Trigeminal sensory neuropathy associated with connective tissue diseases Neil A. Hagen, MD; J. Clarke Stevens, MD; and Clement J. Michet, Jr., MD
Article abstract-We reviewed the clinical and laboratory features of 81 patients who had trigeminal sensory neuropathy (TSN) and a connective tissue disease (CTD). The neuropathy developed before the symptoms of CTD in 6/81 patients (7%),and in 38/81 patients (47%)TSN and CTD were diagnosed concurrently. The most frequently associated CTDs were undifferentiated connective tissue disease (38/81,47%),mixed connective tissue disease (21/81,26%),and scleroderma (15/81,19%).Of 66 patients followed for more than 1year (median, 5 years; range, 1to 26 years), 8/66 patients (12%)had mild improvement and 2/66 (3%)had marked improvement of numbness; no patient had complete return of sensation. The facial numbness was frequently associated with moderate to severe facial pain that was usually resistant to pharmacologic therapy. None of the patients developed clinical or laboratory evidence of systemic vasculitis. The etiology of this cranial sensory neuropathy remains obscure. NEUROLOGY 1990;40:891-896
The occurrence of a trigeminal sensory neuropathy (TSN) in association with a connective tissue disease (CTD) is rare. Cases have been reported in patients with ~cleroderma,'-~ Sjogren's syndrome,8sg mixed connective tissue disease (MCTD),lo-I4systemic lupus erythematosus (SLE),15rheumatoid arthritis (RA),16and dermatomyositis (DM).Io In this retrospective study we report a series of patients with TSN and CTD in order t o (1) determine the spectrum of clinical manifestations and ultimate prognosis of the neuropathy; (2) document response to treatment; and (3) delineate the nature of associated
CTDs. Methods. Patients with a CTD and facial numbness assessed at the Mayo Clinic from 1970 to 1986 were identified by computer search using the facilities of the Mayo Epidemiology Program Project. Categories searched included records coded for trigeminal neuropathy, trigeminal neuritis, or facial numbness from patients who also had scleroderma, polymyositis, DM, Sjogren's syndrome, RA, SLE, MCTD, or undifferentiated connective tissue disease (UD-CTD). In addition, cases collected by the authors before 1970 were added. Criteria for entry of patients into the study included (1)history and physical examination findings consistent with trigeminal neuropathy, and (2) clinical diagnosis of a diffuse CTD syndrome. When American Rheumatism Association (ARA) classification criteria were present, they were used. Cases were excluded if numbness of the face could have been due to another condition. Patients were excluded if they had evidence of active systemic vasculitis at the time of onset of
TSN (1 patient), but they were not excluded if vasculitis developedsubsequently (no patients). Systemic vasculitis was defined by histopathologic evidence from biopsy material. Information was abstracted on a specificallydesigned form for computer analysis. Ninety-four patients with TSN and a CTD were identified. Of these, 13 patients had facial numbness and a CTD but were rejected. Eight patients had evidence of conditions that could account for the facial numbness, including cerebrovasculardisease (2), cerebral metastasis (I), syrinx (l), postoperative changes (I), trauma (I), drug-associated vasculitis (l), and advanced peripheral neuropathy (1); 5 additional patients had incomplete medical records. Eighty-one patients were entered into the study. At the time of the chart review, 10 patients had died or were lost to follow-up, and 3 had been examined within the previous 12 months. The remaining 68 patients were sent a letter requesting permission for a telephone interview. The format for the letter and telephone survey was approved by the Institutional Review Board. Thirty-six patients indicated willingness to participate. Duration of follow-up was defined as the interval between the onset of TSN symptoms and the most recent date of contact (clinic visit or telephone survey).
