyte imbalances, kidney stones, renal insufficiency, and nephrotic syndrome. In our case, renal panel function testing showed an eGFR of 49, but the patient was asymptomatic.
Conclusion
We experienced a rare case of Sjögren's syndrome with liver and renal involvement.
Reviewer 2 Report
No additional suggestions
Author Response
We would like to thank the reviewers for their thorough and helpful comments.
