NEUROLOGICAL RARITIES
Recognising facial onset sensory motor neuronopathy syndrome: insight from six new cases R Broad, P N Leigh
Neurology Department, Brighton and Sussex medical School, Trafford Centre for Medical Research, University of Sussex, Brighton, East Sussex, UK Correspondence to Dr Rebecca Broad, Department of Neurology, Brighton and Sussex Medical School, Trafford Centre for Medical Research, University of Sussex, Brighton BN1 9RY, UK; [email protected] Received 12 September 2014 Revised 21 March 2015 Accepted 22 April 2015
To cite: Broad R, Leigh PN. Pract Neurol Published Online First: [ please include Day Month Year] doi:10.1136/ practneurol-2014-000984
ABSTRACT Facial onset sensory and motor neuronopathy (FOSMN) was first described in 2006 as an apparently sporadic neurodegenerative disease. Thirty cases have been reported to date. We summarise six new cases, highlighting the key clinical aspects of FOSMN and how to differentiate it from motor neurone disease (amyotrophic lateral sclerosis). Typically, patients present with slowly evolving numbness of the face followed by bulbar and proximal (neck and arm) weakness. However, one of our patients presented with a motor syndrome and his abnormal blink reflex studies provided a useful diagnostic clue. This extends the spectrum of the syndrome and emphasises that FOSMN should be considered in the differential diagnosis of motor neurone disease. We discuss the pathophysiology, diagnosis, prognosis and management considerations of FOSMN.
INTRODUCTION Facial onset sensory and motor neuronopathy (FOSMN) was first described by Vucic et al in 2006;1 there have been 30 cases reported to date.1 2 Its cardinal features are onset with asymmetrical facial numbness or paraesthesia, with impaired light touch and pain sensation evolving in a mantle distribution, followed by bulbar symptoms with facial atrophy and weakness. There is also gradually developing atrophy and weakness of the neck, shoulder girdle, and proximal upper limb muscles and (in some cases) the legs. As it progresses, the sensory changes often involve the trunk, arms and legs.1 2 The rate of progression and prognosis vary considerably, ranging from months to decades.1 2 The purpose of this paper is, first, to bring FOSMN to the attention of neurologists as a recently recognised and distinctive disorder. Second, while most
patients with FOSMN have a highly distinctive phenotype, one of our patients presented with a slowly progressive motor neurone disorder without sensory symptoms, widening the FOSMN phenotype. Thus FOSMN must be regarded as a ‘motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS)-mimic’. Third, the syndrome of FOSMN poses interesting but unresolved questions in relation to pathogenesis. CLINICAL FEATURES Six male patients presented with progressive sensory and motor deficits starting in the trigeminal nerve distribution and spreading in a rostral to caudal sequential manner to involve the head, neck, upper trunk, shoulder girdle, upper limbs and in three cases the lower limbs. All were diagnosed with FOSMN following clinical, laboratory, neurophysiological and neuroradiological assessment. Table 1 provides a summary of the patients’ cardinal features. The mean age of onset of symptoms was 56 years (42–66 years) and mean duration of illness was at least 6.5 years (1.5 years to >10 years). Five patients presented with perioral and facial numbness but one presented with dysarthria, dysphagia, and wasting and weakness of the facial, neck, shoulder girdle and upper limb muscles (case 2, table 1). This person’s masseter and temporalis muscle wasting was particularly striking (figure 1) but it was also evident in other cases to varying degrees. Five patients had bulbar involvement at presentation; three of these had elements of dysarthria and mild dysphagia. One patient (case 2) required gastrostomy insertion 10 years after symptom onset. Another developed additional vocal cord involvement with
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
1
2
M 66
6
Bilateral trigeminal
Trigeminal, left worse than right
Bilateral trigeminal
Right trigeminal
None
Bilateral Trigeminal
Dysarthria and dysphagia
Dysarthria and dysphagia
None
Dysphagia
Mild dysarthria and dysphagia
Dysarthria, dysphonia and mild inspiratory stridor
Bulbar syndrome
Facial, neck, upper limb, lower limb
Facial, upper limb, head drop but normal power Facial, neck
Facial, neck, upper limb, lower limb
Facial, neck, upper limb
Facial, neck, upper limb, lower limb
Muscle wasting and weakness
>10
3
No
No
>6
Anti-MAG and antisulfatide antibody negative Monoclonal gammopathy Anti-MAG and antisulfatide antibody negative
1.5
No
No
CK 118 IU/L CSF IgG 32 mg/L (0–30) Anti-MAG and antisulfatide antibody negative CK 894 IU/L CSF protein 484 mg/L Anti-MAG and antisulfatide antibody negative Anti-MAG and antisulfatide antibody negative
>10
Yes Brisk knee reflexes with bilateral adductor jerks
Laboratory findings CK 758 IU/L Anti-MAG and antisulfatide antibody negative
Disease duration (years) >10
No
Upper motor neurone signs
Anti-MAG, antimyelin associated glycoprotein; CK, creatine kinase; CSF, cerebrospinal fluid.