Results. There were 67 women and 14 men who had a TSN and an associated CTD (table 1). The neuropathy preceded symptoms of the CTD in 16/81 patients, but never by more than 30 months and usually by less than 12 months. Onset of symptoms of CTD was within 1 month of onset of neuropathy in 9 patients. CTD symptoms preceded neuropathy by less than 1 year i n 17
From the Department of Neurology (Drs. Hagen and Stevens) and the Division of Rheumatology and Internal Medicine (Dr. Michet), Mayo Clinic and Mayo Foundation, Rochester, MN. Presented in part at the 40th annual meeting of the American Academy of Neurology, Cincinnati, OH, April 1988. Received February 6, 1989. Accepted for publication in final form November 14,1989. Address correspondence and reprint requests to Dr. Clement J. Michet, Division of Rheumatology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
June 1990 NEUROLOGY 40 891
Table 1. Demographics in 81 patients
Table 3. Clinical characteristics Patients
Characteristic
Sex
67 women; 14 men Median, 51 yrs
Age
Objective sensory loss Weakness of V muscles Other cranial nerve involvement
(range, 25-74) Onset of neuropathy (no. pts) Neuropathy preceded CTD Diagnoses made concurrently Diagnoses more than 5 yrs apart Time to maximal numbness (mo) Range 4mo >5 yrs
6 38 5
VII
6-24 7Ph 2Ph
Table 2. Symptoms Patients
No.
Symptom Numbness Initially unilateral Unilateral V2 Eventually bilateral Eventual oropharynx involvement Other symptoms Pain Paresthesias Altered taste Lost food or pills in mouth Slurred speech Raynaud’s of the tongue
%
64 30
79
Sensory IX Motor IX Nasal septa1 perforation Myopathy Definite Possible EMG findings only Median nerve entrapment a t the wrist (carpal tunnel syndrome) Other neuropathy Peripheral neuropathy Mononeuritis multiplex Focal neuropathy EMG findings without clinical accompaniment
70 66 2 7
82 2
2 31
2 38
20
25
12
15
9
3 3 1
17 10 4
5 0 2 5
37% 48 71
59 88
49 45 38 25 18 2
60 56 47 31 22 2
patients, by 1to 5 years in 23 patients, and by more than 5 years in 13patients. In 2 patients the CTD symptoms preceded the onset of TSN by more than 30 years. At time of onset of neuropathy, CTD activity and severity were judged to be only mild to moderate in the majority of patients based on clinical and laboratory features. Hence, the onset of distressing symptoms of TSN often led to the additional diagnosis of preexistent CTD; in 38 (47%) patients, the diagnoses of TSN and CTD were made concurrently. The mode of onset of the neuropathy was described as gradual in 61 patients (symptoms noticed over 2 to 4 weeks), subacute in 1(more than 7 to 14 days), acute in 16 (less than 7 days), and unknown in 3. The face was initially affected unilaterally in the distribution of the maxillary division in 30/81 cases, although it sometimes began bilaterally (16 cases), or in only the distribution of the mandibular division (12 cases) (table 2). The area subserved by the ophthalmic division was involved initially in 6 cases, and as the disease progressed it was frequently involved to a lesser degree than other areas of the face. Oropharyngeal involvement was both early and prominent. The time to maximal distribution and severity of numbness from the onset of TSN ranged from less than 1month (7 patients) to more than 5 years (2 patients); most patients had maximal numbness within 6 to 24 months of onset. Usually, numbness progressed steadily 892 NEUROLOGY 40 June 1990
No.
