Downloaded from jnnp.bmj.com on March 14, 2013 - Published by group.bmj.com
PostScript Table 1 Clinical and image findings in five Taiwanese patients with hereditary spastic paraparesis and thin corpus callosum Family No 1
Family No 2
Patient IV:3
Patient IV:5*
Patient III:2
Patient III:5
Patient III:6*
M/35
M/30
F/34
F/28
M/25
Findings Sex/age at examination (y) Age at onset (y) Cognitive decline Gait disturbance Cognitive function Verbal IQ Performance IQ Full scale IQ Frontal releasing sign LL hyperreflexia+spasticity UL hyperreflexia+spasticity Extensor plantar response Pseudobulbar dysarthria Cerebellar ataxia Distal amyotrophy Urinary dysfunction
12 16
10 15
9 17
15 18
9 13
44 52 48 + + – + + + – –
45 49 49 + + – + + + – Frequency + incontinence
45 46 47 + + + C – – + Incontinence
47 44 47 – + + + – – + Frequency
48 51 50 + + + + + + – Frequency
Brain MRI Age at scan (y) Thin corpus callosum
35 All
30 All
34 All
25 All
F, Pv F, T +
F, Pv F, T +
F, Pv F, T +
29 All (nearly absent) F, Pv F –
F, Pv F, T +
45 8.4
ND ND
Absent Absent
34 6.0
38 7.1
White matter change Cortical atrophy Cerebellar atrophy Tibial nerve, right MNCV (m/s) CMAP (mV) Sural nerve, right SNCV (m/s) SAP (mV) EMG Other features
heterozygous for this change. However, only the affected individuals carried both mutations. Neither change was observed in a 150 Taiwanese controls samples. By following the segregation of the two SPG11 alleles through the pedigree in family No 2, it appears that the two nucleotide deletion segregates with the 41234 haplotype which is the homozygous haplotype of the affected individuals in family No 1. This would suggest that the deletion mutation has a common origin in the two families. To date, 30 ARHSP-TCC families worldwide have been identified with genetic linkage to SPG11. Thus far, the only SPG11 gene mutations to be described come from families around the Mediterranean Sea.5 6 Thus our characterisation of two Taiwanese families with SPG11 gene mutations provides additional corroboration that the SPG11 is the responsible gene for ARHSP-TCC. M-J Lee,1,2 T-W Cheng,1 M-S Hua,3 M-K Pan,1 J Wang,2 D A Stephenson,4 C-C Yang1 1 Department of Neurology, National Taiwan University School of Medicine, Taipei, Taiwan; 2 Medical Genetics, National Taiwan University School of Medicine, Taipei, Taiwan; 3 Department of Psychology, National Taiwan University, Taipei, Taiwan; 4 Pharmacology Department, School of Pharmacy, Brunswick Square, London, UK
Correspondence to: Dr C-C Yang, Department of Neurology, National Taiwan University Hospital, 7 ChungShan South Road, Taipei 100, Taiwan; jesse@ ha.mc.ntu.edu.tw Competing interests: None.
47 5.0 Giant MUP
ND ND ND
37 4.2 NPW
Square wave jerks, saccadic pursuit
Saccadic pursuit
40 13.8 Spontaneous activities
39 14.3 Giant MUP, NPW. Saccadic pursuit, generalised epilepsy
All, all parts of the corpus callosum; C, contracture of Achilles tendon; CMAP, compound muscle action potential; F, frontal; LL, lower limb; MNCV, motor nerve conduction velocity; MUP, motor unit potential; ND, not done; NPW, neurogenic polyphasic waves; Pv, periventricular; SAP, sensory action potential; SNCV, sensory nerve conduction velocity; T, temporal; UL, upper limb. *, proband; +, presence; –, absence.
