2014 - Juvenile distal segmental spinal muscular atrophy

1. Juvenile distal segmental spinal muscular atrophy
Hirayama’s disease
Jo Caekebeke
VNV 2014

2. Casus
• Jonge man °1995, rechts handig, 1m81, 63kg
• Vlotte student, jogging
• Medische voorgeschiedenis: geen bijzonderheden
• Familiale anamnese: geen bijzonderheden
• Anamnese:
• Sinds > 1 jaar traag progressieve last in de rechter hand
• Minder kracht en oa last bij het schrijven…
• Iets beter na het opwarmen van de handen
• Geen pijn noch gevoelsstoornis of krampen
• Geen last in de andere ledematen
• Geen andere neurologische klachten

3. Casus
• Neurologisch onderzoek:
• Helder bewustzijn, hogere cerebrale fie normaal
• Craniale zenuwen: normaal, anamnestisch geen slikstoornis
• Kracht:
• In benen: normaal
• In armen: volgende dia
• Sensibiliteit: voor alle kwaliteiten symmetrisch en normaal
• Reflexen symmetrisch en normaal, VZR: in flexie
• Coördinatie: normaal
• Gangpatroon: normaal

4. Casus: kracht in de armen
Spieren Rechts Links
Kracht Atrofie Kracht Atrofie
Deltoideus & schouder spieren 5 - 5 -
Biceps brachii & brachialis 5 - 5 -
Triceps brachii 5 - 5 -
Brachioradialis 5 - 5 -
Pols & vinger extensoren 5- + 5 -
Pols & vinger flexoren 4 ++ 5 -
Centrale intrinsieke handspieren 4 +++ 5- +-
Duimmuis spieren 4 ++ 5 -
Pinkmuis spieren 4- +++ 5- +-

5. Casus
• Lab
• Hematologie, chemie: normaal
• CRP, CK, TSH: normaal
• Borrelia serologie: negatief
• Anti gangliosides Ab: negatief
• Β hexosaminidase: normaal
• EMG:
• Normale motorische en sensibele geleidingssnelheden
• PSW’s en fibrillaties in distale armspieren
• Geen geleidingsblocks

8. Differential diagnosis: more than weakness ?
• Asymmetric distal weakness but also pain and/or sensory deficit…
• Carpal tunnel syndrome
• Ulnar neuropathy at elbow (or at the wrist)
• Sudeck’s atrophy
• Thoracic outlet syndrome
• Neuralgic amyotrophy (Parsonage -Turner)
• Occasional cases with a near painless onset
• Polyneuropathy
• Mononeuritis multiplex
• Spinal radiculopathy
• Intrinsic and extrinsic cervical myelum pathology

9. Differential diagnosis: progressive focal weakness ?
• Acute poliomyelitis and postpolio progressive muscular atrophy (PPMA)
• Multifocal motor neuropathy (MMN)
• Immune-mediated, anti GM1 Ab (20 – 60%)
• Slowly progressive asymmetrical distal weakness
• Predominant upper limb involvement
• Cramps and fasciculations
• Conduction blocks...
• IVIg therapy
• Hereditary Welander distal myopathy
• AD, predominantly affecting the hands, slow progression
• Sweden & Finland, TIA1 mutation

10. Differential diagnosis: progressive focal weakness ?
• ALS and ALS-like diseases
• Juvenile ALS (JALS): onset of disease before 25 years, typically familial
• UMN & LMN signs, slow disease progression (Stephen Hawking?)
• Flail arm syndrome
• Man-in-the-barrel syndrome or brachial amyotrophic diplegia
• Proximal > distal; symmetric, slow progression
• Kennedy’s disease: spinobulbar muscular atrophy (SBMA)
• X-linked, expansion of CAG repeats in androgen receptor gene
• Proximal > distal LMN signs, gynecomastia, testicular atrophy...
• Lower motor neuron diseases
• LMND: after > 4 years only < 10% continue to show LMN signs only
• Hereditary and sporadic spinal muscular atrophy

11. Differential diagnosis: hereditary HMN / SMA ?
• Proximal HMN or classical hereditary SMA (type IV, adult onset)
• SMN1,2 gene related
• Symmetrical proximal muscular atrophy
• Distal HMN or hereditary distal SMA1
• Clinical and genetic heterogeneity, mostly foot predominance
• Resemble axonal CMT2 syndromes (spinal CMT)
• > 7 subtypes (I – VII); AD, AR, X-linked
• Distal HMN V (AD, BSCL2, GARS… mutation)
• Hand predominance, adolescent onset, asymmetrical
• Cave de novo mutations
1. Rossor A. J Neurol Neurosurg Psychiatry 2012; 83: 6-14