Characteristic
or haltingly until the condition arrested. Eventually, 54/81 patients (67%) had bilateral numbness, which was asymmetrical in 34/81 cases (42%). Forty-nine patients complained of pain, usually burning or lancinating in quality; however, no patient had symptoms consistent with classical trigeminal neuralgia. Forty-five patients complained of paresthesias, often having an unpleasant quality. The distress from pain and numbness was graded as minimal or none in 17, mild in 18,moderate in 33, and severe in 13. Twentysix patients noted they would unknowingly bite their tongue, and 25 would find pills or food in their mouths long after having finished eating. Three patients had ulcers of the inside of the mouth, presumably because of unwitting dental trauma. T h r e e p a t i e n t s had Raynaud’s phenomenon of the tongue and lips. Eighteen patients complained of slurred speech, usually ascribing it to loss of sensation of the oropharynx and lips. Half of the patients complained of altered or absent taste, but whenever they were formally tested, primary gustatory sensibility was always present. There was a family history of peripheral neuropathy in 1 patient and of migraine in 5. Two patients had a remote history of seizures, 1of remote cerebrovascular accident, and 1of essential tremor. On neurologic examination, 81% (66 patients) had objective evidence of sensory loss (table 3). Sensory changes involved both pain and light touch sensation and, when tested, 2-point discrimination. A few patients had impaired temperature sensation. Numbness remained largely confined to the perioral distribution in 17% (14 patients); all other cases had prominent involvement of both labio-oral and cheek areas, or only the cheeks. In no case did the distribution of facial numbness remain confined to the entire distribution of a single trigeminal nerve division. Two patients (2%) had weakness of muscles of mastication. Fourteen patients (17%) had reduced or absent corneal reflexes.
Table 4. Clinical manifestations of the associated connective tissue diseases
Table 5. Abnormal laboratory tests observed Patients
Patients ( n Clinical m a n i f e s t a t i o n s Raynaud’s phenomenon Inflammatory arthritis* Sclerodact yly Esophageal dysmotilityt Proximal scleroderma Telangiectasias Finger pad changes Pulmonary fibrosis or restrictive lung disease+ Sicca syndrome Photosensitivity Butterfly rash Serositis Discoid lupus Cutaneous vasculitis
=
81)
No.
%
64 41 36 31 24 22 17 17
79 51 44 38 30 27 21 21
12 5 5 5 4 3
15 6 6 6 5
4
Finding Erythrocyte sedimentation rate 1 2 0 mm in 1 hr Hematologic disorder* LE cells False-positive VDRL Positive antinuclear antibody Extractable nuclear antigen antibodies Anti-RNP antibody Anti-SSA antibody Anti-SSB antibody Anti-DNA antibody Anti-Sm antibody
No.
%
63/80
79
21/62 4/45 1/60 68/74
34 9 2 92
28/42 318 1/30 11/44 3/41
67 38 3 25
7
* Hemolytic anemia, leukopenia (leukocytes
Article abstract-We reviewed the clinical and laboratory features of 81 patients who had trigeminal sensory neuropathy (TSN) and a connective tissue disease (CTD). The neuropathy developed before the symptoms of CTD in 6/81 patients (7%),and in 38/81 patients (47%)TSN and CTD were diagnosed concurrently. The most frequently associated CTDs were undifferentiated connective tissue disease (38/81,47%),mixed connective tissue disease (21/81,26%),and scleroderma (15/81,19%).Of 66 patients followed for more than 1year (median, 5 years; range, 1to 26 years), 8/66 patients (12%)had mild improvement and 2/66 (3%)had marked improvement of numbness; no patient had complete return of sensation. The facial numbness was frequently associated with moderate to severe facial pain that was usually resistant to pharmacologic therapy. None of the patients developed clinical or laboratory evidence of systemic vasculitis. The etiology of this cranial sensory neuropathy remains obscure. NEUROLOGY 1990;40:891-896