M 64
3
5
M 53
2
M 64
M 45
1
4
M 42
Case
Sensory dysfunction at presentation
Summary of the clinical features, laboratory findings and neurophysiology results
Sex/age at onset (years)
Table 1
Chronic partial denervation in all four limbs CMCT normal Widespread chronic partial denervation Widespread chronic partial denervation with fasciculation in the upper and lower limbs
Absent bilaterally
R1 and R2 components absent bilaterally
Widespread chronic partial denervation. Neurogenic changes orbicularis oculi
Widespread neurogenic changes with fasciculation in upper and lower limbs CMCT normal to hands but prolonged to feet Denervation in cervical and upper limb muscles with neurogenic changes and fasciculation CMCT normal
Delayed R2 responses bilaterally
Absent bilaterally
Delayed R2 responses bilaterally
Absent bilaterally
Blink reflex
Electromyography and central motor conduction time (CMCT)
No intravenous immunoglobulin
No intravenous immunoglobulin
No improvement Progressed rapidly
No intravenous immunoglobulin
Subjective benefit initially but continued to progress
Response to treatment
NEUROLOGICAL RARITIES
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
NEUROLOGICAL RARITIES
Figure 1
Masseter and temporalis muscle wasting in case 2, 10 years after symptom onset.
dysphonia and mild inspiratory stridor (case 1, table 1). Four patients described severe neck pain, not associated with significant neck weakness, as an early and prominent feature of their condition. Steroid injection proved helpful in managing this and provided dramatic pain relief in one patient. The corneal reflexes were either absent or decreased in all patients. There was reduced facial sensation to pinprick, and poorer two-point discrimination on the lips in five of the patients at presentation, progressing in a centrifugal manner rather than conforming to the distribution of the peripheral trigeminal nerve branches, thereby supporting the diagnosis of a central trigeminal sensory neuronopathy. This was symmetrical and bilateral in three of our patients. All patients showed bilateral lower motor neurone facial weakness. The only patient (case 2) who did not present with sensory symptoms nonetheless developed subtle sensory abnormalities some 10 years after the onset of motor symptoms. This patient also had upper motor neurone signs at presentation, along with the lower motor features seen in all our patients. The serum creatine kinase concentration was markedly elevated in two patients. One of these had elevated cerebrospinal fluid protein (case 3) and suffered a more rapid progression of muscles weakness, dying within 18 months of symptoms onset. Antimyelin associated glycoprotein (anti-MAG) and antisulfatide antibodies were not elevated in any of our patients. One patient had a monoclonal gammopathy of unknown significance and died within 3 years of FOSMN symptom onset. Electromyography (EMG) showed denervation in five patients, with neurogenic changes in two and fasciculation in three. The blink reflex was either absent or exhibited delayed R2 components bilaterally in all patients. Two of our patients received intravenous immunoglobulin but both continued to progress with no measurable benefit. Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
DISCUSSION FOSMN is a distinctive neurodegenerative disorder.1 The developed phenotype of facial onset sensory disturbance associated with facial and bulbar weakness, progression of sensory loss in a cape distribution, and weakness progressing to affect the arms and finally the legs, is characteristic. However, the profile of FOSMN at presentation varies and the rate of progression differs considerably between individuals.1 2 Initially, FOSMN can be mistaken for a form of trigeminal sensory neuropathy. Later in its course it may appear as an unusual case of MND, particularly when there is rapid progression and an upper motor neurone component.1 2 A confident diagnosis therefore depends on when the patient is seen during the evolution of the condition. In those with predominantly sensory features, it is easy to exclude syringomyelia and autoimmune disorders such as Sjögren’s syndrome using dedicated imaging and antibody testing. Clinicians should consider MND if motor features predominate, and genetic testing can exclude Kennedy’s disease, facioscapulohumeral