fig 1A, the affected members (patients IV:3 and IV:5) from the consanguineous marriage (family No 1) were homozygous for the five microsatellite markers surrounding the SPG11 gene. The unaffected sib (IV:4) and parent (III:3) carried the heterozygous allele at these loci. These data are suggestive that the disease gene probably segregates with the homozygous genotype. In family No 2 (fig 2A), affected family members (III:2, III:5 and III:6) shared a common genotype that was not present in unaffected members (II:1, II:3, III:1, III:3 and III:4). Furthermore, the affected individuals carry a haplotype (41234) that is also present in affected members from family No 1. Again the data are not inconsistent with linkage of the disease gene to this region of the genome. BigDye Terminator chemistry (Applied Biosystems, Foster City, California, USA) and an ABI3100 automatic DNA sequencer J Neurol Neurosurg Psychiatry May 2008 Vol 79 No 5
was used to analyse the sequence of all 40 exons of the SPG11 gene in the two families. This analysis identified a two nucleotide deletion in exon 26 (c.4461..4462delGT) affecting both families (fig 1B, 2B) which is predicted to cause a frameshift (p. Cys1487fs) mutation leading to a truncated protein. In family No 1, involving a consanguineous marriage, the affected children (IV:3 and IV:5) were homozygous for the two nucleotide deletion whereas the unaffected child (IV:4) and parent (III:3) were heterozygous. Both affected (III:2, III:5 and III:6) and unaffected (II:1 and III:1) individuals in family No 2 were heterozygous for the two nucleotide deletion in exon 26. However, a CRT transition in exon 32 at nucleotide 6091 was also detected in this family (fig 2B) which is predicted to introduce a premature stop codon at arginine 2031. Both affected (III:2, IIII:5 and III:6) and unaffected (II:3 and III:3) were
J Neurol Neurosurg Psychiatry 2008;79:607–609. doi:10.1136/jnnp.2007.136390
REFERENCES 1.
2.
3.
4.
5.
6.
Ueda M, Katayama Y, Kamiya T, et al. Hereditary spastic paraplegia with a thin corpus callosum and thalamic involvement in Japan. Neurology 1998;51:1751–4. Nakamura A, Izumi K, Umehara F, et al. Familial spastic paraplegia with mental impairment and thin corpus callosum. J Neurol Sci 1995;131:35–42. Tang BS, Chen X, Zhao GH, et al. Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J (Engl) 2004;117:1002–5. Martinez MF, Kobayashi H, Pegoraro E, et al. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13–15. Neurology 1999;53:50–6. Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 2007;39:366–72. Del BR, Di FA, Ghezzi S, et al. SPG11: a consistent clinical phenotype in a family with homozygous Spatacsin truncating mutation. Neurogenetics 2007;8:301–5.
Relapsing polychondritis: an uncommon cause of dementia Relapsing polychondritis (RP) is a rare disorder that is characterised by recurrent and progressive inflammation of cartilaginous structures.1 Nervous system involvement in RP has been described.1–5 We describe two cases of RP with subacute dementia. 609
Downloaded from jnnp.bmj.com on March 14, 2013 - Published by group.bmj.com
PostScript CASE 1 A 51-year-old lawyer was diagnosed with RP when he presented with bilateral ear swelling. He was treated with 10 mg/day of oral prednisone during this attack, with a brief taper. He continued to have flare-ups during the next several years and was treated with a short duration of prednisone ranging from 10 to 40 mg/day. Episodes of iritis and scleritis were treated with steroid eye drops. One year after the diagnosis of RP, he started to experience gradual-onset coordination problems, difficulty presenting verbal arguments, distractibility and emotional lability. He developed insomnia and nocturnal myoclonic jerks. Neuropsychological evaluation showed perseveration, prominent attention and concentration deficits. Brain MRI showed extensive periventricular and deep white matter high-signal abnormalities. There was reduced metabolic activity in bilateral temporal cortices and parietal lobes on PET scan. Electroencephalogram was normal. Cerebrospinal