12. Differential diagnosis: sporadic LMN disease1,2,3 ?
• Progressive (spinal) muscular atrophy (PMA)
• Slowly progressive generalized weakness & symmetrical distal weakness
• LMND but after years: ALS may still develop
• Segmental proximal (spinal) muscular atrophy (SPMA)
• Non-generalized asymmetrical proximal weakness
• Segmental distal (spinal) muscular atrophy (SDMA)
• Non-generalized asymmetrical distal weakness
• Progressive segmental distal SMA
• O’Sullivan-McLeod syndrome
• Non-progressive segmental distal SMA
• Hirayama disease
1. Van den Berg-Vos R. Brain 2003; 126:1036-1047
2. Visser J. Archives of neurology 2007; 64: 522-528
3. Van den Berg-Vos R. Archives of neurology 2009; 66: 751-757

13. Hirayama disease1
• 1959: Hirayama disease, (Keizo Hirayama neurologist in Japan)
• 12 pt with predominantly unilateral weakness, atrophy of fingers and hand
• Largest series in Japan, India, Taiwan, Singapore and China
• Nosology:
• Hirayama disease (HD)
• Monomelic amyotrophy (MMA)
• Juvenile muscular atrophy of unilateral upper extremity
• Juvenile muscular atrophy of the distal upper extremity (JMADUE)
• Juvenile asymmetric segmental SMA (JASSMA)
• Segmental distal SMA
• Hirayama flexion myelopathy
1. Hirayama K. Japanese journal of psychiatry and neurology 1959; 61: 2190-2197

14. Clinical features
• Young persons (11 – 25y), mostly in males (89%)
• Often slender sportsman
• Almost all cases are sporadic
• Not linked to SOD1, SMN1, SMN2, BSCL2, GARS, androgen receptor genes
• A few reports of familial Hirayama disease with or without MRI findings1
• Insidious onset of unilateral or asymmetric atrophy of the hand and forearm
• Without precipitant toxic history, infection or trauma
• Nearly all patients report worsening of weakness in cold environment
• Often first notice their disease during winter
1. Atchayaram N. Neurology India 2009; 57: 810-812

15. Clinical features
• Atrophy and weakness in C7 – T1 myotomes
• Brachioradialis muscle is mostly spared (oblique amyotrophy)
• Right side is more often affected, regardless of handedness
• Ulnar territory is more affected than median one
• Unilateral in most patients (72%)
• Asymmetrically bilateral in 25%
• Rarely symmetric in 3%
• May progress to the opposite site

16. Clinical features
• Moderate extension of the fingers produces fine, fast, irregular tremor
• Minipolymyoclonus, contractile fasciculation
• Fasciculations are rare when the hand is at rest
• No sensory impairment
• Occasional hypoesthesia in dorsum of the hand
• No involvement of cranial nerves, lower limbs or pyramidal signs
• Reflexes are within normal range ore reduced in upper limbs
• Sometimes hyperreflexia in lower limbs, babinski sign in very few cases

17. Prognosis
• Initial progressive course, followed by a spontaneous arrest:
• In 70%: within 3 years
• In 90%: within 6 years
• Before the age of 25 years in majority of cases
• After this period of time, the disease neither improves nor worsens
• Some cases do progress but extremely slowly
• O’Sullivan-McLeod syndrome versus Hirayama disease
• Lumpers versus splitters

18. Neurophysiology
• Needle EMG shows chronic denervation in C7, C8, T1 myotomes
• Ulnar territory is more affected than median territory
• Common subclinical involvement of:
• C5, C6 myotomes & “unaffected” upper limb
• EMG of the lower limbs shows a normal pattern
• Sensory neurography is normal
• SSEP: usually normal in neutral and neck flexion
• Sometimes attenuation of responses particularly during neck flexion
• MEP: normal in latency and amplitude
• CMCT between cortex and C8/T1 is sometimes marginally prolonged

19. Routine cervical spine MRI findings
• May show atrophy of the lower cervical cord
• Mild antero-posterior flattering of spinal cord, at C6 vertebral level
• Asymmetrical, corresponding to the more atrophied limb
• Loss of attachment between the posterior dural sac and subjacent lamina
• Most valuable finding for diagnosing Hirayama disease in routine MRI1
• Specificity 100%, sensitivity 70 – 93%2
• No abnormal intrinsic cord signal
1. Chen CJ. Radiology 2004; 231: 39-44
2. Lehman V. Am J Neuroradiol 2013; 34: 451-456

20. Routine cervical spine MRI findings (Sag T2 FRFSE)

21. Hyperflexion cervical spine MRI findings
• If routine MRI and clinical investigations are inconclusive:
• MRI with hyperflexion contrast study is the gold standard
• Full neck flexion induces forward displacement of the dural sac1,2
• Unequivocal finding in the progressive stage (in 87%)
• Dynamic cord compression with remarkable flattering of the spinal cord at C5-7
vertebral level
1. Biondi A. Am j neuroradiol 1989; 10: 263-268
2. Raval M. Indian J Radiol Imaging 2010; 20: 245-249