muscular dystrophy and Brown-Vialetto-Van Laere syndrome. Case 2 in our cohort expands the phenotype of FOSMN to include a motor syndrome mimicking MND, and highlights the challenges in diagnosing FOSMN. Table 2 summarises the main distinguishing features as well as the similarities between FOSMN and MND. The blink reflex provides a useful electrophysiological investigation in FOSMN. The trigeminal supraorbital nerve is stimulated and the blink response measured in both eyes. The blink reflex is a more reliable method of detecting a problem within the central trigeminal pathways than the corneal reflex. Delayed or absent R2 responses in the blink reflex indicate an abnormality within the spinal trigeminal tract or nucleus, while delay or absence of R1 is caused by trigeminal and facial nerve pathology. There is no
3
NEUROLOGICAL RARITIES Table 2
Distinguishing features and similarities of facial onset sensory and motor neuronopathy (FOSMN) and motor neurone disease Similarities between FOSMN and motor neurone disease
Clinical features
Distinguishing features of FOSMN
Presentation
FOSMN usually presents with insidious onset of sensory disturbance affecting the mouth and face. Often initially unilateral but becoming bilateral. Sensory symptoms followed by wasting of trigeminal and facial nerve innervated muscles (eg, masseter and temporalis muscles), see figure 1. Corneal reflexes are reduced or absent. Vocal cord weakness and inspiratory stridor may occur relatively early in disease course. Central sensory trigeminal symptoms may occur up to a decade before onset of motor features. Spread of sensory disturbance usually coincides with spreading of marked wasting and mild weakness in proximal to distal manner. Neck weakness often develops and head drop can occur.2 Neck pain is often prominent. Ultimately motor and sensory symptoms and signs develop in the limbs. Most patients show purely lower motor neurone features. Serum creatine kinase concentrations may be normal or significantly elevated, see table 1, cases 1 and 3. Some cases in the literature have anti-MAG and antisulfatide antibodies. Atrophy of the cervical spinal cord on contrast MRI occurs in a few patients with FOSMN. The blink reflex is typically abnormal in FOSMN, with either a delayed R2 response or complete absence of any response. In contrast to motor neurone disease, there is no evidence of cortical hyperexcitability in transcranial magnetic stimulation studies of FOSMN cases. People with FOSMN have a higher resting motor threshold, lower motor evoked potential amplitude (expressed as % of compound muscle action potential) and lack the marked loss of intracortical inhibition seen in motor neurone disease during paired pulse transcranial magnetic stimulation at short interstimulus intervals (1–7 ms). FOSMN cases may have reduced and low amplitude sensory nerve action potentials in the limbs on nerve conduction studies. Most postmortem studies have not found features associated with motor neurone disease, such as TDP-43 inclusions, ubiquitin inclusions or Bunina bodies. There currently are no reported familial cases of FOSMN. Any underlying genetic mutation is yet to be discovered.
Progression
Laboratory findings
MRI findings Blink reflex TMS, EMG and nerve conduction studies
Neuropathology
Genetics
Patients may have dysarthria and dysphagia. Occasionally FOSMN presents with focal motor symptoms in the limbs. A few FOSMN patients have upper motor neurone features at presentation. Fasciculations typically occur and may be florid in FOSMN.
FOSMN may progress rapidly, in keeping with motor neurone disease, see case 3. Upper motor neurone signs develop in some cases, see table 1 case 2. Dysphagia may progress leading to requirement for gastrostomy. Ultimately respiratory function may also become impaired.
Serum creatine kinase is usually mildly or moderately elevated. Antiganglioside and other antibodies are usually negative. MR scan of brain and whole spine are typically normal in FOSMN and motor neurone disease. The blink reflex is only occasionally abnormal in the later stages of motor neurone disease. Evidence of active denervation and chronic reinnervation can be observed on EMG in motor neurone disease and FOSMN.
One study found widespread TDP-43 inclusion bodies, more typical of motor neurone disease, in a case of FOSMN.