The occurrence of a trigeminal sensory neuropathy (TSN) in association with a connective tissue disease (CTD) is rare. Cases have been reported in patients with ~cleroderma,'-~ Sjogren's syndrome,8sg mixed connective tissue disease (MCTD),lo-I4systemic lupus erythematosus (SLE),15rheumatoid arthritis (RA),16and dermatomyositis (DM).Io In this retrospective study we report a series of patients with TSN and CTD in order t o (1) determine the spectrum of clinical manifestations and ultimate prognosis of the neuropathy; (2) document response to treatment; and (3) delineate the nature of associated
CTDs. Methods. Patients with a CTD and facial numbness assessed at the Mayo Clinic from 1970 to 1986 were identified by computer search using the facilities of the Mayo Epidemiology Program Project. Categories searched included records coded for trigeminal neuropathy, trigeminal neuritis, or facial numbness from patients who also had scleroderma, polymyositis, DM, Sjogren's syndrome, RA, SLE, MCTD, or undifferentiated connective tissue disease (UD-CTD). In addition, cases collected by the authors before 1970 were added. Criteria for entry of patients into the study included (1)history and physical examination findings consistent with trigeminal neuropathy, and (2) clinical diagnosis of a diffuse CTD syndrome. When American Rheumatism Association (ARA) classification criteria were present, they were used. Cases were excluded if numbness of the face could have been due to another condition. Patients were excluded if they had evidence of active systemic vasculitis at the time of onset of
TSN (1 patient), but they were not excluded if vasculitis developedsubsequently (no patients). Systemic vasculitis was defined by histopathologic evidence from biopsy material. Information was abstracted on a specificallydesigned form for computer analysis. Ninety-four patients with TSN and a CTD were identified. Of these, 13 patients had facial numbness and a CTD but were rejected. Eight patients had evidence of conditions that could account for the facial numbness, including cerebrovasculardisease (2), cerebral metastasis (I), syrinx (l), postoperative changes (I), trauma (I), drug-associated vasculitis (l), and advanced peripheral neuropathy (1); 5 additional patients had incomplete medical records. Eighty-one patients were entered into the study. At the time of the chart review, 10 patients had died or were lost to follow-up, and 3 had been examined within the previous 12 months. The remaining 68 patients were sent a letter requesting permission for a telephone interview. The format for the letter and telephone survey was approved by the Institutional Review Board. Thirty-six patients indicated willingness to participate. Duration of follow-up was defined as the interval between the onset of TSN symptoms and the most recent date of contact (clinic visit or telephone survey).
Results. There were 67 women and 14 men who had a TSN and an associated CTD (table 1). The neuropathy preceded symptoms of the CTD in 16/81 patients, but never by more than 30 months and usually by less than 12 months. Onset of symptoms of CTD was within 1 month of onset of neuropathy in 9 patients. CTD symptoms preceded neuropathy by less than 1 year i n 17
From the Department of Neurology (Drs. Hagen and Stevens) and the Division of Rheumatology and Internal Medicine (Dr. Michet), Mayo Clinic and Mayo Foundation, Rochester, MN. Presented in part at the 40th annual meeting of the American Academy of Neurology, Cincinnati, OH, April 1988. Received February 6, 1989. Accepted for publication in final form November 14,1989. Address correspondence and reprint requests to Dr. Clement J. Michet, Division of Rheumatology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
June 1990 NEUROLOGY 40 891
Table 1. Demographics in 81 patients
Table 3. Clinical characteristics Patients
Characteristic
Sex
67 women; 14 men Median, 51 yrs
Age
Objective sensory loss Weakness of V muscles Other cranial nerve involvement
(range, 25-74) Onset of neuropathy (no. pts) Neuropathy preceded CTD Diagnoses made concurrently Diagnoses more than 5 yrs apart Time to maximal numbness (mo) Range 4mo >5 yrs
6 38 5
VII
6-24 7Ph 2Ph
Table 2. Symptoms Patients
No.