22. Hyperflexion cervical spine MRI (Sag T1 FS & T2 FRFSE)

23. Hyperflexion cervical spine MRI (Ax T1 Gd+)
C6
C5
T2

24. Hyperflexion cervical spine MRI findings
• Posterior epidural space:
• Crescent-shaped T1 isointense and T2 hyperintense area
• From C4 – T1 (max at C5 – C7)
• Linear or round flow void signals (low signal) in the high signal area
• Passive dilatation of the posterior epidural venous plexus
• Due to negative pressure in the posterior spinal canal
• Compress of anterior venous plexus and increased burden of
posterior venous plexus
• Venous drainage of jugular veins is reduced in neck flexion, which
impedes venous return of the internal venous plexus
• Uniform enhancement on contrast images

25. Hyperflexion cervical spine MRI findings
• Full dynamic MRI signs are observed when disease duration > 18 months1,2
• In older patients who have reached a stable stage
• The dynamic findings are absent
• But atrophy of the lower cervical cord is still present
• The sensitivity and specificity of the MRI findings are not known
• Discrepant findings In healthy controls:
• Neither cord flattering nor epidural high intensity on flexion1
• Versus anterior dural shift in nearly 50%3
1. Hirayama K. Neurology 2000; 54: 1922-1926
2. Hassan K. Biomed research international 2013; 478516
3. Lai V. Eur J Radiol 2011; 80: 724-728

26. MRI findings1,2
1. Hassan K. Biomed research international 2013; 478516
2. Raval M. Indian journal of radiology and imaging 2010; 20: 245-249

27. Hyperflexion cervical spine MRI (Sag T1 & myelography)

28. MRI evaluation in neutral and flexion position
• Localized lower cervical cord atrophy
• Asymmetric cord flattering
• Abnormal cervical curvature
• Loss of attachment between posterior dural sac and subjacent lamina
• Anterior shifting of posterior wall of cervical dural canal
• Enhancing epidural component with flow voids
• Intramedullary signal hyperintensity

29. Pathology1
• First autopsy (1982)
• 38 y, died of lung cancer, Hirayama’s disease for 23 years, (l > r)
• Second autopsy case
• 76 y, Disease onset at age 24, but also cervical spondylosis later in life
• Antero-posterior flattering and asymmetrical ischemic necrotic changes of
anterior horns of the cervical cord at C5 – T1, mostly at C7 – C8
• Circulatory insufficiency ?
• But intra- and extra-medullary vessels were normal
• Spinal cord atrophy in later stages of the disease
1. Hirayama K. J Neurol Neurosurg Psychiatry 1987; 50: 285-290

30. Pathophysiology: hypotheses
1. Chronic progressive degenerative disease of cervical motor neurons (LMND)
• Sporadic and familial cases without MRI abnormalities1,2
2. Flexion myelopathy3
• On neck flexion, a tight dural sac cannot compensate for the increased
lenght of the posterior wall, which causes anterior shifting of the posterior
dural wall and consequent compression of the cord
• Difference in length between extension and flexion from atlas to T1
1.5 cm at the anterior wall and 5 cm at the posterior wall
• Increased intramedullary pressure, resulting in microcirculatory
disturbance in the anterior horn
1. Willeit J. Acta Neurol Scan 2001; 104: 320-322
2. Andreadou E. Neurologist 2009; 15: 156-160
3. Kikuchi S. Intern Med 2002; 41: 746-748

31. Pathophysiology: spinal dura mater
• Spinal dura mater is a slack, loose sheath1
• Attachment to the periosteum in two places:
• At the foramen magnum and the dorsal surfaces of C2-3
• At the coccyx
• Anchored in the vertebral canal by the nerve roots
• Further suspended, cushioned by epidural fat, venous plexus and loose
connective tissue
• With transverse folds compensating for increased length of a neck in fexion
1. Williams P. Gray’s Anatomy 1987: 1086-1092

32. Pathophysiology: tight dural sac1
• A disproportionate growth between vertebral column and the contents of the
spinal cord
• Leading to a tight dural sac and forward displacement of the myelum
• Dispoportionate shortening of the dural sac is perhaps accentuated during
juvenile growth spurt, explaining the preponderance in adolescence
• Different growth rates between males and females probably related to male
preponderance1
• How to explain racial differences ?
• The absence of forward displacement in a later and non-progressive stage of the
disease suggested that the dynamic compression had pathogenic significance
1. Kikuchi S. Clin Neurol (Tokyo) 1987; 27: 412-419

33. Treatment based on “flexion myelopathy”
• Early recognition1:
• Benign, non-progressive disorder
1. Hard cervical collar therapy, no RCT
• Early therapy may minimize the functional disability2
• For 3 – 4 years, during the progressive stage ?
2. Surgery, case based
• Cervical decompression and/or fusion, duraplasty3 may be an option ?
3. Muscle strengthening exercises and training in hand-coordination
1. Hirayama K. Brain nerve 2008; 60: 17-29
2. Tokumaru Y. Clin Neurol (Tokyo) 1992; 32: 1102-1106
3. Arrese I. Neurocirugia 2009; 20: 555-558

34. Domo Arigato Gozaimasu
The best test of a physician’s suitability for
the specialized practice of neurology is not
his ability to memorize improbable
syndromes but whether he can continue to
support a case of motor neuron disease, and
keep the patient, his relatives and himself in
a reasonable cheerful frame of mind. Matthews WB