One case of FOSMN had a heterozygous D90A mutation in the SOD 1 gene, the first genetic mutation linked to familial motor neurone disease. Anti-MAG, antimyelin associated glycoprotein; EMG, electromyogram; SOD, superoxide dismutase; TDP, transactive-response DNA-binding protein; TMS, transcranial magnetic stimulation.
cortical hyperexcitability on transcranial magnetic stimulation (TMS) in FOSMN compared with MND/ ALS, in keeping with the predominantly lower motor neurone nature of degeneration in FOSMN.2 There is good neuroanatomical correlation between the clinical features and pathological findings in FOSMN.1 2 The pattern of the sensory and motor abnormalities observed in FOSMN support the initial spread of pathology within the brainstem trigeminal system, namely the chief sensory trigeminal nucleus, trigeminal motor nucleus, spinal trigeminal nucleus and spinal trigeminal tract. Postmortem studies have shown neuronal loss and gliosis in the spinal trigeminal nucleus and tract as well as in the nuclei of the 4
affected cranial nerves (V, VII, IX, X, XII).1 2 In addition, the dorsal root ganglia, anterior horn cells and anterior spinal roots were all markedly atrophic in a patient with widespread involvement including neck, upper limb and lower limb weakness.2 The prognosis of FOSMN is generally better than MND, with some patients surviving longer than 10 years.2 Neck pain in FOSMN can be a striking feature and our anecdotal experience suggests that local corticosteroid injection may help this. Patients with FOSMN risk developing corneal abrasion and ulceration and patients should be warned regarding this potential risk and given advice regarding appropriate eye care.
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
NEUROLOGICAL RARITIES Practice points ▸ Peri-oral paraesthesia and numbness are typically the first features of facial onset sensory and motor neuronopathy (FOSMN). ▸ Facial sensory disturbance can precede any motor disturbance for many years; this highlights the importance of including FOSMN in the differential diagnosis of all patients presenting with a central trigeminal sensory abnormality. ▸ Marked wasting of muscles innervated by cranial nerves V and VII gives a striking facial appearance in some FOSMN cases (figure 1). ▸ Although FOSMN is mainly a lower motor neurone syndrome, some patients have upper motor neurone signs, making it an important MND/ALS mimic. ▸ Corneal reflexes are typically reduced or absent and this can be confirmed electrophysiologically through the blink reflex. ▸ The key differential diagnoses include motor neurone disease, structural brain stem lesions such as syringobulbia, inherited syndromes such as Kennedy’s disease, facioscapulohumeral muscular dystrophy and Brown–Vialetto–Van Laere syndrome, and autoimmune disorders such as Sjögren’s syndrome.
What causes FOSMN? There is no convincing evidence that FOSMN is a neuroimmunological disorder. Despite finding antibodies (antisulfatide, anti-MAG) in some cases,1 2 there is no evidence that immune modulation provides any benefit. FOSMN may best be seen as a variant of MND/ALS: yet another nuance in the expanding phenotypical spectrum of the
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
MND syndrome. One case of FOSMN had TDP43-immunoreactive inclusions in glia and neurones in the brainstem tegmentum, and as skein-like inclusions in spinal motor neurones, the latter being typical of MND. However, there have been no familial cases of FOSMN to date and no consistently identified genetic lesion. We believe that next generation sequencing approaches will most likely provide insights into the pathogenesis of FOSMN, calling for international collaboration. Acknowledgements The authors thank all the patients who contributed to this publication. The authors thank Dr C P Chandrasekera for providing local neurophysiological assessment and Professor K R Mills for providing further neurophysiological assessments including blink reflexes, which often facilitated the diagnosis of FOSMN in these patients. Thanks are also due to Dr G Saldanha and Dr R Hadden for referring this patient and for permission to report this patient. The authors thank the MND Association of England Wales and Northern Ireland for their support. Contributors RB and PNL were involved in assessing patients for this article and deciding on the article content. RB collected the clinical information, consented patients and wrote the first draft of this article. PNL diagnosed FOSMN in the patients, revised the manuscript and gave final approval. Competing interests None declared. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Martin Turner, Oxford, UK.
REFERENCES 1 Vucic S, Tian D, Siao P, et al. Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain 2006;129:3384–90. 2 Vucic S, Stein TD, Hedley-Whyte ET, et al. FOSMN syndrome: novel insight into disease pathophysiology. Neurology 2012;3:73–9.