fluid (CSF) contained 89 mg/dL of protein, 52 mg/dL glucose, 39 white blood cells (WBCs) (65% lymphocytes) and 2 red blood cells (RBCs). CSF tau/ amyloid levels and ratio were considered to be consistent with Alzheimer’s disease. CSF IgG index and synthesis rate were elevated. CSF 14–3–3 protein, borrelia PCR, cryptococcal antigen, paraneoplastic titres, serum HIV serology, VDRL, heavy metal screen, pand c-ANCA, and RPR were negative. HSV 1/2 IgG antibody was mildly elevated; IgM was negative. Serum WBCs, sedimentation rate and C-reactive protein (CRP) were normal during the course of his progressive dementia. Cerebral angiogram was normal. Given the lack of a diagnosis after noninvasive investigations, brain biopsy of the right frontal cortex was performed 5 months after the onset of neurological symptoms. Biopsy showed findings of nonspecific inflammation without evidence of vasculitis (see supplementary fig 1). A diagnosis of meningoencephalitis secondary to RP was made. Prednisone was increased to 80 mg/day without clinical improvement. Cyclophosphamide was added at 150 mg/day 6 months after onset of neurological symptoms. He continued to decline, with increased confusion, speech latency, word-finding difficulty and increased myoclonus. He died 5 months after brain biopsy. Autopsy confirmed diagnosis of non-specific meningoencephalitis involving the meninges, cortical and deep brain parenchyma. There was no evidence of vasculitis. Microglial nodules suggestive of viral encephalitis and protease-resistant prion protein were absent (see supplementary fig 1).
CASE 2 A 68-year-old college instructor presented with myalgias, headache, fever and bilateral ear swelling, and was diagnosed with RP. He was started on a low dosage of prednisone, which was discontinued due to side effects. 610
Two months later, he developed a hoarse voice and vertigo, recurrence of ear swelling and was started on dapsone. Around the same time, he started exhibiting comprehension problems, emotional lability and visuospatial problems. During the course of his illness, he had flare-ups of ear swelling. He also developed conjunctival involvement and lost 30 pounds. Over a course of 8 months, he gradually continued to decline cognitively to a degree where he was unable to perform dayto-day activities independently. He also had two discrete episodes of worsening confusion and language problems lasting several hours. Neuropsychological testing showed impairment in verbal and visual memory, executive dysfunction, visuospatial impairment and mild anomia. CSF contained 49 mg/dl protein, 4 WBCs (44% lymphocytes), 124 RBCs and 39 mg/dl glucose. CSF fungal, viral and bacterial cultures, cryptococcal antigen, VDRL, angiotensin-converting enzyme, stain and culture for acid-fast bacilli were negative. Serum lyme titres, VDRL, paraneoplastic markers, anti-ss-DNA, anti-ds-DNA, antiENA, anti-SSA, anti-SSB antibodies, HIV serology, treponemal antibody, serological markers for Sjorgen’s disease, SLE and Wegener’s were negative. Sedimentation rates ranged from 9–15 mm/h and CRP was 0.2 mg/l. Brain MRI at the onset of his symptoms was normal. MRI at 5 months after symptom onset showed oedema and high T2 signal in the right medial temporal lobe, and a small area of enhancement in the left caudate with contrast administration. Repeat brain MRI 1 month later (6 months after onset of neurological symptoms) showed resolution of temporal lobe oedema and caudate enhancement, increased T2 signal in both caudate heads and the right medial temporal lobe with atrophy (see supplementary fig 2). Electroencephalogram showed bilateral low amplitude with beta frequency. He was diagnosed with CNS involvement of RP without brain biopsy and started on 80 mg of prednisone 11 months after the onset of neurological symptoms, with no further deterioration over a 12-month follow-up. Both patients meet diagnostic criteria for RP.1 CNS involvement has been attributed either to vasculitis or meningoencephalitis.1–3 Only a few case reports describe histopathological findings in CNS involvement in RP.2 3 (See supplementary table 1 for all case reports.) Dementia and limbic encephalitis have been reported.3–5 Imaging findings of nonspecific white matter changes, preferential involvement of the medial temporal lobes and brain atrophy have been reported.3–5 Cerebrospinal fluid may show inflammatory changes.2–5 The pathophysiology of CNS involvement in RP is not well understood. Diagnosis and treatment are not well established. Diagnosis may be delayed when patients present with CNS symptoms while on immunosuppressants for systemic disease