Symptom Numbness Initially unilateral Unilateral V2 Eventually bilateral Eventual oropharynx involvement Other symptoms Pain Paresthesias Altered taste Lost food or pills in mouth Slurred speech Raynaud’s of the tongue
%
64 30
79
Sensory IX Motor IX Nasal septa1 perforation Myopathy Definite Possible EMG findings only Median nerve entrapment a t the wrist (carpal tunnel syndrome) Other neuropathy Peripheral neuropathy Mononeuritis multiplex Focal neuropathy EMG findings without clinical accompaniment
70 66 2 7
82 2
2 31
2 38
20
25
12
15
9
3 3 1
17 10 4
5 0 2 5
37% 48 71
59 88
49 45 38 25 18 2
60 56 47 31 22 2
patients, by 1to 5 years in 23 patients, and by more than 5 years in 13patients. In 2 patients the CTD symptoms preceded the onset of TSN by more than 30 years. At time of onset of neuropathy, CTD activity and severity were judged to be only mild to moderate in the majority of patients based on clinical and laboratory features. Hence, the onset of distressing symptoms of TSN often led to the additional diagnosis of preexistent CTD; in 38 (47%) patients, the diagnoses of TSN and CTD were made concurrently. The mode of onset of the neuropathy was described as gradual in 61 patients (symptoms noticed over 2 to 4 weeks), subacute in 1(more than 7 to 14 days), acute in 16 (less than 7 days), and unknown in 3. The face was initially affected unilaterally in the distribution of the maxillary division in 30/81 cases, although it sometimes began bilaterally (16 cases), or in only the distribution of the mandibular division (12 cases) (table 2). The area subserved by the ophthalmic division was involved initially in 6 cases, and as the disease progressed it was frequently involved to a lesser degree than other areas of the face. Oropharyngeal involvement was both early and prominent. The time to maximal distribution and severity of numbness from the onset of TSN ranged from less than 1month (7 patients) to more than 5 years (2 patients); most patients had maximal numbness within 6 to 24 months of onset. Usually, numbness progressed steadily 892 NEUROLOGY 40 June 1990
No.
Characteristic
or haltingly until the condition arrested. Eventually, 54/81 patients (67%) had bilateral numbness, which was asymmetrical in 34/81 cases (42%). Forty-nine patients complained of pain, usually burning or lancinating in quality; however, no patient had symptoms consistent with classical trigeminal neuralgia. Forty-five patients complained of paresthesias, often having an unpleasant quality. The distress from pain and numbness was graded as minimal or none in 17, mild in 18,moderate in 33, and severe in 13. Twentysix patients noted they would unknowingly bite their tongue, and 25 would find pills or food in their mouths long after having finished eating. Three patients had ulcers of the inside of the mouth, presumably because of unwitting dental trauma. T h r e e p a t i e n t s had Raynaud’s phenomenon of the tongue and lips. Eighteen patients complained of slurred speech, usually ascribing it to loss of sensation of the oropharynx and lips. Half of the patients complained of altered or absent taste, but whenever they were formally tested, primary gustatory sensibility was always present. There was a family history of peripheral neuropathy in 1 patient and of migraine in 5. Two patients had a remote history of seizures, 1of remote cerebrovascular accident, and 1of essential tremor. On neurologic examination, 81% (66 patients) had objective evidence of sensory loss (table 3). Sensory changes involved both pain and light touch sensation and, when tested, 2-point discrimination. A few patients had impaired temperature sensation. Numbness remained largely confined to the perioral distribution in 17% (14 patients); all other cases had prominent involvement of both labio-oral and cheek areas, or only the cheeks. In no case did the distribution of facial numbness remain confined to the entire distribution of a single trigeminal nerve division. Two patients (2%) had weakness of muscles of mastication. Fourteen patients (17%) had reduced or absent corneal reflexes.
Table 4. Clinical manifestations of the associated connective tissue diseases
Table 5. Abnormal laboratory tests observed Patients
Patients ( n Clinical m a n i f e s t a t i o n s Raynaud’s phenomenon Inflammatory arthritis* Sclerodact yly Esophageal dysmotilityt Proximal scleroderma Telangiectasias Finger pad changes Pulmonary fibrosis or restrictive lung disease+ Sicca syndrome Photosensitivity Butterfly rash Serositis Discoid lupus Cutaneous vasculitis
=
81)
No.
%
64 41 36 31 24 22 17 17
79 51 44 38 30 27 21 21
12 5 5 5 4 3
15 6 6 6 5
4
Finding Erythrocyte sedimentation rate 1 2 0 mm in 1 hr Hematologic disorder* LE cells False-positive VDRL Positive antinuclear antibody Extractable nuclear antigen antibodies Anti-RNP antibody Anti-SSA antibody Anti-SSB antibody Anti-DNA antibody Anti-Sm antibody
No.
%
63/80
79
21/62 4/45 1/60 68/74
34 9 2 92
28/42 318 1/30 11/44 3/41
67 38 3 25
7
* Hemolytic anemia, leukopenia (leukocytes