5
Recognising facial onset sensory motor neuronopathy syndrome: insight from six new cases R Broad, P N Leigh
Neurology Department, Brighton and Sussex medical School, Trafford Centre for Medical Research, University of Sussex, Brighton, East Sussex, UK Correspondence to Dr Rebecca Broad, Department of Neurology, Brighton and Sussex Medical School, Trafford Centre for Medical Research, University of Sussex, Brighton BN1 9RY, UK; [email protected] Received 12 September 2014 Revised 21 March 2015 Accepted 22 April 2015
To cite: Broad R, Leigh PN. Pract Neurol Published Online First: [ please include Day Month Year] doi:10.1136/ practneurol-2014-000984
ABSTRACT Facial onset sensory and motor neuronopathy (FOSMN) was first described in 2006 as an apparently sporadic neurodegenerative disease. Thirty cases have been reported to date. We summarise six new cases, highlighting the key clinical aspects of FOSMN and how to differentiate it from motor neurone disease (amyotrophic lateral sclerosis). Typically, patients present with slowly evolving numbness of the face followed by bulbar and proximal (neck and arm) weakness. However, one of our patients presented with a motor syndrome and his abnormal blink reflex studies provided a useful diagnostic clue. This extends the spectrum of the syndrome and emphasises that FOSMN should be considered in the differential diagnosis of motor neurone disease. We discuss the pathophysiology, diagnosis, prognosis and management considerations of FOSMN.
INTRODUCTION Facial onset sensory and motor neuronopathy (FOSMN) was first described by Vucic et al in 2006;1 there have been 30 cases reported to date.1 2 Its cardinal features are onset with asymmetrical facial numbness or paraesthesia, with impaired light touch and pain sensation evolving in a mantle distribution, followed by bulbar symptoms with facial atrophy and weakness. There is also gradually developing atrophy and weakness of the neck, shoulder girdle, and proximal upper limb muscles and (in some cases) the legs. As it progresses, the sensory changes often involve the trunk, arms and legs.1 2 The rate of progression and prognosis vary considerably, ranging from months to decades.1 2 The purpose of this paper is, first, to bring FOSMN to the attention of neurologists as a recently recognised and distinctive disorder. Second, while most
patients with FOSMN have a highly distinctive phenotype, one of our patients presented with a slowly progressive motor neurone disorder without sensory symptoms, widening the FOSMN phenotype. Thus FOSMN must be regarded as a ‘motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS)-mimic’. Third, the syndrome of FOSMN poses interesting but unresolved questions in relation to pathogenesis. CLINICAL FEATURES Six male patients presented with progressive sensory and motor deficits starting in the trigeminal nerve distribution and spreading in a rostral to caudal sequential manner to involve the head, neck, upper trunk, shoulder girdle, upper limbs and in three cases the lower limbs. All were diagnosed with FOSMN following clinical, laboratory, neurophysiological and neuroradiological assessment. Table 1 provides a summary of the patients’ cardinal features. The mean age of onset of symptoms was 56 years (42–66 years) and mean duration of illness was at least 6.5 years (1.5 years to >10 years). Five patients presented with perioral and facial numbness but one presented with dysarthria, dysphagia, and wasting and weakness of the facial, neck, shoulder girdle and upper limb muscles (case 2, table 1). This person’s masseter and temporalis muscle wasting was particularly striking (figure 1) but it was also evident in other cases to varying degrees. Five patients had bulbar involvement at presentation; three of these had elements of dysarthria and mild dysphagia. One patient (case 2) required gastrostomy insertion 10 years after symptom onset. Another developed additional vocal cord involvement with
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
1
2
M 66
6
Bilateral trigeminal
Trigeminal, left worse than right
Bilateral trigeminal
Right trigeminal
None
Bilateral Trigeminal
Dysarthria and dysphagia
Dysarthria and dysphagia
None
Dysphagia
Mild dysarthria and dysphagia
Dysarthria, dysphonia and mild inspiratory stridor
Bulbar syndrome
Facial, neck, upper limb, lower limb
Facial, upper limb, head drop but normal power Facial, neck
Facial, neck, upper limb, lower limb
Facial, neck, upper limb
Facial, neck, upper limb, lower limb
Muscle wasting and weakness
>10
3
No
No
>6
Anti-MAG and antisulfatide antibody negative Monoclonal gammopathy Anti-MAG and antisulfatide antibody negative
1.5
No
No
CK 118 IU/L CSF IgG 32 mg/L (0–30) Anti-MAG and antisulfatide antibody negative CK 894 IU/L CSF protein 484 mg/L Anti-MAG and antisulfatide antibody negative Anti-MAG and antisulfatide antibody negative
>10
Yes Brisk knee reflexes with bilateral adductor jerks
Laboratory findings CK 758 IU/L Anti-MAG and antisulfatide antibody negative
Disease duration (years) >10
No
Upper motor neurone signs
Anti-MAG, antimyelin associated glycoprotein; CK, creatine kinase; CSF, cerebrospinal fluid.