and opportunistic infections are in the differential. To rule out steroid contraindications, a CSF examination to exclude bacterial, fungal or TB meningitis, and brain MRI to rule out ring-enhancing lesions should be adequate. Empirical treatment for herpes encephalitis can be initiated early while awaiting PCR diagnosis. Brain biopsy and cerebral angiogram seem to provide minimal diagnostic information in most cases. Steroids or cytotoxic agents have been used for treatment, whereas response to treatment is not consistent and relapses in medication use have been reported.2 3 Greater awareness of the existence of a polychondritis-associated encephalitis may spare patients the morbidity of brain biopsy, and may also lead to prompt and aggressive immunosuppressant therapy, which may reduce morbidity and mortality. D Erten-Lyons,1,2 B Oken,1 R L Woltjer,3 J Quinn1,2 1 Department of Neurology, Oregon Health & Science University, Portland, OR, USA; 2 The Veteran’s Affairs Medical Center, Portland, OR, USA; 3 Department of Pathology, Oregon Health and Science University, Portland, OR, USA
Correspondence to: Deniz Erten-Lyons, MD, National Institute of Aging-Layton Alzheimer’s Disease Center, 3181 SW Sam Jackson Park Road CR 131, Portland, OR 97239, USA;
[email protected] Funding: Research Career Development Award, Office of Research and Development, Department of Veterans Affairs, National Institute on Aging, National Institutes of Health (AG08017, MO1 RR000334). Competing interests: None. Figs 1 and 2 and table 1 are published online only at http://jnnp.bmj.com/content/vol79/issue5 c
Published Online First 21 January 2008 J Neurol Neurosurg Psychiatry 2008;79:609–610. doi:10.1136/jnnp.2007.131425
REFERENCES 1.
2.
3.
4.
5.
Letko E, Zafirakis P, Baltatzis S, et al. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum 2002;31:384–95. Stewart SS, Ashizawa T, Dudley AW Jr, et al. Cerebral vasculitis in relapsing polychondritis. Neurology 1988;38:150–2. Fujiki F, Tsuboi Y, Hashimoto K, et al. Non-herpetic limbic encephalitis associated with relapsing polychondritis. J Neurol Neurosurg Psychiatry 2004;75:1646–7. Ohta Y, Nagano I, Niiya D, et al. Nonparaneoplastic limbic encephalitis with relapsing polychondritis. J Neurol Sci 2004;220:85–8. Hosford I, Glass J, Baker N. Relapsing polychondritis—an unusual but potentially treatable cause of cognitive impairment. N Z Med J 2003;116:U463.
Heat stress disorders and headache: a case of new daily persistent headache secondary to heat stroke The most severe condition among the group of heat stress disorders is heat stroke (HS). It may be divided into two forms: classic and exertional. The former is due to environmental heat exposure and characterised by J Neurol Neurosurg Psychiatry May 2008 Vol 79 No 5
Downloaded from jnnp.bmj.com on March 14, 2013 - Published by group.bmj.com
Relapsing polychondritis: an uncommon cause of dementia D Erten-Lyons, B Oken, R L Woltjer, et al. J Neurol Neurosurg Psychiatry 2008 79: 609-610 originally published online January 21, 2008
doi: 10.1136/jnnp.2007.131425
Updated information and services can be found at: http://jnnp.bmj.com/content/79/5/609.full.html
These include:
Data Supplement
"web only appendix" http://jnnp.bmj.com/content/suppl/2008/03/27/79.5.609.DC1.html
References
This article cites 5 articles, 2 of which can be accessed free at: http://jnnp.bmj.com/content/79/5/609.full.html#ref-list-1
Article cited in: http://jnnp.bmj.com/content/79/5/609.full.html#related-urls
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