M 64
3
5
M 53
2
M 64
M 45
1
4
M 42
Case
Sensory dysfunction at presentation
Summary of the clinical features, laboratory findings and neurophysiology results
Sex/age at onset (years)
Table 1
Chronic partial denervation in all four limbs CMCT normal Widespread chronic partial denervation Widespread chronic partial denervation with fasciculation in the upper and lower limbs
Absent bilaterally
R1 and R2 components absent bilaterally
Widespread chronic partial denervation. Neurogenic changes orbicularis oculi
Widespread neurogenic changes with fasciculation in upper and lower limbs CMCT normal to hands but prolonged to feet Denervation in cervical and upper limb muscles with neurogenic changes and fasciculation CMCT normal
Delayed R2 responses bilaterally
Absent bilaterally
Delayed R2 responses bilaterally
Absent bilaterally
Blink reflex
Electromyography and central motor conduction time (CMCT)
No intravenous immunoglobulin
No intravenous immunoglobulin
No improvement Progressed rapidly
No intravenous immunoglobulin
Subjective benefit initially but continued to progress
Response to treatment
NEUROLOGICAL RARITIES
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
NEUROLOGICAL RARITIES
Figure 1
Masseter and temporalis muscle wasting in case 2, 10 years after symptom onset.
dysphonia and mild inspiratory stridor (case 1, table 1). Four patients described severe neck pain, not associated with significant neck weakness, as an early and prominent feature of their condition. Steroid injection proved helpful in managing this and provided dramatic pain relief in one patient. The corneal reflexes were either absent or decreased in all patients. There was reduced facial sensation to pinprick, and poorer two-point discrimination on the lips in five of the patients at presentation, progressing in a centrifugal manner rather than conforming to the distribution of the peripheral trigeminal nerve branches, thereby supporting the diagnosis of a central trigeminal sensory neuronopathy. This was symmetrical and bilateral in three of our patients. All patients showed bilateral lower motor neurone facial weakness. The only patient (case 2) who did not present with sensory symptoms nonetheless developed subtle sensory abnormalities some 10 years after the onset of motor symptoms. This patient also had upper motor neurone signs at presentation, along with the lower motor features seen in all our patients. The serum creatine kinase concentration was markedly elevated in two patients. One of these had elevated cerebrospinal fluid protein (case 3) and suffered a more rapid progression of muscles weakness, dying within 18 months of symptoms onset. Antimyelin associated glycoprotein (anti-MAG) and antisulfatide antibodies were not elevated in any of our patients. One patient had a monoclonal gammopathy of unknown significance and died within 3 years of FOSMN symptom onset. Electromyography (EMG) showed denervation in five patients, with neurogenic changes in two and fasciculation in three. The blink reflex was either absent or exhibited delayed R2 components bilaterally in all patients. Two of our patients received intravenous immunoglobulin but both continued to progress with no measurable benefit. Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
DISCUSSION FOSMN is a distinctive neurodegenerative disorder.1 The developed phenotype of facial onset sensory disturbance associated with facial and bulbar weakness, progression of sensory loss in a cape distribution, and weakness progressing to affect the arms and finally the legs, is characteristic. However, the profile of FOSMN at presentation varies and the rate of progression differs considerably between individuals.1 2 Initially, FOSMN can be mistaken for a form of trigeminal sensory neuropathy. Later in its course it may appear as an unusual case of MND, particularly when there is rapid progression and an upper motor neurone component.1 2 A confident diagnosis therefore depends on when the patient is seen during the evolution of the condition. In those with predominantly sensory features, it is easy to exclude syringomyelia and autoimmune disorders such as Sjögren’s syndrome using dedicated imaging and antibody testing. Clinicians should consider MND if motor features predominate, and genetic testing can exclude Kennedy’s disease, facioscapulohumeral muscular dystrophy and Brown-Vialetto-Van Laere syndrome. Case 2 in our cohort expands the phenotype of FOSMN to include a motor syndrome mimicking MND, and highlights the challenges in diagnosing FOSMN. Table 2 summarises the main distinguishing features as well as the similarities between FOSMN and MND. The blink reflex provides a useful electrophysiological investigation in FOSMN. The trigeminal supraorbital nerve is stimulated and the blink response measured in both eyes. The blink reflex is a more reliable method of detecting a problem within the central trigeminal pathways than the corneal reflex. Delayed or absent R2 responses in the blink reflex indicate an abnormality within the spinal trigeminal tract or nucleus, while delay or absence of R1 is caused by trigeminal and facial nerve pathology. There is no
3
NEUROLOGICAL RARITIES Table 2
Distinguishing features and similarities of facial onset sensory and motor neuronopathy (FOSMN) and motor neurone disease Similarities between FOSMN and motor neurone disease
Clinical features
Distinguishing features of FOSMN
Presentation
FOSMN usually presents with insidious onset of sensory disturbance affecting the mouth and face. Often initially unilateral but becoming bilateral. Sensory symptoms followed by wasting of trigeminal and facial nerve innervated muscles (eg, masseter and temporalis muscles), see figure 1. Corneal reflexes are reduced or absent. Vocal cord weakness and inspiratory stridor may occur relatively early in disease course. Central sensory trigeminal symptoms may occur up to a decade before onset of motor features. Spread of sensory disturbance usually coincides with spreading of marked wasting and mild weakness in proximal to distal manner. Neck weakness often develops and head drop can occur.2 Neck pain is often prominent. Ultimately motor and sensory symptoms and signs develop in the limbs. Most patients show purely lower motor neurone features. Serum creatine kinase concentrations may be normal or significantly elevated, see table 1, cases 1 and 3. Some cases in the literature have anti-MAG and antisulfatide antibodies. Atrophy of the cervical spinal cord on contrast MRI occurs in a few patients with FOSMN. The blink reflex is typically abnormal in FOSMN, with either a delayed R2 response or complete absence of any response. In contrast to motor neurone disease, there is no evidence of cortical hyperexcitability in transcranial magnetic stimulation studies of FOSMN cases. People with FOSMN have a higher resting motor threshold, lower motor evoked potential amplitude (expressed as % of compound muscle action potential) and lack the marked loss of intracortical inhibition seen in motor neurone disease during paired pulse transcranial magnetic stimulation at short interstimulus intervals (1–7 ms). FOSMN cases may have reduced and low amplitude sensory nerve action potentials in the limbs on nerve conduction studies. Most postmortem studies have not found features associated with motor neurone disease, such as TDP-43 inclusions, ubiquitin inclusions or Bunina bodies. There currently are no reported familial cases of FOSMN. Any underlying genetic mutation is yet to be discovered.
Progression
Laboratory findings
MRI findings Blink reflex TMS, EMG and nerve conduction studies
Neuropathology
Genetics
Patients may have dysarthria and dysphagia. Occasionally FOSMN presents with focal motor symptoms in the limbs. A few FOSMN patients have upper motor neurone features at presentation. Fasciculations typically occur and may be florid in FOSMN.
FOSMN may progress rapidly, in keeping with motor neurone disease, see case 3. Upper motor neurone signs develop in some cases, see table 1 case 2. Dysphagia may progress leading to requirement for gastrostomy. Ultimately respiratory function may also become impaired.
Serum creatine kinase is usually mildly or moderately elevated. Antiganglioside and other antibodies are usually negative. MR scan of brain and whole spine are typically normal in FOSMN and motor neurone disease. The blink reflex is only occasionally abnormal in the later stages of motor neurone disease. Evidence of active denervation and chronic reinnervation can be observed on EMG in motor neurone disease and FOSMN.
One study found widespread TDP-43 inclusion bodies, more typical of motor neurone disease, in a case of FOSMN.
One case of FOSMN had a heterozygous D90A mutation in the SOD 1 gene, the first genetic mutation linked to familial motor neurone disease. Anti-MAG, antimyelin associated glycoprotein; EMG, electromyogram; SOD, superoxide dismutase; TDP, transactive-response DNA-binding protein; TMS, transcranial magnetic stimulation.
cortical hyperexcitability on transcranial magnetic stimulation (TMS) in FOSMN compared with MND/ ALS, in keeping with the predominantly lower motor neurone nature of degeneration in FOSMN.2 There is good neuroanatomical correlation between the clinical features and pathological findings in FOSMN.1 2 The pattern of the sensory and motor abnormalities observed in FOSMN support the initial spread of pathology within the brainstem trigeminal system, namely the chief sensory trigeminal nucleus, trigeminal motor nucleus, spinal trigeminal nucleus and spinal trigeminal tract. Postmortem studies have shown neuronal loss and gliosis in the spinal trigeminal nucleus and tract as well as in the nuclei of the 4
affected cranial nerves (V, VII, IX, X, XII).1 2 In addition, the dorsal root ganglia, anterior horn cells and anterior spinal roots were all markedly atrophic in a patient with widespread involvement including neck, upper limb and lower limb weakness.2 The prognosis of FOSMN is generally better than MND, with some patients surviving longer than 10 years.2 Neck pain in FOSMN can be a striking feature and our anecdotal experience suggests that local corticosteroid injection may help this. Patients with FOSMN risk developing corneal abrasion and ulceration and patients should be warned regarding this potential risk and given advice regarding appropriate eye care.
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
NEUROLOGICAL RARITIES Practice points ▸ Peri-oral paraesthesia and numbness are typically the first features of facial onset sensory and motor neuronopathy (FOSMN). ▸ Facial sensory disturbance can precede any motor disturbance for many years; this highlights the importance of including FOSMN in the differential diagnosis of all patients presenting with a central trigeminal sensory abnormality. ▸ Marked wasting of muscles innervated by cranial nerves V and VII gives a striking facial appearance in some FOSMN cases (figure 1). ▸ Although FOSMN is mainly a lower motor neurone syndrome, some patients have upper motor neurone signs, making it an important MND/ALS mimic. ▸ Corneal reflexes are typically reduced or absent and this can be confirmed electrophysiologically through the blink reflex. ▸ The key differential diagnoses include motor neurone disease, structural brain stem lesions such as syringobulbia, inherited syndromes such as Kennedy’s disease, facioscapulohumeral muscular dystrophy and Brown–Vialetto–Van Laere syndrome, and autoimmune disorders such as Sjögren’s syndrome.
What causes FOSMN? There is no convincing evidence that FOSMN is a neuroimmunological disorder. Despite finding antibodies (antisulfatide, anti-MAG) in some cases,1 2 there is no evidence that immune modulation provides any benefit. FOSMN may best be seen as a variant of MND/ALS: yet another nuance in the expanding phenotypical spectrum of the
Broad R, et al. Pract Neurol 2015;0:1–5. doi:10.1136/practneurol-2014-000984
MND syndrome. One case of FOSMN had TDP43-immunoreactive inclusions in glia and neurones in the brainstem tegmentum, and as skein-like inclusions in spinal motor neurones, the latter being typical of MND. However, there have been no familial cases of FOSMN to date and no consistently identified genetic lesion. We believe that next generation sequencing approaches will most likely provide insights into the pathogenesis of FOSMN, calling for international collaboration. Acknowledgements The authors thank all the patients who contributed to this publication. The authors thank Dr C P Chandrasekera for providing local neurophysiological assessment and Professor K R Mills for providing further neurophysiological assessments including blink reflexes, which often facilitated the diagnosis of FOSMN in these patients. Thanks are also due to Dr G Saldanha and Dr R Hadden for referring this patient and for permission to report this patient. The authors thank the MND Association of England Wales and Northern Ireland for their support. Contributors RB and PNL were involved in assessing patients for this article and deciding on the article content. RB collected the clinical information, consented patients and wrote the first draft of this article. PNL diagnosed FOSMN in the patients, revised the manuscript and gave final approval. Competing interests None declared. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Martin Turner, Oxford, UK.
REFERENCES 1 Vucic S, Tian D, Siao P, et al. Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain 2006;129:3384–90. 2 Vucic S, Stein TD, Hedley-Whyte ET, et al. FOSMN syndrome: novel insight into disease pathophysiology. Neurology 2012;3:73–9.
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